Community Academic Profiles - Faculty & Researchers

All Publications

Safety and Performance of the Tandem t:slim X2 with Control-IQ Automated Insulin Delivery System in Toddlers and Preschoolers. Diabetes technology & therapeutics Ekhlaspour, L., Schoelwer, M. J., Forlenza, G. P., DeBoer, M. D., Norlander, L., Hsu, L. J., Kingman, R. S., Boranian, E., Berget, C., Emory, E. G., Buckingham, B. A., Breton, M. D., Wadwa, R. P. 2020
Abstract

BACKGROUND: Glycemic control is particularly challenging for toddlers and preschoolers with type 1 diabetes (T1D), and data on the use of closed-loop systems in this age range is limited.MATERIALS AND METHODS: We studied use of a modified investigational version of the Tandem t:slim X2 Control-IQ system in children aged 2 to 5 years during 48 hours in a supervised outpatient hotel (SH) setting followed by 3 days of home use to examine the safety of this system in young children. Meals and snacks were not restricted and boluses were estimated per parents' usual routine. At least 30 minutes of daily exercise was required during the SH phase. All participants were remotely monitored by study staff while on closed-loop in addition to monitoring by at least one parent throughout the study.RESULTS: Twelve participants diagnosed with T1D for at least three months with mean age 4.7�1.0 years (range 2.0-5.8 years) and HbA1c of 7.3�0.8% were enrolled at three sites. With use of Control-IQ, the percentage of participants meeting our prespecified goals of less than 6% time below 70 mg/dL and less than 40% time above 180 mg/dL increased from 33% to 83%. Control-IQ use significantly improved percent time in range (70-180 mg/dL) compared to baseline (71.3�12.5 vs. 63.7�15.1, p=0.016). All participants completed the study with no adverse events.CONCLUSIONS: In this brief pilot study, use of the modified Control-IQ system was safe in 2-5 year-old children with T1D and improved glycemic control.

View details for DOI 10.1089/dia.2020.0507

View details for PubMedID 33226837
Glucose Management during physical Activity/Sport by Using continuous Glucose Meters (CGM/isCGM) in Type 1 Diabetes - EASD/ISPAD Position Statement, supported by ADA and JDRF Moser, O., Riddell, M. C., Eckstein, M. L., Adolfsson, P., Rabasa-Lhoret, R., van den Boom, L., Gillard, P., Norgaard, K., Oliver, N. S., Zaharieva, D. P., Battelino, T., De Beaufort, C., Bergenstal, R. M., Buckingham, B., Cengiz, E., Deeb, A., Heise, T., Heller, S., Kowalski, A. J., Leelarathna, L., Mathieu, C., Stettler, C., Tauschmann, M., Thabit, H., Wilmot, E. G., Sourij, H., Smart, C. E., Jacobs, P. G., Bracken, R. M., Mader, J. K. SPRINGER WIEN. 2020: S340?S341
View details for Web of Science ID 000589995100017
Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA). Pediatric diabetes Moser, O., Riddell, M. C., Eckstein, M. L., Adolfsson, P., Rabasa-Lhoret, R., van den Boom, L., Gillard, P., Norgaard, K., Oliver, N. S., Zaharieva, D. P., Battelino, T., de Beaufort, C., Bergenstal, R. M., Buckingham, B., Cengiz, E., Deeb, A., Heise, T., Heller, S., Kowalski, A. J., Leelarathna, L., Mathieu, C., Stettler, C., Tauschmann, M., Thabit, H., Wilmot, E. G., Sourij, H., Smart, C. E., Jacobs, P. G., Bracken, R. M., Mader, J. K. 2020
Abstract

Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (ie, before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes.

View details for DOI 10.1111/pedi.13105

View details for PubMedID 33047481
Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA). Diabetologia Moser, O., Riddell, M. C., Eckstein, M. L., Adolfsson, P., Rabasa-Lhoret, R., van den Boom, L., Gillard, P., Norgaard, K., Oliver, N. S., Zaharieva, D. P., Battelino, T., de Beaufort, C., Bergenstal, R. M., Buckingham, B., Cengiz, E., Deeb, A., Heise, T., Heller, S., Kowalski, A. J., Leelarathna, L., Mathieu, C., Stettler, C., Tauschmann, M., Thabit, H., Wilmot, E. G., Sourij, H., Smart, C. E., Jacobs, P. G., Bracken, R. M., Mader, J. K. 2020
Abstract

Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (i.e. before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes. Graphical abstract.

View details for DOI 10.1007/s00125-020-05263-9

View details for PubMedID 33047169
A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes. The New England journal of medicine Breton, M. D., Kanapka, L. G., Beck, R. W., Ekhlaspour, L., Forlenza, G. P., Cengiz, E., Schoelwer, M., Ruedy, K. J., Jost, E., Carria, L., Emory, E., Hsu, L. J., Oliveri, M., Kollman, C. C., Dokken, B. B., Weinzimer, S. A., DeBoer, M. D., Buckingham, B. A., Chernavvsky, D., Wadwa, R. P., iDCL Trial Research Group, Schoelwer, M., Breton, M., DeBoer, M., Gonder-Frederick, L., Chernavvsky, D., Robic, J., Emory, E., Voelmle, M., Conschafter, K., Morris, K., Barnett, C., Carr, K., Hellmann, J., Kime, M., Oliveri, M., Wadwa, R. P., Forlenza, G., Alonso, G. T., Slover, R., Messer, L., Cobry, E., Jost, E., Berget, C., Towers, L., Lange, S., Buckingham, B., Maahs, D., Lal, R., Ekhlaspour, L., Norlander, L., Hood, K., Town, M., Weir, C., Smith, K., Hsu, L., Shinksy, D., Viana, J., Cengiz, E., Weinzimer, S., Weyman, K., Carria, L., Zgorski, M., Ruedy, K., Beck, R., Borgman, S., Rusnak, J., Kanapka, L., Kollman, C., Murphy, C., Arreza-Rubin, G., Green, N., Kovatchev, B., Brown, S., Anderson, S., Laffel, L., Pinsker, J., Levy, C., Kudva, Y. C., Doyle, F. 3., Renard, E., Cobelli, C., Reznik, Y., Lum, J., Janicek, R., Gabrielson, D. 2020; 383 (9): 836?45
Abstract

BACKGROUND: A closed-loop system of insulin delivery (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes.METHODS: In a 16-week, multicenter, randomized, open-label, parallel-group trial, we assigned, in a 3:1 ratio, children 6 to 13 years of age who had type 1 diabetes to receive treatment with the use of either a closed-loop system of insulin delivery (closed-loop group) or a sensor-augmented insulin pump (control group). The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring.RESULTS: A total of 101 children underwent randomization (78 to the closed-loop group and 23 to the control group); the glycated hemoglobin levels at baseline ranged from 5.7 to 10.1%. The mean (�SD) percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter increased from 53�17% at baseline to 67�10% (the mean over 16 weeks of treatment) in the closed-loop group and from 51�16% to 55�13% in the control group (mean adjusted difference, 11 percentage points [equivalent to 2.6 hours per day]; 95% confidence interval, 7 to 14; P<0.001). In both groups, the median percentage of time that the glucose level was below 70 mg per deciliter was low (1.6% in the closed-loop group and 1.8% in the control group). In the closed-loop group, the median percentage of time that the system was in the closed-loop mode was 93% (interquartile range, 91 to 95). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group.CONCLUSIONS: In this 16-week trial involving children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with the use of a closed-loop system than with the use of a sensor-augmented insulin pump. (Funded by Tandem Diabetes Care and the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT03844789.).

View details for DOI 10.1056/NEJMoa2004736

View details for PubMedID 32846062
Clinically Significant Hypoglycemia Is Rare in Youth with T1D during Partial Clinical Remission Addala, A., Gu, A., Zaharieva, D., Prahalad, P., Buckingham, B. A., Scheinker, D., Maahs, D. M. AMER DIABETES ASSOC. 2020
View details for DOI 10.2337/db20-1294-P

View details for Web of Science ID 000554509803068
Trust in hybrid closed loop among people with diabetes: Perspectives of experienced system users JOURNAL OF HEALTH PSYCHOLOGY Tanenbaum, M. L., Iturralde, E., Hanes, S. J., Suttiratana, S. C., Ambrosino, J. M., Ly, T. T., Maahs, D. M., Naranjo, D., Walders-Abramson, N., Weinzimer, S. A., Buckingham, B. A., Hood, K. K. 2020; 25 (4): 429?38
View details for DOI 10.1177/1359105317718615

View details for Web of Science ID 000523776100001
Randomized Controlled Trial of Mobile Closed-Loop Control. Diabetes care Kovatchev, B., Anderson, S. M., Raghinaru, D., Kudva, Y. C., Laffel, L. M., Levy, C., Pinsker, J. E., Wadwa, R. P., Buckingham, B., Doyle, F. J., Brown, S. A., Church, M. M., Dadlani, V., Dassau, E., Ekhlaspour, L., Forlenza, G. P., Isganaitis, E., Lam, D. W., Lum, J., Beck, R. W., iDCL Study Group, Kovatchev, B., Anderson, S. M., Brown, S. A., Emory, E., Voelmle, M., Conshafter, K., Morris, K., Oliveri, M., Mitchell, H., Calvo, K., Wakeman, C., Breton, M., Laffel, L. M., Isganaitis, E., Ambler-Osborn, L., Flint, E., Schultz, A., Kim, K., Pinsker, J. E., Church, M. M., Andre, C., Levy, C., Lam, D. W., O'Malley, G., Levister, C., Ogyaadu, S., Kudva, Y. C., Dadlani, V., Simha, V., McCrady-Spitzer, S., Reid, C., Wadwa, R. P., Forlenza, G. P., Jost, E., Messer, L., Berget, C., Towers, L., Buckingham, B., Ekhlaspour, L., Hsu, L., Loebner, S., Doyle, F. J., Dassau, E., Lum, J., Beck, R. W., Campos, T., Passman, S., Murphy, C., Patibandla, N., Raghinaru, D., Kollman, C. 2020
Abstract

OBJECTIVE: Assess the efficacy of inControl AP: a mobile closed-loop control (CLC) system.RESEARCH DESIGN AND METHODS: This protocol, NCT02985866, is a 3-month parallel group, multicenter, randomized unblinded trial designed to compare mobile CLC with sensor augmented pump (SAP) therapy. Eligibility criteria were type 1 diabetes for at least 1 year, use of insulin pumps for at least 6 months, age ?14 years, and baseline HbA1c <10.5% (91 mmol/mol). The study was designed to assess two coprimary outcomes: superiority of CLC over SAP in continuous glucose monitor (CGM)-measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L.RESULTS: Between November 2017 and May 2018, 127 participants were randomly assigned 1:1 to CLC (n = 65) versus SAP (n = 62); 125 participants completed the study. CGM time below 3.9 mmol/L was 5.0% at baseline and 2.4% during follow-up in the CLC group vs. 4.7% and 4.0%, respectively, in the SAP group (mean difference -1.7% [95% CI -2.4, -1.0%]; P < 0.0001 for superiority). CGM time above 10 mmol/L was 40% at baseline and 34% during follow-up in the CLC group vs. 43% and 39%, respectively, in the SAP group (mean difference -3.0% [95% CI -6.1, +0.1%]; P < 0.0001 for noninferiority). One severe hypoglycemic event occurred in the CLC group, which was unrelated to the study device.CONCLUSIONS: In meeting its coprimary end points, superiority of CLC over SAP in CGM-measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L, the study has demonstrated that mobile CLC is feasible and could offer certain usability advantages over embedded systems, provided the connectivity between system components is stable.

View details for DOI 10.2337/dc19-1310

View details for PubMedID 31937608
Longitudinal Changes in Continuous Glucose Monitoring Use Among Individuals With Type 1 Diabetes: International Comparison in the German and Austrian DPV and U.S. T1D Exchange Registries. Diabetes care Miller, K. M., Hermann, J., Foster, N., Hofer, S. E., Rickels, M. R., Danne, T., Clements, M. A., Lilienthal, E., Maahs, D. M., Holl, R. W., T1D Exchange and DPV Registries, Weinstock, R., Izquierdo, R., Sheikh, U., Conboy, P., Bulger, J., Bzdick, S., Klingensmith, G., Banion, C., Barker, J., Cain, C., Nadeau, K., Rewers, M., Rewers, A., Slover, R., Steck, A., Wadwa, P., Zeitler, P., Alonso, G., Forlenza, G., Gerard-Gonzalez, A., Green, M., Gross, S., Majidi, S., Messer, L., Reznick-Lipina, T., Simmons, E., Thivener, K., Weber, I., Willi, S., Lipman, T., Kucheruk, O., Minnock, P., Carchidi, C., Grant, B., Olivos, D., DiMeglio, L., Hannon, T., Evans-Molina, C., Hansen, D., Pottorff, T., Woerner, S., Hildinger, M., Hufferd, R., Newnum, A., Purtlebaugh, D., Smith, L., Wendholt, K., Goland, R., Gandica, R., Williams, K., Pollack, S., Casciano, E., Hochberg, J., Uche, C., Lee, J., Gregg, B., Tan, M., Ang, L., Pop-Busui, R., Thomas, I., Dhadphale, E., Dominowski, J., Garrity, A., Leone, V., Plunkett, C., Plunkett, B., Monzavi, R., Cheung, C., Fisher, L., Kim, M., Miyazaki, B., Pitukcheewanont, P., Sandstrom, A., Austin, J., Change, N., Raymond, J., Ichihara, B., Lipton, M., Flores Garcia, J., Garg, S., Michels, A., Garcetti, R., Green, M., Gutin, R., Nadeau, K., Polsky, S., Shah, V., Voelmle, M., Myers, L., Coe, G., Demmitt, J., Garcia Reyes, Y., Giordano, D., Joshee, P., Nease, E., Nguyen, N., Wolfsdorf, J., Quinn, M., Fontanet, C., Mukherjee, S., Bethin, K., Quattrin, T., Majumdar, I., Mastrandrea, L., Gorman, E., House, A., Michalovic, S., Musial, W., Shine, B., Ahmann, A., Castle, J., Joarder, F., Aby-Daniel, D., Guttmann-Bauman, I., Klopfenstein, B., Morimoto, V., Cady, N., Fitch, R., DeFrang, D., Jahnke, K., Patoine, C., Raman, V., Foster, C., Murray, M., Brown, T., Davis, C., Slater, H., Langvardt, J., Bode, B., Boyd, J., Johnson, J., Newton, C., Ownby, J., Hosey, R., Rastogi, N., Winslett, B., Hirsch, I., DeSantis, A., Failor, R. A., Greenbaum, C., Trence, D., Trikudanathan, S., Khakpour, D., Thomson, P., Sameshima, L., Tordillos, C., Clements, M., Turpin, A., Babar, G., Broussard, J., Cernich, J., Dileepan, K., Feldt, M., Moore, W., Musick, T., Patton, S., Yan, Y., Tsai, S., Bedard, J., Elrod, A., Hester, L., Beidelschies, M., de la Garza, J., Haith, E., James, J., Ramey, E., Slover, J., Valentine, A., Watkins, D., Whisenhunt, M., Wierson, J., Wilson, D., Buckingham, B., Maahs, D., Prahalad, P., Hsu, L., Kingman, R., Tabatabai, I., Liljenquist, D., Sulik, M., Vance, C., Halford, J., Funke, C., Appiagyei-Dankah, Y., Beltz, E., Moran, K., Starkman, H., Cerame, B., Chin, D., Ebner-Lyon, L., Sabanosh, K., Silverman, L., Wagner, C., Cheruvu, S., Fox, M., Melchionne, F., Bergenstal, R., Madden, M., Martens, T., Criego, A., Powers, M., Carlson, A., Beasley, S., Olson, B., Thomas, L., McCann, K., Dunnigan, S., Ashanti, C., Simmons, J., Russell, W., Jaser, S., Kelley, J., Brendle, F., Williams, L., Savin, K., Flowers, K., Williams, G., Hamburger, E., Davis, A., Hammel, B., Cengiz, E., Tamborlane, W., Weyman, K., Van Name, M., Patel, N., Sherr, J., Tichy, E., Steffen, A., Zgorski, M., Carria, L., Finnegan, J., Duran, E., Mehta, S., Katz, M., Laffel, L., Giani, E., Snelgrove, R., Hanono, A., Commissariat, P., Griffith, J., Atkins, A., Harrington, K., Kim, K., Masclans, L., Naik, N., Ambler-Osborn, L., Schultz, A., Cohen, C., Anderson, B., McGill, J., Granados, A., Clifton, M. J., Hurst, S., Kissel, S., Recklein, C., Kruger, D., Bhan, A., Brown, T., Tassopoulos, A., Hailey, A., Remtema, H., Cushman, T., Wintergerst, K., Watson, S., Kingery, S., Rayborn, L., Rush, H., Foster, M., Deuser, A., Rodriguez-Luna, M., Eubanks, S., Rodriguez, H., Bollepalli, S., Smith, L., Shulman, D., Jorgensen, E. V., Eyth, E., Brownstein, R., Rodriguez, J., O'Bria, J., Aleppo-Kacmarek, G., Hahr, A., Molitch, M., Muayed, E., Toft, D., Fulkerson, C., Adelman, D., Massaro, E., Webb, K., Peters, A., Ruelas, V., Harmel, M., Daniels, M., Forghani, N., Flannery, T., Reh, C., Bhangoo, A., Kashmiri, H., Montgomery, K., Trinh, L., Speer, H., Lane, K., Bergenstal, R., Martens, T., Madden, M., Powers, M., Criego, A., Carlson, A., Olson, B., Beasley, S., McCann, K., Thomas, L., Miller, C., Ashanti, C., Solorzano, C. B., Puskaric, J., Benjamin, R., Adkins, D., Spruill, A., Williams, C., Tsalikian, E., Tansey, M., Bansl, N., Cabbage, J., Coffey, J., Schatz, D., Clare-Salzler, M., Cusi, K., Fudge, B., Haller, M., Meehan, C., Rohrs, H., Silverstein, J., Walker, A., Albanese-O'Niell, A., Foss, S., Adams, J., Cintron, M., Thomas, N., Gottschalk, M., Newfield, R., Hashiguchi, M., Sparling, D., Tryggested, J., Beck, J., Less, J., Weber, L., Adi, S., Gitelman, S., Sanda, S., Wong, J., McDonnell, M., Mueller, M., Izadi, Z., Mistry, S., Nelson, B., Looper, L., Frost, C., Redondo, M., Lyons, S., Klinepeter, S., Fegan-Bohm, K., Bacha, F., DeSalvo, D., Butler, A., Hilliard, M., Khetani, F., Yulatic, R., Hudson, R., Irvine, L., Zubair, S., Pace, C., Pitrello, A., Levy, W., Njoku, C., Zipf, W., Dyer, J., Lozano, R., Seiple, D., Corven, G., Jaycox, M., Wood, J., Macleish, S., Gubitosi-Klug, R., Adams, R., McGuigan, P., Casey, T., Campbell, W., Kittelsrud, J., Gupta, A., Peterson, V., Libman, I., Diaz, A., Jelley, D., Crowder, C., Greer, D., Crawford, J., Goudeau, S., Pihoker, C., Yi-Frazier, J., Kearns, S., Pascual, M., Loots, B., Beauregard, N., Rickels, M., O'Brien, S., Agarwal, S., Peleckis, A., Dalton-Bakes, C., Markmann, E., Umpierrez, G., Muir, A., Ramos, C., Behbahani, K., Dhruv, N., Gartzman, N., Nathan, B., Bellin, M., Sunni, M., Flaherty, N., Leschyshyn, J., Schmid, K., Weingartner, D., Ludwig, M., Nelson, B., Kogler, A., Bartyzal, A., Street, A., Pappenfus, B., Sweet, J., Buse, J., Young, L., Bergamo, K., Goley, A., Kirkman, M., Diner, J., Kass, A., Dezube, M., Arnold, K., Evans, T., Sellers, S., Blackman, S., Abel, K., Rasbach, L., Ali, O., Wolfgram, P., Fiallo-Sharer, R., Kramer, J., Beesley, C., Bingham-Tyson, C., Unteutsh, R., Harlan, D., Lee, M., Soyka, L., Feldman, P., Thompson, M., Gallagher-Dorval, K., Hubacz, L., Hartigan, C., Ciccarelli, C., Edelen, R., Edelen, M., Borgwadt, T., Stauffacher, K., DeGrote, K., Gruetzmacher, C., Shepperd, M., Bhargava, A., Wright, D., Fitzgerald, K., Khoo, T., Young, N., Borg, L., Stifel, K., Rail, C., Casas, L., Eidenshink, E., Huber, C., Rieder, A., Tuchscherer, A., Broadbent, M., Dolan, L., Corathers, S., Kichler, J., Sheanon, N., Baugh, H., Standiford, D., Weis, T., Fox, C., Schultz, C., Ritter, A., Vendrame, F., Blashke, C., Matheson, D., Sanders-Branca, N., Rudolph, J., Biersdorf, D., Fitch-Danielson, J., Eckerle-Mize, D., Brendle, F., Fry, J., Davis, D., Lovell, C., Hammel, B., Williams, L., Hoffman, R., Chaudhari, M., Kamboj, M., Carr, L., Casas, L., Blehm, J., Tello, A., Walter, J. A., Ward, R., Broadbent, M., Blomquist, G., Stewart, M., Cross, P., Racki, S., Sterchi, L., Gouine, D., Kiesow, B., Welch, S., Philis-Tsimikas, A., Daily, G., Chang, A., McCallum, J., Garcia, I., Vela, T., Loupasi, I., Rosal, R., Toschi, E., Middelbeek, R., Munshi, M., Slyne, C., Atakov-Castillo, A., Fox, L., Mauras, N., Wasserman, R., Damaso, L., Englert, K., Sikes, K., Ponthieux, K., Phillipson, L., Cohen, A., Gannon, G., Deeb, L., Shiver, A., Schroeder, L., Schworm, W., Graham, K., Levy, C., Lam, D., Burtman, E., Levister, C., Ogyaadu, S., Gassner, H., Duke, J., Touger, L., Newbern, D., Hoekstra, F., Harwood, K., Prasad, V., Daguanno, J., Pratley, R., Corbin, K., Wright, M., Nagel, S., Water, N., Ghere, M., Whitaker, K., Heptulla, R., Katikaneni, R., Johnson-Newell, D., Crandall, J., Powell, D., Anghel, V., Ghanny, S., Aisenberg, J., Chartoff, A., Sivitz, J., Mathus, S., Cospito, T., Thailkill, K., Fowlkes, J., Kalaitzoglou, E., Morales Pozzo, A., Edwards, K. 2020; 43 (1): e1?e2
View details for DOI 10.2337/dc19-1214

View details for PubMedID 31672703
Fast-Acting Insulin Aspart Use with the MiniMed? 670G System. Diabetes technology & therapeutics Hsu, L. J., Buckingham, B. A., Basina, M., Ekhlaspour, L., von Eyben, R., Wang, J., Lal, R. A. 2020
Abstract

BACKGROUND This study assessed the efficacy and safety of ultra-rapid insulin Fiasp� in the hybrid closed-loop MiniMed? 670G system. METHODS This was a pilot randomized, double-blinded, cross-over study among established MiniMed? 670G users comparing percent time in range (TIR) and hypoglycemia for Novolog� and Fiasp�. Following two weeks optimization with their home insulin, participants were randomized to receive Novolog� or Fiasp� for two weeks, followed by the other insulin for the next two weeks. Data from the second week of blinded insulin use was analyzed to allow one week for 670G adaptation. During the second week, individuals were asked to eat the same breakfast for three days to assess differences in meal pharmacodynamics. RESULTS Nineteen adults were recruited with mean age of 40�18 years, diabetes duration of 27�12 years and median HbA1c of 7.1 (6.9,7.5)%, using 0.72 (0.4,1.2) units/kg/day. For Novolog� and Fiasp� respectively the %TIR (70-180mg/dL) was 75.3�9.5 and 78.4 �9.3; %time <70mg/dL was 3.1�2.1 and 2.3�2.0; %time >180mg/dL was 21.6�9.0 and 19.3�8.9; mean glucose was 147�12 and 146�12mg/dL; coefficient of variation was 28.6�4.5% and 26.8�4.4%; %time in Auto Mode 86.4�9.2 and 84.4�9.2. All comparisons were non-significant for insulin type. Total daily dose (Novolog� 48.8�28.4 vs. Fiasp� 52.4�31.7 units; p=0.01) and daily basal (Novolog� 17.6 (15.5,33.8) vs. Fiasp� 19.1 (15.3,38.5) units; p=0.07) correlated with TIR and %time >180mg/dL. For insulin delivery in Auto Mode there was no statistical difference in total daily dose or daily basal between arms. Paired analysis for matched breakfast meals revealed no significant differences in time to maximum glucose, peak glucose or glucose excursion. CONCLUSIONS In this pilot study the use of either Novolog� or Fiasp� in a commercially available MiniMed? 670G system operating in Auto Mode resulted in clinically similar glycemic outcomes, with a slight increase in daily insulin requirements using Fiasp�.

View details for DOI 10.1089/dia.2020.0083

View details for PubMedID 32520594
Glycemic Outcomes of Use of CLC Versus PLGS in Type 1 Diabetes: A Randomized Controlled Trial. Diabetes care Brown, S. A., Beck, R. W., Raghinaru, D., Buckingham, B. A., Laffel, L. M., Wadwa, R. P., Kudva, Y. C., Levy, C. J., Pinsker, J. E., Dassau, E., Doyle, F. J., Ambler-Osborn, L., Anderson, S. M., Church, M. M., Ekhlaspour, L., Forlenza, G. P., Levister, C., Simha, V., Breton, M. D., Kollman, C., Lum, J. W., Kovatchev, B. P. 2020; 43 (8): 1822?28
Abstract

Limited information is available about glycemic outcomes with a closed-loop control (CLC) system compared with a predictive low-glucose suspend (PLGS) system.After 6 months of use of a CLC system in a randomized trial, 109 participants with type 1 diabetes (age range, 14-72 years; mean HbA1c, 7.1% [54 mmol/mol]) were randomly assigned to CLC (N = 54, Control-IQ) or PLGS (N = 55, Basal-IQ) groups for 3 months. The primary outcome was continuous glucose monitor (CGM)-measured time in range (TIR) for 70-180 mg/dL. Baseline CGM metrics were computed from the last 3 months of the preceding study.All 109 participants completed the study. Mean � SD TIR was 71.1 � 11.2% at baseline and 67.6 � 12.6% using intention-to-treat analysis (69.1 � 12.2% using per-protocol analysis excluding periods of study-wide suspension of device use) over 13 weeks on CLC vs. 70.0 � 13.6% and 60.4 � 17.1% on PLGS (difference = 5.9%; 95% CI 3.6%, 8.3%; P < 0.001). Time >180 mg/dL was lower in the CLC group than PLGS group (difference = -6.0%; 95% CI -8.4%, -3.7%; P < 0.001) while time <54 mg/dL was similar (0.04%; 95% CI -0.05%, 0.13%; P = 0.41). HbA1c after 13 weeks was lower on CLC than PLGS (7.2% [55 mmol/mol] vs. 7.5% [56 mmol/mol], difference -0.34% [-3.7 mmol/mol]; 95% CI -0.57% [-6.2 mmol/mol], -0.11% [1.2 mmol/mol]; P = 0.0035).Following 6 months of CLC, switching to PLGS reduced TIR and increased HbA1c toward their pre-CLC values, while hypoglycemia remained similarly reduced with both CLC and PLGS.

View details for DOI 10.2337/dc20-0124

View details for PubMedID 32471910
Continuous Glucose Monitors and Automated Insulin Dosing Systems in the Hospital Consensus Guideline. Journal of diabetes science and technology Galindo, R. J., Umpierrez, G. E., Rushakoff, R. J., Basu, A., Lohnes, S., Nichols, J. H., Spanakis, E. K., Espinoza, J., Palermo, N. E., Awadjie, D. G., Bak, L., Buckingham, B., Cook, C. B., Freckmann, G., Heinemann, L., Hovorka, R., Mathioudakis, N., Newman, T., O'Neal, D. N., Rickert, M., Sacks, D. B., Seley, J. J., Wallia, A., Shang, T., Zhang, J. Y., Han, J., Klonoff, D. C. 2020: 1932296820954163
Abstract

This article is the work product of the Continuous Glucose Monitor and Automated Insulin Dosing Systems in the Hospital Consensus Guideline Panel, which was organized by Diabetes Technology Society and met virtually on April 23, 2020. The guideline panel consisted of 24 international experts in the use of continuous glucose monitors (CGMs) and automated insulin dosing (AID) systems representing adult endocrinology, pediatric endocrinology, obstetrics and gynecology, advanced practice nursing, diabetes care and education, clinical chemistry, bioengineering, and product liability law. The panelists reviewed the medical literature pertaining to five topics: (1) continuation of home CGMs after hospitalization, (2) initiation of CGMs in the hospital, (3) continuation of AID systems in the hospital, (4) logistics and hands-on care of hospitalized patients using CGMs and AID systems, and (5) data management of CGMs and AID systems in the hospital. The panelists then developed three types of recommendations for each topic, including clinical practice (to use the technology optimally), research (to improve the safety and effectiveness of the technology), and hospital policies (to build an environment for facilitating use of these devices) for each of the five topics. The panelists voted on 78 proposed recommendations. Based on the panel vote, 77 recommendations were classified as either strong or mild. One recommendation failed to reach consensus. Additional research is needed on CGMs and AID systems in the hospital setting regarding device accuracy, practices for deployment, data management, and achievable outcomes. This guideline is intended to support these technologies for the management of hospitalized patients with diabetes.

View details for DOI 10.1177/1932296820954163

View details for PubMedID 32985262
First outpatient evaluation of a tubeless automated insulin delivery system with customizable glucose targets in children and adults with type 1 diabetes. Diabetes technology & therapeutics Forlenza, G. P., Buckingham, B. A., Brown, S., Bode, B. W., Levy, C., Criego, A., Wadwa, R. P., Cobry, E., Slover, R. J., Messer, L., Berget, C., McCoy, S., Ekhlaspour, L., Kingman, R. S., Voelmle, M. K., Boyd, J., O'Malley, G., Grieme, A., Kivilaid, K., Kleve, K., Dumais, B., Vienneau, T., Huyett, L. M., Lee, J. B., O'Connor, J., Benjamin, E., Ly, T. T. 2020
Abstract

The objective of this study was to assess the safety and effectiveness of the first commercial configuration of a tubeless automated insulin delivery system, Omnipod^� 5, in children (6-13.9 years) and adults (14-70 years) with type 1 diabetes in an outpatient setting.This was a single-arm, multicenter, prospective clinical study. Data were collected over a 14-day standard therapy (ST) phase followed by a 14-day hybrid closed-loop (HCL) phase, where participants (n=36) spent 72 hours at each of three pre-specified glucose targets (130, 140 and 150mg/dL, nine days total) then five days with free choice of glucose targets (110-150mg/dL) using the Omnipod 5. Remote safety monitoring alerts were enabled during the HCL phase. Primary endpoints were difference in time in range (TIR) (70-180mg/dL) between ST and HCL phases and proportion of participants reporting serious device-related adverse events.Mean TIR was significantly higher among children in the free-choice period overall (64.9 � 12.2%, p<0.01) and when using a 110mg/dL target (71.2 � 10.2%, p<0.01), a 130mg/dL target (61.5 � 7.7%, p<0.01), and a 140mg/dL target (64.8 � 11.6%, p<0.01), and among adults using a 130mg/dL target (75.1 � 11.6%, p<0.05), compared to the ST phase (children: 51.0 � 13.3% and adults: 65.6 � 15.7%). There were no serious device-related adverse events reported during the HCL phase, nor were there episodes of severe hypoglycemia or diabetic ketoacidosis.The Omnipod 5 System was safe and effective when used at glucose targets from 110 to 150mg/dL for 14 days at home in children and adults with type 1 diabetes.

View details for DOI 10.1089/dia.2020.0546

View details for PubMedID 33325779
Functional Near-Infrared Spectroscopy (fNIRS) detects increased activation of the brain frontal-parietal network in youth with type 1 diabetes. Pediatric diabetes Mazaika, P. K., Marzelli, M., Tong, G., Foland-Ross, L. C., Buckingham, B. A., Aye, T., Reiss, A. L. 2020
Abstract

When considered as a group, children with type 1 diabetes have subtle cognitive deficits relative to neurotypical controls. However, the neural correlates of these differences remain poorly understood. Using functional near-infrared spectroscopy (fNIRS), we investigated the brain functional activations of young adolescents (19 individuals with type 1 diabetes, 18 healthy controls, ages 8-16?years) during a Go/No-Go response inhibition task. Both cohorts had the same performance on the task, but the individuals with type 1 diabetes subjects had higher activations in a frontal-parietal network including the bilateral supramarginal gyri and bilateral rostrolateral prefrontal cortices. The activations in these regions were positively correlated with fewer parent-reported conduct problems (i.e. lower Conduct Problem scores) on the BASC-2 behavioral assessment. Lower Conduct Problem scores are characteristic of less rule-breaking behavior suggesting a link between this brain network and better self-control. These findings are consistent with a large functional magnetic resonance imaging (fMRI) study of children with type 1 diabetes using completely different participants. Perhaps surprisingly, the between-group activation results from fNIRS were statistically stronger than the results using fMRI. This pilot study is the first fNIRS investigation of executive function for individuals with type 1 diabetes. The results suggest that fNIRS is a promising functional neuroimaging resource for detecting the brain correlates of behavior in the pediatric clinic. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/pedi.12992

View details for PubMedID 32003523
A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs. Nature biomedical engineering Maikawa, C. L., Smith, A. A., Zou, L., Roth, G. A., Gale, E. C., Stapleton, L. M., Baker, S. W., Mann, J. L., Yu, A. C., Correa, S., Grosskopf, A. K., Liong, C. S., Meis, C. M., Chan, D., Troxell, M., Maahs, D. M., Buckingham, B. A., Webber, M. J., Appel, E. A. 2020
Abstract

Treatment of patients with diabetes with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. However, because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100?h at 37?�C under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10?h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin from 0.4?�?0.2 to 0.7?�?0.1 (mean?�?s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.

View details for DOI 10.1038/s41551-020-0555-4

View details for PubMedID 32393892
Sensitive detection of multiple islet autoantibodies in type 1 diabetes using small sample volumes by agglutination-PCR. PloS one Cortez, F. d., Gebhart, D., Robinson, P. V., Seftel, D., Pourmandi, N., Owyoung, J., Bertozzi, C. R., Wilson, D. M., Maahs, D. M., Buckingham, B. A., Mills, J. R., Roforth, M. M., Pittock, S. J., McKeon, A., Page, K., Wolf, W. A., Sanda, S., Speake, C., Greenbaum, C. J., Tsai, C. 2020; 15 (11): e0242049
Abstract

Islet autoantibodies are predominantly measured by radioassay to facilitate risk assessment and diagnosis of type 1 diabetes. However, the reliance on radioactive components, large sample volumes and limited throughput renders radioassay testing costly and challenging. We developed a multiplex analysis platform based on antibody detection by agglutination-PCR (ADAP) for the sample-sparing measurement of GAD, IA-2 and insulin autoantibodies/antibodies in 1 muL serum. The assay was developed and validated in 7 distinct cohorts (n = 858) with the majority of the cohorts blinded prior to analysis. Measurements from the ADAP assay were compared to radioassay to determine correlation, concordance, agreement, clinical sensitivity and specificity. The average overall agreement between ADAP and radioassay was above 91%. The average clinical sensitivity and specificity were 96% and 97%. In the IASP 2018 workshop, ADAP achieved the highest sensitivity of all assays tested at 95% specificity (AS95) rating for GAD and IA-2 autoantibodies and top-tier performance for insulin autoantibodies. Furthermore, ADAP correctly identified 95% high-risk individuals with two or more autoantibodies by radioassay amongst 39 relatives of T1D patients tested. In conclusion, the new ADAP assay can reliably detect the three cardinal islet autoantibodies/antibodies in 1muL serum with high sensitivity. This novel assay may improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies.

View details for DOI 10.1371/journal.pone.0242049

View details for PubMedID 33186361
Closed-Loop Insulin Therapy Improves Glycemic Control in Adolescents and Young Adults: Outcomes from the International Diabetes Closed-Loop (iDCL) Trial. Diabetes technology & therapeutics Isganaitis, E., Raghinaru, D., Ambler-Osborn, L., Pinsker, J. E., Buckingham, B. A., Wadwa, R. P., Ekhlaspour, L., Kudva, Y. C., Levy, C., Forlenza, G. P., Beck, R. W., Kollman, C., Lum, J., Brown, S., Laffel, L. M. 2020
Abstract

To assess the efficacy and safety of closed-loop control (CLC) insulin delivery system in adolescents and young adults with type 1 diabetes.Pre-specified sub-analysis of outcomes in adolescents and young adults 14-24 years old with type 1 diabetes in a previously published 6-month multicenter randomized trial. Participants were randomly assigned 2:1 to CLC (Tandem Control-IQ) or sensor augmented pump (SAP, various pumps+Dexcom G6 CGM) and followed for six months.Mean age of the 63 participants was 17 years, median type 1 diabetes duration was 7 years, and mean baseline HbA1c was 8.1%. All 63 completed the trial. Time in Range (TIR) increased by 13% with CLC versus decreasing by 1% with SAP (adjusted treatment group difference = +13% [+3.1 hours/day]; 95% CI 9% to 16%, P<0.001), which largely reflected a reduction in time >180 mg/dL (adjusted difference -12% [-2.9 hours/day], P<0.001). Time <70 mg/dL decreased by 1.6% with CLC versus 0.3% with SAP (adjusted difference -0.7% [-10 min/day], 95% CI -1.0% to -0.2%, P=0.002). CLC use averaged 89% of the time over 6 months. The mean adjusted difference in HbA1c after 6 months was 0.30% in CLC vs. SAP (95% CI -0.67 to +0.08, P=0.13). There was one DKA episode in the CLC group.CLC use over 6 months was substantial and associated with improved TIR and reduced hypoglycemia in adolescents and young adults with type 1 diabetes. Thus, CLC has the potential to improve glycemic outcomes in this challenging age group.

View details for DOI 10.1089/dia.2020.0572

View details for PubMedID 33216667
Brain Function Differences in Children With Type 1 Diabetes: An fMRI Study of Working Memory. Diabetes Foland-Ross, L. C., Tong, G., Mauras, N., Cato, A., Aye, T., Tansey, M., White, N. H., Weinzimer, S. A., Englert, K., Shen, H., Mazaika, P. K., Reiss, A. L. 2020
Abstract

Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean age � SD, 11.5�1.8 years; 46% female) and 47 children without diabetes ("control", mean age 11.8�1.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to control children, as well as greater modulation of activation (i.e., showed greater a increase in activation with higher working memory load). Post-hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted.

View details for DOI 10.2337/db20-0123

View details for PubMedID 32471809
Executive task-based brain function in children with type 1 diabetes: An observational study. PLoS medicine Foland-Ross, L. C., Buckingam, B., Mauras, N., Arbelaez, A. M., Tamborlane, W. V., Tsalikian, E., Cato, A., Tong, G., Englert, K., Mazaika, P. K., Reiss, A. L., Diabetes Research in Children Network (DirecNet) 2019; 16 (12): e1002979
Abstract

BACKGROUND: Optimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood.METHODS AND FINDINGS: Using a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 � 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 � 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of "no-go > go" were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct "go" trials; r = -0.36, 95% CI -0.53 to -0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < -0.29, 95% CIs -0.47 to -0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = -0.22, 95% CI -0.41 to -0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI -0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown.CONCLUSIONS: These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.

View details for DOI 10.1371/journal.pmed.1002979

View details for PubMedID 31815939
Safety and Performance of the Omnipod Hybrid Closed-Loop System in Adults, Adolescents, and Children with Type 1 Diabetes Over 5 Days Under Free-Living Conditions. Diabetes technology & therapeutics Sherr, J., Buckingham, B. A., Forlenza, G., Galderisi, A., Ekhlaspour, L., Wadwa, R. P., Carria, L., Hsu, L. J., Berget, C. L., Peyser, T. A., Lee, J. B., O'Connor, J., Dumais, B., Huyett, L. M., Layne, J. E., Ly, T. T. 2019
Abstract

BACKGROUND: The objective of this study was to assess the safety and performance of the Omnipod personalized model predictive control (MPC) algorithm in adults, adolescents, and children aged ?6 years with type 1 diabetes (T1D) under free-living conditions using an investigational device.METHODS: A 96-h hybrid closed-loop (HCL) study was conducted in a supervised hotel/rental home setting following a 7-day outpatient standard therapy (ST) phase. Eligible participants were aged 6-65 y with A1C <10.0% using CSII or MDI. Meals during HCL were unrestricted, with boluses administered per usual routine. There was daily physical activity. The primary endpoints were percentage of time with sensor glucose <70 mg/dL and ?250 mg/dL.RESULTS: Participants were 11 adults, 10 adolescents, and 15 children aged (mean�SD) 28.8�7.9 y, 14.3�1.3 y, and 9.9�1.0 y, respectively. Percentage time ?250 mg/dL during HCL was 4.5�4.2%, 3.5�5.0%, and 8.6�8.8% per respective age group, a 1.6-, 3.4-, and 2.0-fold reduction compared to ST (p=0.1, p=0.02, and p=0.03). Percentage time <70 mg/dL during HCL was 1.9�1.3%, 2.5�2.0%, and 2.2�1.9%, a statistically significant decrease in adults when compared to ST (p=0.005, p=0.3, and p=0.3). Percentage time 70-180 mg/dL increased during HCL compared to ST, reaching significance for adolescents and children: HCL 73.7�7.5% vs. ST 68.0�15.6% for adults (p=0.08), HCL 79.0�12.6% vs. ST 60.6�13.4% for adolescents (p=0.01), and HCL 69.2�13.5% vs. ST 54.9�12.9% for children (p=0.003).CONCLUSIONS: The Omnipod personalized MPC algorithm was safe and performed well over 5 days and 4 nights of use by a cohort of participants ranging from youth aged ?6 years to adults with T1D under supervised free-living conditions with challenges including daily physical activity and unrestricted meals.

View details for DOI 10.1089/dia.2019.0286

View details for PubMedID 31596130
Closed loop control in adolescents and children during winter sports: Use of the Tandem Control-IQ AP system PEDIATRIC DIABETES Ekhlaspour, L., Forlenza, G. P., Chernavvsky, D., Maahs, D. M., Wadwa, R., Deboer, M. D., Messer, L. H., Town, M., Pinnata, J., Kruse, G., Kovatchev, B. P., Buckingham, B. A., Breton, M. D. 2019; 20 (6): 759?68
View details for DOI 10.1111/pedi.12867

View details for Web of Science ID 000478602200012
Fluoroscopic-assisted laparoscopic retrieval of retained glucose sensor wire from the omentum CLINICAL CASE REPORTS Sang, A. X., Lal, R., August, A., Danzer, E., Buckingham, B., Mueller, C. M. 2019
View details for DOI 10.1002/ccr3.2348

View details for Web of Science ID 000478842500001
Realizing a Closed-Loop (Artificial Pancreas) System for the Treatment of Type 1 Diabetes. Endocrine reviews Lal, R. A., Ekhlaspour, L., Hood, K., Buckingham, B. 2019
Abstract

Recent, rapid changes in the treatment of type 1 diabetes have allowed for commercialization of an "artificial pancreas" which is better described as a closed-loop controller of insulin delivery. This review presents the current state of closed-loop control systems and expected future developments with a discussion of the human factor issues in allowing automation of glucose control. The goal of these systems is to minimize or prevent both short and long-term complications from diabetes and to decrease the daily burden of managing diabetes. The closed-loop systems are generally very effective and safe at night, have allowed for improved sleep and have decreased the burden of diabetes management overnight. However, there are still significant barriers to achieving excellent daytime glucose control while simultaneously decreasing the burden of daytime diabetes management. These systems utilize a subcutaneous continuous glucose sensor, an algorithm that accounts for the current glucose and rate of change of the glucose, and the amount of insulin which has already been delivered in order to safely deliver insulin to control hyperglycemia, while minimizing the risk of hypoglycemia. The future challenge will be to allow for full closed-loop control with minimal burden on the patient during the day alleviating meal announcements, carbohydrate counting, alerts and maintenance. The human factors involved with interfacing with a closed-loop system and allowing the system to take control of diabetes management are significant. It is important to find a balance between enthusiasm and realistic expectations and experiences with closed loop.

View details for DOI 10.1210/er.2018-00174

View details for PubMedID 31276160
Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes care Battelino, T., Danne, T., Bergenstal, R. M., Amiel, S. A., Beck, R., Biester, T., Bosi, E., Buckingham, B. A., Cefalu, W. T., Close, K. L., Cobelli, C., Dassau, E., DeVries, J. H., Donaghue, K. C., Dovc, K., Doyle, F. J., Garg, S., Grunberger, G., Heller, S., Heinemann, L., Hirsch, I. B., Hovorka, R., Jia, W., Kordonouri, O., Kovatchev, B., Kowalski, A., Laffel, L., Levine, B., Mayorov, A., Mathieu, C., Murphy, H. R., Nimri, R., Norgaard, K., Parkin, C. G., Renard, E., Rodbard, D., Saboo, B., Schatz, D., Stoner, K., Urakami, T., Weinzimer, S. A., Phillip, M. 2019
Abstract

Improvements in sensor accuracy, greater convenience and ease of use, and expanding reimbursement have led to growing adoption of continuous glucose monitoring (CGM). However, successful utilization of CGM technology in routine clinical practice remains relatively low. This may be due in part to the lack of clear and agreed-upon glycemic targets that both diabetes teams and people with diabetes can work toward. Although unified recommendations for use of key CGM metrics have been established in three separate peer-reviewed articles, formal adoption by diabetes professional organizations and guidance in the practical application of these metrics in clinical practice have been lacking. In February 2019, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address this issue. This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.

View details for DOI 10.2337/dci19-0028

View details for PubMedID 31177185
670G Clinical Experience Lal, R., Basina, M., Maahs, D. M., Buckingham, B. A., Hood, K. K., Conrad, B. P., Leverenz, J., Chmielewski, A., Peterson, K., Wilson, D. AMER DIABETES ASSOC. 2019
View details for DOI 10.2337/db19-80-OR

View details for Web of Science ID 000501366900157
A Review of Continuous Glucose Monitoring Data Interpretation in the Age of Automated Insulin Delivery. Journal of diabetes science and technology Ekhlaspour, L., Tabatabai, I., Buckingham, B. 2019: 1932296819851790
Abstract

Using a continuous glucose monitor (CGM) improves glycemic control in patients with type 1 diabetes. The ambulatory glucose profile (AGP) has been recommended as a standard method for reporting CGM data. However, in recently developed automated insulin delivery (AID) systems, a standard format for reporting data has not yet been developed. Instead, reports are specific to each system being used. Currently, the only FDA approved AID system is a hybrid closed-loop insulin pump. In these systems, the patient is still required to announce a meal, respond to alerts, and keep the system in automated insulin delivery. The integrated pump and sensor information provides insights into how the system is performing, and how to make changes to tunable parameters, such as carbohydrate to insulin ratios. The reports also offer a window into human behavior related to performing diabetes tasks, responding to alarms, reasons for exiting HCL, and how glycemic goals are being met. This article reviews the pump and CGM data provided by several of the current closed-loop systems with a focus on systems that are currently approved in the United States (MiniMed 670G, Tandem Basal:IQ) and those used by patients using do-it-yourself systems. A step-wise approach to reviewing the nuances of these systems is provided. The comparison may reinforce the importance of the continued need for streamlining a standard report for providers to be able to interpret the CGM data of these systems.

View details for DOI 10.1177/1932296819851790

View details for PubMedID 31130007
Optimizing the use of continuous glucose monitoring in young children with type 1 diabetes with an adaptive study design and multiple randomizations. Contemporary clinical trials Berget, C., Driscoll, K. A., Lagges, A., Lange, S., DiMeglio, L. A., Hannon, T. S., Woerner, S. E., Iturralde, E., Barley, R. C., Hanes, S., Hood, K. K., Buckingham, B. B. 2019
Abstract

Parents of young children with type 1 diabetes (T1D) experience unique, developmental challenges in managing their child's T1D, resulting in psychosocial distress. Only a small portion of young children reach glucose goals and adherence to diabetes devices that help improve T1D management have historically been low in this population. The purpose of this study is to test four interventions that couple developmentally tailored behavioral supports with education to optimize use of diabetes devices and reduce psychosocial distress for parents of young children with T1D. The study team designed four behavioral interventions, two aimed at improving glucose control and two aimed at optimizing use of diabetes devices. The goal of this paper is to describe the behavioral interventions developed for this study, including the results of a pilot test, and describe the methods and analysis plan to test this intervention strategy with ninety participants in a large-scale, randomized trial using a SMART design. A SMART design will permit a clinically relevant evaluation of the intervention strategy, as it allows multiple randomizations based on individualized assessments throughout the study instead of a fixed intervention dose seen in most traditional randomized controlled trials.

View details for DOI 10.1016/j.cct.2019.05.008

View details for PubMedID 31129370
A Feasibility Study to Detect Neonatal Hypoglycemia in Infants of Diabetic Mothers Using Real-Time Continuous Glucose Monitoring DIABETES TECHNOLOGY & THERAPEUTICS Nally, L., Bondy, N., Doiev, J., Buckingham, B. A., Wilson, D. M. 2019; 21 (4): 170?76
View details for DOI 10.1089/dia.2018.0337

View details for Web of Science ID 000463602900003
Performance of Omnipod Personalized Model Predictive Control Algorithm with Moderate Intensity Exercise in Adults with Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Forlenza, G. P., Buckingham, B. A., Christiansen, M. P., Wadwa, R., Peyser, T. A., Lee, J., O'Connor, J., Dassau, E., Huyett, L. M., Layne, J. E., Ly, T. T. 2019
View details for DOI 10.1089/dia.2019.0017

View details for Web of Science ID 000462756300001
Successful At-Home Use of the Tandem Control-IQ Artificial Pancreas System in Young Children During a Randomized Controlled Trial DIABETES TECHNOLOGY & THERAPEUTICS Forlenza, G. P., Ekhlaspour, L., Breton, M., Maahs, D. M., Wadwa, R., DeBoer, M., Messer, L. H., Town, M., Pinnata, J., Kruse, G., Buckingham, B. A., Chernavvsky, D. 2019; 21 (4): 159?69
View details for DOI 10.1089/dia.2019.0011

View details for Web of Science ID 000461625400001
Successful At-Home Use of the Tandem Control-IQ Artificial Pancreas System in Young Children During a Randomized Controlled Trial. Diabetes technology & therapeutics Forlenza, G. P., Ekhlaspour, L., Breton, M., Maahs, D. M., Wadwa, R. P., DeBoer, M., Messer, L. H., Town, M., Pinnata, J., Kruse, G., Buckingham, B. A., Chernavvsky, D. 2019
Abstract

OBJECTIVE: Hybrid closed-loop (HCL) artificial pancreas (AP) systems are now moving from research settings to widespread clinical use. In this study, the inControl algorithm developed by TypeZero Technologies was embedded to a commercial Tandem t:slim X2 insulin pump, now called Control-IQ, paired with a Dexcom G6 continuous glucose monitor and tested for superiority against sensor augmented pump (SAP) therapy. Both groups were physician-monitored throughout the clinical trial.RESEARCH DESIGN AND METHODS: In a randomized controlled trial, 24 school-aged children (6-12 years) with type 1 diabetes (T1D) participated in a 3-day home-use trial at two sites: Stanford University and the Barbara Davis Center (50% girls, 9.6�1.9 years of age, 4.5�1.9 years of T1D, baseline hemoglobin A1c 7.35%�0.68%). Study subjects were randomized 1:1 at each site to either HCL AP therapy with the Control-IQ system or SAP therapy with remote monitoring.RESULTS: The primary outcome, time in target range 70-180mg/dL, using Control-IQ significantly improved (71.0%�6.6% vs. 52.8%�13.5%; P=0.001) and mean sensor glucose (153.6�13.5 vs. 180.2�23.1mg/dL; P=0.003) without increasing hypoglycemia time <70mg/dL (1.7% [1.3%-2.1%] vs. 0.9% [0.3%-2.7%]; not significant). The HCL system was active for 94.4% of the study period. Subjects reported that use of the system was associated with less time thinking about diabetes, decreased worry about blood sugars, and decreased burden in managing diabetes.CONCLUSIONS: The use of the Tandem t:slim X2 with Control-IQ HCL AP system significantly improved time in range and mean glycemic control without increasing hypoglycemia in school-aged children with T1D during remote monitored home use.

View details for PubMedID 30888835
A Feasibility Study to Detect Neonatal Hypoglycemia in Infants of Diabetic Mothers Using Real-Time Continuous Glucose Monitoring. Diabetes technology & therapeutics Nally, L. M., Bondy, N., Doiev, J., Buckingham, B., Wilson, D. M. 2019
Abstract

BACKGROUND: Infants born to mothers with diabetes commonly experience asymptomatic hypoglycemia after birth. Continuous glucose monitors (CGM) can detect asymptomatic hypoglycemia in this population without the need for painful glucose checks.METHODS: Infants born after 34 weeks of gestation to mothers with diabetes had a CGM placed after birth. One group of infants was remotely monitored in real-time by research staff during the hospitalization, whereas another group wore a blinded CGM. In both groups, hospital standard-of-care (SOC) glucose checks were performed. Clinical staff and families were blinded to CGM data. For CGM readings <45mg/dL, research staff requested a verification blood glucose (BG) using the point-of-care glucometer.RESULTS: Sixteen infants were studied; 4 with a blinded CGM and 12 with remote monitoring (RM). When there were confirmatory hospital glucometer readings, the sensitivity of the CGM to detect hypoglycemia was 86% and the specificity was 91%. The positive predictive value was 55% and the negative predictive value was 98%. In the full cohort, hypoglycemia (<45mg/dL) was confirmed in 12 of 16 infants with 30 events at <12 hours of life (HOL), 3 events between 12 and 24 HOL, and 1 event at >48 HOL. In the RM group, CGM detected hypoglycemia five times when the infant was not due for a BG check based on the SOC. Overall, the CGM detected five false-positive alerts and six true-positive alerts for hypoglycemia. Only one hypoglycemic episode was missed by CGM in the RM group. Barriers to recruitment included fear of pain with glucose checks, concerns with CGM use, satisfaction with the hospital SOC, personal reasons independent of the study, and lack of interest in participating in research.CONCLUSIONS: Although there were barriers to recruitment and retention in the study, we conclude that CGM can provide added benefit for detecting hypoglycemia when used early after birth.

View details for PubMedID 30839229
Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes DIABETES CARE Triolo, T. M., Fouts, A., Pyle, L., Yu, L., Gottlieb, P. A., Steck, A. K., Greenbaum, C. J., Atkinson, M., Baidal, D., Battaglia, M., Becker, D., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., DiMeglio, L., Gitelman, S., Goland, R., Gottlieb, P., Goland, R., Gottlieb, P., Herold, K., Knip, M., Krischer, J., Lernmark, A., Moore, W., Moran, A., Muir, A., Palmer, J., Peakman, M., Philipson, L., Raskin, P., Redondo, M., Rodriguez, H., Russell, W., Spain, L., Schatz, D. A., Sosenko, J., Wentworth, J., Wherrett, D., Wilson, D., Winter, W., Ziegler, A., Anderson, M., Antinozzi, P., Benoist, C., Blum, J., Bourcier, K., Chase, P., Clare-Salzler, M., Clynes, R., Eisenbarth, G., Fathman, C. G., Grave, G., Hering, B., Insel, R., Kaufman, F., Kay, T., Leschek, E., Mahon, J., Marks, J. B., Nanto-Salonen, K., Nepom, G., Orban, T., Parkman, R., Pescovitz, M., Peyman, J., Pugliese, A., Roep, B., Roncarolo, M., Savage, P., Simell, O., Sherwin, R., Siegelman, M., Skyler, J. S., Steck, A., Thomas, J., Trucco, M., Wagner, J., Krischer, J. P., Leschek, E., Rafkin, L., Bourcier, K., Cowie, C., Foulkes, M., Insel, R., Krause-Steinrauf, H., Lachin, J. M., Malozowski, S., Peyman, J., Ridge, J., Savage, P., Skyler, J. S., Zafonte, S. J., Rafkin, L., Sosenko, J. M., Kenyon, N. S., Santiago, Krischer, J. P., Bundy, B., Abbondondolo, M., Adams, T., Amado, D., Asif, Boonstra, M., Burroughs, C., Cuthbertson, D., Deemer, M., Eberhard, C., Fiske, S., Ford, J., Garmeson, J., Guillette, H., Geyer, S., Hays, B., Henderson, C., Henry, M., Heyman, K., Hsiao, B., Karges, C., Keaton, N., Kinderman, A., Law, P., Leinbach, A., Liu, S., Lloyd, J., Malloy, J., Maddox, K., Martin, J., Miller, J., Milliot, E., Moore, M., Muller, S., Nguyen, T., O'Donnell, R., Roberts, A., Sadler, K., Stavros, T., Tamura, R., Wood, K., Xu, P., Young, K., Alies, P., Badias, F., Baker, A., Bassi, M., Beam, C., Boulware, D., Bounmananh, L., Bream, S., Freeman, D., Gough, J., Ginem, J., Granger, M., Kieffer, M., Lane, P., Linton, C., Nallamshetty, L., Oduah, Parrimon, Y., Paulus, K., Pilger, J., Ramiro, J., Ritzie, A., Sharma, A., Shor, A., Song, X., Terry, A., Weinberger, J., Wootten, M., Lachin, J. M., Foulkes, M., Harding, P., Krause-Steinrauf, H., McDonough, S., McGee, P. F., Hess, K., Phoebus, D., Quinlan, S., Raiden, E., Batts, E., Buddy, C., Kirpatrick, K., Ramey, M., Shultz, A., Webb, C., Romesco, M., Fradkin, J., Leschek, E., Spain, L., Savage, P., Aas, S., Blumberg, E., Beck, G., Brillon, D., Gubitosi-Klug, R., Laffel, L., Vigersky, R., Wallace, D., Braun, J., Lernmark, A., Lo, B., Mitchell, H., Naji, A., Nerup, J., Orchard, T., Steffes, M., Tsiatis, A., Veatch, R., Zinman, B., Loechelt, B., Baden, L., Green, M., Weinberg, A., Marcovina, S., Palmer, J. P., Weinberg, A., Yu, L., Babu, S., Winter, W., Eisenbarth, G. S., Bingley, P., Clynes, R., DiMeglio, L., Eisenbarth, G., Hays, B., Leschek, E., Marks, J., Matheson, D., Rafkin, L., Rodriguez, H., Spain, L., Wilson, D., Redondo, M., Gomez, D., McDonald, A., Pena, S., Pietropaolo, M., Shippy, K., Batts, E., Brown, T., Buckner, J., Dove, A., Hammond, M., Hefty, D., Klein, J., Kuhns, K., Letlau, M., Lord, S., McCulloch-Olson, M., Miller, L., Nepom, G., Odegard, J., Ramey, M., Sachter, E., St Marie, M., Stickney, K., VanBuecken, D., Vellek, B., Webber, C., Allen, L., Bollyk, J., Hilderman, N., Ismail, H., Lamola, S., Sanda, S., Vendettuoli, H., Tridgell, D., Monzavi, R., Bock, M., Fisher, L., Halvorson, M., Jeandron, D., Kim, M., Wood, J., Geffner, M., Kaufman, F., Parkman, R., Salazar, C., Goland, R., Clynes, R., Cook, S., Freeby, M., Gallagher, P. M., Gandica, R., Greenberg, E., Kurland, A., Pollak, S., Wolk, A., Chan, M., Koplimae, L., Levine, E., Smith, K., Trast, J., DiMeglio, L., Blum, J., Evans-Molina, C., Hufferd, R., Jagielo, B., Kruse, C., Patrick, Rigby, M., Spall, M., Swinney, K., Terrell, J., Christner, L., Ford, L., Lynch, S., Menendez, M., Merrill, P., Pescovitz, M., Rodriguez, H., Alleyn, C., Baidal, D., Fay, S., Gaglia, J., Resnick, B., Szubowicz, S., Weir, G., Benjamin, R., Conboy, D., deManbey, A., Jackson, R., Jalahej, H., Orban, T., Ricker, A., Wolfsdorf, J., Zhang, H. H., Wilson, D., Aye, T., Baker, B., Barahona, K., Buckingham, B., Esrey, K., Esrey, T., Fathman, G., Snyder, R., Aneja, B., Chatav, M., Espinoza, O., Frank, E., Liu, J., Perry, J., Pyle, R., Rigby, A., Riley, K., Soto, A., Gitelman, S., Adi, S., Anderson, M., Berhel, A., Breen, K., Fraser, K., Gerard-Gonzalez, A., Jossan, P., Lustig, R., Moassesfar, S., Mugg, A., Ng, D., Prahalod, P., Rangel-Lugo, M., Sanda, S., Tarkoff, J., Torok, C., Wesch, R., Aslan, Buchanan, J., Cordier, J., Hamilton, C., Hawkins, L., Ho, T., Jain, A., Ko, K., Lee, T., Phelps, S., Rosenthal, S., Sahakitrungruang, T., Stehl, L., Taylor, L., Wertz, M., Wong, J., Philipson, L., Briars, R., Devine, N., Littlejohn, E., Grant, T., Gottlieb, P., Klingensmith, G., Steck, A., Alkanani, A., Bautista, K., Bedoy, R., Blau, A., Burke, B., Cory, L., Dang, M., Fitzgerald-Miller, L., Fouts, A., Gage, Garg, S., Gesauldo, P., Gutin, R., Hayes, C., Hoffman, M., Ketchum, K., Logsden-Sackett, N., Maahs, D., Messer, L., Meyers, L., Michels, A., Peacock, S., Rewers, M., Rodriguez, P., Sepulbeda, F., Sippl, R., Steck, A., Taki, Tran, B. K., Tran, T., Wadwa, R. P., Zeitler, P., Barker, J., Barry, S., Birks, L., Bomsburger, L., Bookert, T., Briggs, L., Burdick, P., Cabrera, R., Chase, P., Cobry, E., Conley, A., Cook, G., Daniels, J., DiDomenico, D., Eckert, J., Ehler, A., Eisenbarth, G., Fain, P., Fiallo-Scharer, R., Frank, N., Goettle, H., Haarhues, M., Harris, S., Horton, L., Hutton, J., Jeffrrey, J., Jenison, R., Jones, K., Kastelic, W., King, M. A., Lehr, D., Lungaro, J., Mason, K., Maurer, H., Nguyen, L., Proto, A., Realsen, J., Schmitt, K., Schwartz, M., Skovgaard, S., Smith, J., Vanderwel, B., Voelmle, M., Wagner, R., Wallace, A., Walravens, P., Weiner, L., Westerhoff, B., Westfall, E., Widmer, K., Wright, H., Schatz, D., Abraham, A., Atkinson, M., Cintron, M., Clare-Salzler, M., Ferguson, J., Haller, M., Hosford, J., Mancini, D., Rohrs, H., Silverstein, J., Thomas, J., Winter, W., Cole, G., Cook, R., Coy, R., Hicks, E., Lewis, N., Marks, J., Pugliese, A., Blaschke, C., Matheson, D., Pugliese, A., Sanders-Branca, N., Arce, R. A., Cisneros, M., Sabbag, S., Moran, A., Gibson, C., Fife, B., Hering, B., Kwong, C., Leschyshyn, J., Nathan, B., Pappenfus, B., Street, A., Boes, M. A., Eck, P. S., Finney, L., Fischer, A. T., Martin, A., Muzamhindo, J. C., Rhodes, M., Smith, J., Wagner, J., Wood, B., Becker, D., Delallo, K., Diaz, A., Elnyczky, B., Libman, Pasek, B., Riley, K., Trucco, M., Copemen, B., Gwynn, D., Toledo, F., Rodriguez, H., Bollepalli, S., Diamond, F., Eyth, E., Henson, D., Lenz, A., Shulman, D., Raskin, P., Adhikari, S., Dickson, B., Dunnigan, E., Lingvay, Pruneda, L., Ramos-Roman, M., Raskin, P., Rhee, C., Richard, J., Siegelman, M., Sturges, D., Sumpter, K., White, P., Alford, M., Arthur, J., Aviles-Santa, M. L., Cordova, E., Davis, R., Fernandez, S., Fordan, S., Hardin, T., Jacobs, A., Kaloyanova, P., Lukacova-Zib, Mirfakhraee, S., Mohan, A., Noto, H., Smith, O., Torres, N., Wherrett, D., Balmer, D., Eisel, L., Kovalakovska, R., Mehan, M., Sultan, F., Ahenkorah, B., Cevallos, J., Razack, N., Ricci, J. M., Rhode, A., Srikandarajah, M., Steger, R., Russell, W. E., Black, M., Brendle, F., Brown, A., Moore, D., Pittel, E., Robertson, A., Shannon, A., Thomas, J. W., Herold, K., Feldman, L., Sherwin, R., Tamborlane, W., Weinzimer, S., Toppari, J., Kallio, T., Karkkainen, M., Mantymaki, E., Niininen, T., Nurmi, B., Rajala, P., Romo, M., Suomenrinne, S., Nanto-Salonen, K., Simell, O., Simell, T., Bosi, E., Battaglia, M., Bianconi, E., Bonfanti, R., Grogan, P., Laurenzi, A., Martinenghi, S., Meschi, F., Pastore, M., Falqui, L., Muscato, T. M., Viscardi, M., Bingley, P., Castleden, H., Farthing, N., Loud, S., Matthews, C., McGhee, J., Morgan, A., Pollitt, J., Elliot-Jones, R., Wheaton, C., Knip, M., Siljander, H., Suomalainen, H., Colman, P., Healy, F., Mesfin, S., Redl, L., Wentworth, J., Willis, J., Farley, M., Harrison, L., Perry, C., Williams, F., Mayo, A., Paxton, J., Thompson, Volin, L., Fenton, C., Carr, L., Lemon, E., Swank, M., Luidens, M. K., Salgam, M., Sharma, Schade, D., King, C., Carano, R., Heiden, J., Means, N. D., Holman, L., Thomas, Madrigal, D., Muth, T., Martin, C. L., Plunkett, C., Ramm, C., Auchus, R. J., Lane, W., Avots, E., Buford, M., Hale, C., Hoyle, J., Lane, B., Muir, A., Shuler, S., Raviele, N., Ivie, E., Jenkins, M., Lindsley, K., Hansen, Fadoju, D. O., Felner, E., Bode, B., Hosey, R., Sax, J., Jefferies, C., Mannering, S., Prentis, R., She, J. X., Stachura, M., Hopkins, D., Williams, J., Steed, L., Asatapova, E., Nunez, S., Knight, S., Dixon, P., Ching, J., Donner, T., Longnecker, S., Abel, K., Arcara, K., Blackman, S., Clark, L., Cooke, D., Plotnick, L., Levin, P. A., Bromberger, L., Klein, K., Sadurska, K., Allen, C., Michaud, D., Snodgrass, H., Burghen, G., Chatha, S., Clark, C., Silverberg, J., Wittmer, C., Gardner, J., LeBoeuf, C., Bell, P., McGlore, O., Tennet, H., Alba, N., Carroll, M., Baert, L., Beaton, H., Cordell, E., Haynes, A., Reed, C., Lichter, K., McCarthy, P., McCarthy, S., Monchamp, T., Roach, J., Manies, S., Gunville, F., Marosok, L., Nelson, T., Ackerman, K., Rudolph, J., Stewart, M., McCormick, K., May, S., Falls, T., Barrett, T., Dale, K., Makusha, L., McTernana, C., K, P., Sullivan, K., Narendran, P., Robbie, J., Smith, D., Christensen, R., Koehler, B., Royal, C., Arthur, T., Houser, H., Renaldi, J., Watsen, S., Wu, P., Lyons, L., House, B., Yu, J., Holt, H., Nation, M., Vickers, C., Watling, R., Heptulla, R., Trast, J., Agarwal, C., Newell, D. J., Katikaneni, R., Gardner, C., A, D., Rio, A., Logan, H., Collier, C., Rishton, G., Whalley, A., Ali, S., Ramtoola, T., Quattrin, L., Mastrandea, A. J., House, M., Ecker, C., Huang, C., Gougeon, J., D, H., Pacuad, D., Dunger, J., May, C., O'Brien, C., Acerini, B., Salgin, A., Thankamony, R., Williams, J., Buse, G., Fuller, M., Duclos, J., Tricome, H., Brown, D., Pittard, D., Bowlby, A., Blue, T., Headley, S., Bendre, K., Lewis, K., Sutphin, C., Soloranzo, J., Puskaric, H., Madison, M., Rincon, M., Carlucci, R., B, S., Rusk, E., Tessman, D. M., Huffman, H., Abrams, B., Biederman, M. D., Jones, Leathers, W., Brickman, P., Petrie, D., Zimmerman, J., Howard, L., Miller, R., Alemzadeh, D., Mihailescu, R., Melgozza-Walker, N., Abdulla, C., Boucher-Berry, D., Ize-Ludlow, R., Levy, C., Swenson, B. N., Crimmins, D., Edler, T., Weis, C., Schultz, D., Rogers, D., Latham, C., Mawhorter, C., Switzer, W., Spencer, P., Konstantnopoulus, S., Broder, J., Klein, L., Knight, L., Szadek, G., Welnick, B., Thompson, R., Hoffman, A., Revell, J., Cherko, K., Carter, E., Gilson, J., Haines, G., Arthur, B., Bowen, W. B., Zipf, P., Graves, R. A., Lozano, D., Seiple, K., Spicer, A., Chang, J., Fregosi, J., Harbinson, C., Paulson, S., Stalters, P., Wright, D., Zlock, A. E., Freeth, J., Victory, H., Maheshwari, A., Maheshwari, T., Holmstrom, J., Bueno, R., Arguello, J., Ahern, L., Noreika, Watson, S., Hourse, P., Breyer, C., Kissel, Y., Nicholson, M., Pfeifer, S., Almazan, J., Bajaj, M., Quinn, K., Funk, J., McCance, E., Moreno, R., Veintimilla, A., Wells, J., Cook, S., Trunnel, J., Henske, S., Desai, K., Frizelis, F., Khan, R., Sjoberg, K., Allen, P. P., Manning, G., Hendry, B., Taylor, S., Jones, W., Strader, M. E., Bencomo, T., Bailey, L., Bedolla, C., Roldan, C., Moudiotis, B., Vaidya, C., Anning, S., Bunce, S., Estcourt, E., Folland, E., Gordon, C., Harrill, J., Ireland, J., Piper, L., Scaife, K., Sutton, S., Wilkins, M., Costelloe, J., Palmer, L., Casas, C., Miller, M., Burgard, C., Erickson, J., Hallanger-Johnson, P., Clark, W., Taylor, A., Lafferty, S., Gillett, C., Nolan, M., Pathak, L., Sondrol, T., Hjelle, S., Hafner, J., Kotrba, R., Hendrickson, A. P., Cemeroglu, T., Symington, M., Daniel, Y., Appiagyei-Dankah, D. C., Postellon, M. S., Racine, L., Kleis, K., Barnes, S. E., Godwin, H., McCullough, K., Shaheen, G., Buck, L., Noel, M. L., Warren, S., Weber, S. M., Parker, Gillespie, B. A., Nelson, C., Frost, J., Amrhein, E. C., Moreland, A., Hayes, J., Peggram, J., Aisenberg, M. E., Riordan, J., Zasa, E., Cummings, K., Scott, T., Pinto, A., Mokashi, K., McAssey, E., Helden, P., Hammond, L., Dinning, S., Rahman, S., Ray, C., Dimicri, S., Guppy, H., Nielsen, C. K., Vogel, C., Ariza, L., Morales, Y. T., Chang, R. A., Gabbay, L., Ambrocio, L., Manley, R., Nemery, W., Charlton, P., Smith, L., Kerr, B., Steindel-Kopp, M., Alamaguer, D., Liljenquist, G., Browning, T., Coughenour, M. B., Sulk, E., Tsalikan, M., Tansey, J., Cabbage, N., Dixit, S., Pasha, M., King, K., Adcock, H., Atterberry, L., Fox, K., Englert, N., Mauras, J., Permuy, K., Sikes, T., Berhe, B., Guendling, L., McLennan, L., Paganessi, C., Murphy, M. B., Draznin, M., Kamboj, S., Sheppard, Lewis, L., Coates, W., Moore, G., Babar, J., Bedard, D., Brenson-Hughes, J., Cernich, M., Clements, R., Duprau, S., Goodman, L., Hester, L., Huerta-Saenz, A., Karmazin, T., Letjen, S., Raman, D., Morin, W., Bestermann, E. J., Morawski, J. L., White, A., Brockmyer, R., Bays, S., Campbell, A., Stapleton, N., Stone, A., Donoho, H., Everett, H., Hensley, M., Johnson, C., Marshall, N., Skirvin, P., R, T., Williams, L., Ray, C., Wolverton, D. A., Nickels, C., Dothard, P. W., Speiser, M., Pellizzari, L., Bokor, K., Izuora, S., Abdelnour, P., Cummings, S., Paynor, M., Leahy, M., Riedl, S., Shockley, R., Saad, T., Briones, S., Casella, C., Herz, K., Walsh, J., Greening, F., Hay, S., Hunt, N., Sikotra, L., Simons, D. G., Karounos, R., Oremus, L., Dye, L., Myers, D., Ballard, W., Miers, R., Sparks, K. M., Thraikill, K., Edwards, J., Fowlkes, S., Kemp, A., Morales, L., Holland, L., Johnson, P., Paul, A., Ghatak, K., Phelen, H., Leyland, T., Henderson, D., Brenner, E., Oppenheimer, Mamkin, C., Moniz, C., Clarson, M., Lovell, A., Peters, Ruelas, D., Borut, D., Burt, M., Jordan, S., Castilla, P., Flores, M., Ruiz, L., Hanson, J., Green-Blair, R. J., Sheridan, K. A., Wintergerst, G., Pierce, A., Omoruyi, M., Foster, S., Kingery, A., Lunsford, Cervantes, T., Parker, P., Price, J., Urben, Doughty, H., Haydock, Parker, P., Bergman, S., Duncum, C., Rodda, A., Perelman, R., Calendo, C., Barrera, E., Arce-Nunez, Y., Martinez, M., De la Portilla, Cardenas, L., Garrido, M., Villar, R., Lorini, E., Calandra, G., D'Annuzio, K., Perri, N., Minuto, C., Rebora, R., Callegari, O., Ali, J., Kramer, B., Auble, S., Cabrera, P., Donohoue, R., Fiallo-Scharer, M., Hessner, P., Wolfgram, A., Kansra, N., Bettin, R., McCuller, A., Miller, S., Accacha, J., Corrigan, E., Fiore, R. L., Levine, T. A., Mahoney, C., Polychronakos, Gagne, H., Starkman, M., Fox, D., Chin, F., Melchionne, L. A., Silverman, Marshall, L., Cerracchio, J., Cruz, A., Viswanathan, J., Wilson, S., Chalew, S., Valley, S., Layburn, A., Lala, P., Clesi, M., Genet, G., Uwaifo, A., Charron, T., Allerton, W., Cefalu, L., Melendez-Ramirez, R., Richards, C., Alleyn, E., Gustafson, M., Lizanna, J., Wahlen, S., Aleiwe, M., Hansen, H., Wahlen, C. J., Levy, A., Bonaccorso, R., Rapaport, Y., Tomer, D., Chia, M., Goldis, L., Iazzetti, M., Klein, C., Levister, L., Waldman, E., Wallach, M. O., Regelmann, Z., Antal, M., Aranda, C., Reynholds, A., Vinik, P., Barlow, M., Bourcier, M. L., Nevoret, J., Couper, S., Beresford, N., Thalagne, H., Roper, J., Gibbons, J., Hill, S., Balleaut, C., Brennan, J., Ellis-Gage, L., Fear, T., Gray, L., Jones, C., McNerney, L., Pointer, N., Price, K., Few, D., Tomlinson, N., Leech, D., Wake, C., Owens, M., Burns, J., Wotherspoon, A., Murray, K., Short, G., Curry, S., Kelsey, J., Lawson, J., Porter, S., Stevens, E., Thomson, S., Winship, L., Wynn, E., Wiltshire, J., Krebs, P., Cresswell, H., Faherty, C., Ross, L., Denvir, J., Drew, T., Randell, P., Mansell, S. A., Bell, S., Butler, Y., Hooton, H., Navarra, A., Roper, G., Babington, L., Crate, H., Cripps, A., Ledlie, C., Moulds, R., Norton, B., Petrova, O., Silkstone, C., Smith, K., Ghai, M., Murray, Viswanathan, M., Henegan, O., Kawadry, J. A., Olson, L., Patterson, T., Ahmad, B., Flores, D., Domek, S., Domek, K., Copeland, M., George, J., Less, T., Davis, M., Short, A., Dwarakanathan, P., O'Donnell, B., Boerner, L., Larson, M., Phillips, M., Rendell, K., Larson, C., Smith, K., Zebrowski, L., Kuechenmeister, M., Thevarayapillai, M., Daniels, H., Speer, N., Forghani, R., Quintana, C., Reh, A., Bhangoo, P., Desrosiers, L., Ireland, T., Misla, C., Torres, S., Wells, J., Villar, M., Yu, D., Berry, D., Cook, J., Soder, A., Powell, M., Ng, M., Morrison, Z., Haslam, M., Lawson, B., Bradley, J., Courtney, C., Richardson, C., Watson, E., Keely, D., DeCurtis, M., Vaccarcello-Cruz, Z., Torres, K., Sandberg, H., Hsiang, B., Joy, D., McCormick, A., Powell, H., Jones, J., Bell, S., Hargadon, S., Hudson, M., Kummer, S., Sauder, E., Sutton, K., Gensel, R., Aguirre-Castaneda, Benavides, L. D., Hemp, S., Allen, J., Stear, E., Davis, T., Jones, A., Roberts, J. A., Dart, N., Paramalingam, L. E., Katz, L. N., Chaudhary, K. M., Murphy, S. M., Willi, B., Schwartzman, C., Kapadia, D., Larson, D., McClellan, G., Shaibai, L. A., Kelley, G., Villa, C., Kelley, R., Diamond, M., Kabbani, T., Dajani, F., Hoekstra, M., Magorno, J., Holst, Chauhan, N., Wilson, P., Bononi, M., Sperl, A., Millward, M., Eaton, L., Dean, J., Olshan, H., Renna, C., Milliard, B. L., Bacon, J. B., Quintos, L. S., Topor, S., Bialo, B., Bancroft, A. G., Soto, W., Lagarde, H., Lockemer, T., Vanderploeg, M. A., Ibrahim, M., Huie, Sanchez, R., Edelen, R., Marchiando, J., Palmer, T., Repas, M., Wasson, P., Auker, J., Culbertson, T., Kieffer, D., Voorhees, T., Borgwardt, L., DeRaad, K., Eckert, E., Isaacson, H., Kuhn, A., Carroll, M., Schubert, G., Francis, S., Hagan, T., Le, M., Penn, E., Wickham, C., Leyva, K., Rivera, J., Padilla, Rodriguez, N., Jospe, J., Czyzyk, B., Johnson, U., Nadgir, N., Marlen, G., Prakasam, C., Rieger, N., Glaser, E. C., Heiser, B., Harris, C., Foster, H., Slater, K., Wheeler, D. L., Donaldson, M., Murray, D. E., Hale, R., Tragus, D. R., Word, J., Lynch, L., Pankratz, W., Rogers, R., Newfield, S., Holland, M., Hashiguchi, M., Gottschalk, A., Philis-Tsimikas, R., Rosal, S., Franklin, S. M., Guardado, N., Bohannon, M., Garcia, T., Aguinaldo, J., Phan, Barraza, D., Cohen, J., Pinsker, U., Khan, J., Wiley, L., Jovanovic, P., Misra, M., Wright, D., Cohen, K., Huang, M., Skiles, S., Maxcy, C., Pihoker, K., Cochrane, J., Fosse, S., Kearns, M., Klingsheim, N., Wright, L., Viles, H., Smith, S., Heller, M., Cunningham, A., Daniels, L., Zeiden, J., Field, R., Walker, K. J., Griffin, L., Bartholow, C., Erickson, J., Howard, B., Krabbenhoft, C., Sandman, A., Vanveldhuizen, J., Wurlger, A., Zimmerman, K., Hanisch, L., Davis-Keppen, A., Cotterill, J., Kirby, M., Harris, A., Schmidt, C., Kishiyama, C., Flores, J., Milton, W., Martin, C., Whysham, A., Yerka, T., Freels, J. M., Hassing, J., Webster, R., Green, P., Carter, J., Galloway, D., Hoelzer, S., Roberts, S., Said, P., Sullivan, H. F., Allen, E., Reiter, E., Feinberg, C., Johnson, L. A., Newhook, D., Hagerty, N. H., White, L., Levandoski, J., Kyllo, M., Johnson, C., Benoit, P., Iyer, F., Diamond, H., Hosono, S., Jackman, L., Barette, P., Jones, Sills, S., Bzdick, J., Bulger, R., Weinstock, Douek, R., Andrews, G., Modgill, G., Gyorffy, L., Robin, N., Vaidya, S., Crouch, K., O'Brien, C., Thompson, N., Thorne, J., Blumer, J., Kalic, L., Klepek, J., Paulett, B., Rosolowski, J., Horner, M., Watkins, J. L., Casey, K., Carpenter, C., Burns, J., Horton, C., Pritchard, D., Soetaert, A. G., Wynne, C., Chin, O. Y., Molina, C., Patel, R., Senguttuvan, M., Wheeler, O., Furet, C., Steuhm, D. H., Jelley, S., Goudeau, L., Chalmers, D., Greer, C., Panagiotopoulos, D. L., Metzger, D., Nguyen, M., Horowitz, M. P., Christiansen, E., Glades, C., Morimoto, M., Macarewich, R., Norman, K., Patin, C., Vargas, A., Barbanica, A., Yu, P., Vaidyanathan, W., Osborne, R., Mehra, S., Kaster, S., Neace, J., Horner, G., Reeves, C., Cordrey, L., Marrs, T., Miller, S., Dowshen, D., Doyle, S., Walker, D., Catte, H., Dean, M., Drury-Brown, B., Hackman, M. C., Lee, S., Malkani, K., Cullen, K., Johnson, P., Hampton, M., McCarrell, C., Curtis, E., Paul, Z. Y., Type 1 Diabet TrialNet Study Grp 2019; 42 (2): 192?99
Abstract

There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings.Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years.At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ? 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects.Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.

View details for DOI 10.2337/dc18-0288

View details for Web of Science ID 000457193000013

View details for PubMedID 30061316

View details for PubMedCentralID PMC6341285
The International Diabetes Closed-Loop Study: Testing Artificial Pancreas Component Interoperability DIABETES TECHNOLOGY & THERAPEUTICS Anderson, S. M., Dassau, E., Raghinaru, D., Lum, J., Brown, S. A., Pinsker, J. E., Church, M., Levy, C., Lam, D., Kudva, Y. C., Buckingham, B., Forlenza, G. P., Wadwa, R., Laffel, L., Doyle, F. J., DeVries, J., Renard, E., Cobelli, C., Boscari, F., Del Favero, S., Kovatchev, B. P. 2019; 21 (2): 73?80
View details for DOI 10.1089/dia.2018.0308

View details for Web of Science ID 000463367300004
The International Diabetes Closed-Loop Study: Testing Artificial Pancreas Component Interoperability. Diabetes technology & therapeutics Anderson, S. M., Dassau, E., Raghinaru, D., Lum, J., Brown, S. A., Pinsker, J. E., Church, M. M., Levy, C., Lam, D., Kudva, Y. C., Buckingham, B., Forlenza, G. P., Wadwa, R. P., Laffel, L., Doyle, F. J., DeVries, J. H., Renard, E., Cobelli, C., Boscari, F., Del Favero, S., Kovatchev, B. P. 2019
Abstract

BACKGROUND: Use of artificial pancreas (AP) requires seamless interaction of device components, such as continuous glucose monitor (CGM), insulin pump, and control algorithm. Mobile AP configurations also include a smartphone as computational hub and gateway to cloud applications (e.g., remote monitoring and data review and analysis). This International Diabetes Closed-Loop study was designed to demonstrate and evaluate the operation of the inControl AP using different CGMs and pump modalities without changes to the user interface, user experience, and underlying controller.METHODS: Forty-three patients with type 1 diabetes (T1D) were enrolled at 10 clinical centers (7 United States, 3 Europe) and 41 were included in the analyses (39% female, >95% non-Hispanic white, median T1D duration 16 years, median HbA1c 7.4%). Two CGMs and two insulin pumps were tested by different study participants/sites using the same system hub (a smartphone) during 2 weeks of in-home use.RESULTS: The major difference between the system components was the stability of their wireless connections with the smartphone. The two sensors achieved similar rates of connectivity as measured by percentage time in closed loop (75% and 75%); however, the two pumps had markedly different closed-loop adherence (66% vs. 87%). When connected, all system configurations achieved similar glycemic outcomes on AP control (73% [mean] time in range: 70-180mg/dL, and 1.7% [median] time <70mg/dL).CONCLUSIONS: CGMs and insulin pumps can be interchangeable in the same Mobile AP system, as long as these devices achieve certain levels of reliability and wireless connection stability.

View details for PubMedID 30649925
Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. The New England journal of medicine Brown, S. A., Kovatchev, B. P., Raghinaru, D., Lum, J. W., Buckingham, B. A., Kudva, Y. C., Laffel, L. M., Levy, C. J., Pinsker, J. E., Wadwa, R. P., Dassau, E., Doyle, F. J., Anderson, S. M., Church, M. M., Dadlani, V., Ekhlaspour, L., Forlenza, G. P., Isganaitis, E., Lam, D. W., Kollman, C., Beck, R. W. 2019
Abstract

Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes.In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring.A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (�SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61�17% at baseline to 71�12% during the 6 months and remained unchanged at 59�14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P<0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was >180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was <70 mg per deciliter or <54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P<0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P?=?0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group.In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).

View details for DOI 10.1056/NEJMoa1907863

View details for PubMedID 31618560
Fluoroscopic-assisted laparoscopic retrieval of retained glucose sensor wire from the omentum. Clinical case reports Sang, A. X., Lal, R., August, A., Danzer, E., Buckingham, B., Mueller, C. M. 2019; 7 (9): 1717?20
Abstract

We describe a case in which retained wires from a continuous glucose monitor were removed from the abdominal wall and peritoneum of a 6-year-old boy. We highlight a concern for continuous glucose monitor use in children and discuss surgical techniques used to retrieve tiny, mobile objects from complex body cavities.

View details for DOI 10.1002/ccr3.2348

View details for PubMedID 31534734

View details for PubMedCentralID PMC6745354
Performance of Omnipod Personalized Model Predictive Control Algorithm with Moderate Intensity Exercise in Adults with Type 1 Diabetes. Diabetes technology & therapeutics Forlenza, G. P., Buckingham, B. A., Christiansen, M. P., Wadwa, R. P., Peyser, T. A., Lee, J. B., O'Connor, J., Dassau, E., Huyett, L. M., Layne, J. E., Ly, T. T. 2019
Abstract

The objective of this study was to assess the safety and performance of the Omnipod� personalized model predictive control (MPC) algorithm with variable glucose setpoints and moderate intensity exercise using an investigational device in adults with type 1 diabetes (T1D).A supervised 54-h hybrid closed-loop (HCL) study was conducted in a hotel setting after a 7-day outpatient standard treatment phase. Adults aged 18-65 years with T1D and HbA1c between 6.0% and 10.0% were eligible. Subjects completed two moderate intensity exercise sessions of >30?min duration on consecutive days: the first with the glucose set point increased from 130 to 150?mg/dL and the second with a temporary basal rate of 50%, both started 90?min pre-exercise. Primary endpoints were percentage time in hypoglycemia <70?mg/dL and hyperglycemia ?250?mg/dL.Twelve subjects participated in the study, with (mean?�?standard deviation) age 36.5?�?14.4 years, diabetes duration 21.7?�?15.7 years, HbA1c 7.6%?�?1.1%, and total daily dose 0.60?�?0.22?U/kg. Outcomes for the 54-h HCL period were mean glucose: 136?�?14?mg/dL, percentage time <70?mg/dL: 1.4%?�?1.3%, 70-180?mg/dL: 85.1%?�?9.3%, and ?250?mg/dL: 1.8%?�?2.4%. In the 12-h period after exercise start, percentage time <70?mg/dL was 1.4%?�?2.7% with the raised glucose set point and 1.6%?�?3.0% with reduced basal rate. The percentage time <70?mg/dL overnight was 0%?�?0% on both study nights.The Omnipod personalized MPC algorithm performed well and was safe during day and night use in response to variable glucose set points and with temporarily raised glucose set point or reduced basal rate 90?min in advance of moderate intensity exercise in adults with T1D.

View details for PubMedID 30925077
Hybrid Closed-Loop Control Is Safe and Effective for People with Type 1 Diabetes Who Are at Moderate to High Risk for Hypoglycemia. Diabetes technology & therapeutics Anderson, S. M., Buckingham, B. A., Breton, M. D., Robic, J. L., Barnett, C. L., Wakeman, C. A., Oliveri, M. C., Brown, S. A., Ly, T. T., Clinton, P. K., Hsu, L. J., Kingman, R. S., Norlander, L. M., Loebner, S. E., Reuschel-DiVirglio, S., Kovatchev, B. P. 2019
Abstract

Background: Typically, closed-loop control (CLC) studies excluded patients with significant hypoglycemia. We evaluated the effectiveness of hybrid CLC (HCLC) versus sensor-augmented pump (SAP) in reducing hypoglycemia in this high-risk population. Methods: Forty-four subjects with type 1 diabetes, 25 women, 37?�?2 years old, HbA1c 7.4%?�?0.2% (57?�?1.5?mmol/mol), diabetes duration 19?�?2 years, on insulin pump, were enrolled at the University of Virginia (N?=?33) and Stanford University (N?=?11). Eligibility: increased risk of hypoglycemia confirmed by 1 week of blinded continuous glucose monitor (CGM); randomized to 4 weeks of home use of either HCLC or SAP. Primary/secondary outcomes: risk for hypoglycemia measured by the low blood glucose index (LBGI)/CGM-based time in ranges. Results: Values reported: mean?�?standard deviation. From baseline to the final week of study: LBGI decreased more on HCLC (2.51?�?1.17 to 1.28?�?0.5) than on SAP (2.1?�?1.05 to 1.79?�?0.98), P?
View details for DOI 10.1089/dia.2019.0018

View details for PubMedID 31095423
Safety Evaluation of the MiniMed 670G System in Children 7-13 Years of Age with Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Forlenza, G. P., Pinhas-Hamiel, O., Liljenquist, D. R., Shulman, D. I., Bailey, T. S., Bode, B. W., Wood, M. A., Buckingham, B. A., Kaiserman, K. B., Shin, J., Huang, S., Lee, S. W., Kaufman, F. R. 2019; 21 (1): 11?19
View details for DOI 10.1089/dia.2018.0264

View details for Web of Science ID 000463369200003
Assessing the efficacy, safety and utility of 6-month day-and-night automated closed-loop insulin delivery under free-living conditions compared with insulin pump therapy in children and adolescents with type 1 diabetes: an open-label, multicentre, multinational, single-period, randomised, parallel group study protocol. BMJ open Musolino, G., Allen, J. M., Hartnell, S., Wilinska, M. E., Tauschmann, M., Boughton, C., Campbell, F., Denvir, L., Trevelyan, N., Wadwa, P., DiMeglio, L., Buckingham, B. A., Weinzimer, S., Acerini, C. L., Hood, K., Fox, S., Kollman, C., Sibayan, J., Borgman, S., Cheng, P., Hovorka, R. 2019; 9 (6): e027856
Abstract

Closed-loop systems titrate insulin based on sensor glucose levels, providing novel means to reduce the risk of hypoglycaemia while improving glycaemic control. We will assess effectiveness of 6-month day-and-night closed-loop insulin delivery compared with usual care (conventional or sensor-augmented pump therapy) in children and adolescents with type 1 diabetes.The trial adopts an open-label, multicentre, multinational (UK and USA), randomised, single-period, parallel design. Participants (n=130) are children and adolescents (aged ?6?and <19 years) with type 1 diabetes for at least 1?year, and insulin pump use for at least 3 months with suboptimal glycaemic control (glycated haemoglobin ?58?mmol/mol (7.5%) and ?86?mmol/mol (10%)). After a 2-3?week run-in period, participants will be randomised to 6-month use of hybrid closed-loop insulin delivery, or to usual care. Analyses will be conducted on an intention-to-treat basis. The primary outcome is glycated haemoglobin at 6 months. Other key endpoints include time in the target glucose range (3.9-10?mmol/L, 70-180?mg/dL), mean sensor glucose and time spent above and below target. Secondary outcomes include SD and coefficient of variation of sensor glucose levels, time with sensor glucose levels <3.5?mmol/L (63?mg/dL) and <3.0?mmol/L (54?mg/dL), area under the curve of glucose <3.5?mmol/L (63?mg/dL), time with glucose levels >16.7?mmol/L (300?mg/dL), area under the curve of glucose >10.0?mmol/L (180?mg/dL), total, basal and bolus insulin dose, body mass index z-score and blood pressure. Cognitive, emotional and behavioural characteristics of participants and caregivers and their responses to the closed-loop and clinical trial will be assessed. An incremental cost-effectiveness ratio for closed-loop will be estimated.Cambridge South Research Ethics Committee and Jaeb Center for Health Research Institutional Review Office approved the study. The findings will be disseminated by peer-review publications and conference presentations.NCT02925299; Pre-results.

View details for DOI 10.1136/bmjopen-2018-027856

View details for PubMedID 31164368
Feasibility Studies of an Insulin-Only Bionic Pancreas in a Home-Use Setting. Journal of diabetes science and technology Ekhlaspour, L., Nally, L. M., El-Khatib, F. H., Ly, T. T., Clinton, P., Frank, E., Tanenbaum, M. L., Hanes, S. J., Selagamsetty, R. R., Hood, K., Damiano, E. R., Buckingham, B. A. 2019: 1932296819872225
Abstract

We tested the safety and performance of the "insulin-only" configuration of the bionic pancreas (BP) closed-loop blood-glucose control system in a home-use setting to assess glycemic outcomes using different static and dynamic glucose set-points.This is an open-label non-randomized study with three consecutive intervention periods. Participants had consecutive weeks of usual care followed by the insulin-only BP with (1) an individualized static set-point of 115 or 130 mg/dL and (2) a dynamic set-point that automatically varied within 110 to 130 mg/dL, depending on hypoglycemic risk. Human factors (HF) testing was conducted using validated surveys. The last five days of each study arm were used for data analysis.Thirteen participants were enrolled with a mean age of 28 years, mean A1c of 7.2%, and mean daily insulin dose of 0.6 U/kg (0.4-1.0 U/kg). The usual care arm had an average glucose of 145 � 20 mg/dL, which increased in the static set-point arm (159 � 8 mg/dL, P = .004) but not in the dynamic set-point arm (154 � 10 mg/dL, P = ns). There was no significant difference in time spent in range (70-180 mg/dL) among the three study arms. There was less time <70 mg/dL with both the static (1.8% � 1.4%, P = .009) and dynamic set-point (2.7�1.5, P = .051) arms compared to the usual-care arm (5.5% � 4.2%). HF testing demonstrated preliminary user satisfaction and no increased risk of diabetes burden or distress.The insulin-only configuration of the BP using either static or dynamic set-points and initialized only with body weight performed similarly to other published insulin-only systems.

View details for DOI 10.1177/1932296819872225

View details for PubMedID 31470740
One Year Clinical Experience of the First Commercial Hybrid Closed-Loop. Diabetes care Lal, R. A., Basina, M., Maahs, D. M., Hood, K., Buckingham, B., Wilson, D. M. 2019
Abstract

In September 2016, the U.S. Food and Drug Administration approved the Medtronic 670G "hybrid" closed-loop system. In Auto Mode, this system automatically controls basal insulin delivery based on continuous glucose monitoring data, but requires users enter carbohydrates and blood glucose for boluses. To track real-world experience with this first commercial closed-loop device, we prospectively followed pediatric and adult patients starting the 670G system.This was a 1-year prospective observational study of patients with type 1 diabetes starting the 670G system between May 2017 and May 2018 in clinic.A total of 84 patients received 670G and consented, 5 never returned for follow-up, with 79 (aged 9-61 years) providing data at 1 week and 3, 6, 9, and/or 12 months after Auto Mode initiation. For the 86% (68 out of 79) with 1-week data, 99% (67 out of 68) successfully started. By 3 months, at least 28% (22 out of 79) stopped using Auto Mode; at 6 months, 34% (27 out of 79); at 9 months, 35% (28 out of 79); and by 12 months, 33% (26 out of 79). The primary reason for continuing Auto Mode was desire for increased time in range. Reasons for discontinuation included sensor issues in 62% (16 out of 26), problems obtaining supplies in 12% (3 out of 26), hypoglycemia fear in 12% (3 out of 26), multiple daily injection preference in 8% (2 out of 26), and sports in 8% (2 out of 26). At all visits, there was a significant correlation between hemoglobin A1c (HbA1c) and Auto Mode utilization.While Auto Mode utilization correlates with improved glycemic control, a focus on usability and human factors is necessary to ensure use of Auto Mode. Alarms and sensor calibration are a major patient concern, which future technology should alleviate.

View details for DOI 10.2337/dc19-0855

View details for PubMedID 31548247
Closed Loop Control in Adolescents and Children During Winter Sports: Use of the Tandem Control-IQ AP System. Pediatric diabetes Ekhlaspour, L., Forlenza, G. P., Chernavvsky, D., Maahs, D. M., Wadwa, R. P., DeBoer, M. D., Messer, L. H., Town, M., Pinnata, J., Kruse, G., Kovatchev, B. P., Buckingham, B. A., Breton, M. D. 2019
Abstract

Artificial Pancreas (AP) systems have been shown to improve glycemic control throughout the day and night in adults, adolescents, and children. However, AP testing remains limited during intense and prolonged exercise in adolescents and children. We present the performance of the Tandem Control-IQ AP system in adolescents and children during a winter ski camp study, where high altitude, low temperature, prolonged intense activity, and stress challenged glycemic control.In a randomized controlled trial, 24 adolescents (ages 13-18�years) and 24 school-aged children (6-12�years) with Type 1 Diabetes (T1D) participated in a 48�hr ski camp (?5�h skiing/day) at three sites: Wintergreen, VA; Kirkwood, CA and Breckenridge, CO. Study participants were randomized 1:1 at each site. The control group used remote monitored sensor-augmented pump (RM-SAP), and the experimental group used the t: slim X2 with Control-IQ Technology AP system. All subjects were remotely monitored 24�hours per day by study staff.The Control-IQ system improved percent time within range (70-180�mg/dL) over the entire camp duration: 66.4��16.4vs 53.9��24.8%; P�=�0.01 in both children and adolescents. The AP system was associated with a significantly lower average glucose based on CGM data: 161��29.9 vs 176.8��36.5�mg/dL; P�=�0.023. There were no differences between groups for hypoglycemia exposure or carbohydrate interventions. There were no adverse events.The use of the Control-IQ AP improved glycemic control and safely reduced exposure to hyperglycemia relative to RM-SAP in pediatric patients with type 1 diabetes during prolonged intensive winter sport activities. This article is protected by copyright. All rights reserved.

View details for PubMedID 31099946
Safety Evaluation of the MiniMed 670G System in Children 7-13 Years of Age with Type 1 Diabetes. Diabetes technology & therapeutics Forlenza, G. P., Pinhas-Hamiel, O., Liljenquist, D. R., Shulman, D. I., Bailey, T. S., Bode, B. W., Wood, M. A., Buckingham, B. A., Kaiserman, K. B., Shin, J., Huang, S., Lee, S. W., Kaufman, F. R. 2018
Abstract

OBJECTIVE: To evaluate the safety of in-home use of the MiniMed 670G system with SmartGuard technology in children with type 1 diabetes (T1D).METHODS: Participants (N=105, ages 7-13 years, mean age 10.8�1.8 years) were enrolled at nine centers (eight in the United States and one in Israel) and completed a 2-week baseline run-in phase in Manual Mode followed by a 3-month study phase with Auto Mode enabled. Sensor glucose (SG), glycated hemoglobin (HbA1c), percentage of SG values across glucose ranges, and SG variability, during the run-in and study phases were compared. Participants underwent frequent sample testing with i-STAT venous reference measurement during a hotel period (6 days/5 nights) to evaluate the system's continuous glucose monitoring performance.RESULTS: Auto Mode was used a median of 81% of the time. From baseline to end of study, overall SG dropped by 6.9�17.2mg/dL (P<0.001), HbA1c decreased from 7.9%�0.8% to 7.5%�0.6% (P<0.001), percentage of time in target glucose range (70-180mg/dL) increased from 56.2%�11.4% to 65.0%�7.7% (P<0.001), and the SG coefficient of variation decreased from 39.6%�5.4% to 38.5%�3.8% (P=0.009). The percentage of SG values within target glucose range was 68.2%�9.1% and that of i-STAT reference values was 65.6%�17.7%. The percentage of values within 20%/20 of the i-STAT reference was 85.2%. There were no episodes of severe hypoglycemia or diabetic ketoacidosis during the study phase.CONCLUSION: In-home use of MiniMed 670G system Auto Mode for 3 months by children with T1D, similar to MiniMed 670G system use by adolescents and adults with T1D, was safe and associated with reduced HbA1c levels and increased time in target glucose range, compared with baseline.

View details for PubMedID 30585770
In-Clinic Evaluation of the MiniMed 670G System "Suspend Before Low" Feature in Children with Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Wood, M. A., Shulman, D. I., Forlenza, G. P., Bode, B. W., Pinhas-Hamiel, O., Buckingham, B. A., Kaiserman, K. B., Liljenquist, D. R., Bailey, T. S., Shin, J., Huang, S., Chen, X., Cordero, T. L., Lee, S. W., Kaufman, F. R. 2018
Abstract

The Medtronic predictive low-glucose management (PLGM) algorithm automatically stops insulin delivery when sensor glucose (SG) is predicted to reach or fall below a preset low-glucose value within the next 30?min, and resumes delivery after hypoglycemia recovery. The present study evaluated the PLGM algorithm performance of the MiniMed? 670G system SmartGuard? "suspend before low" feature in children aged 7-13 years with type 1 diabetes (T1D).Participants (N?=?105, mean?�?standard deviation of 10.8?�?1.8 years) underwent an overnight in-clinic evaluation of the "suspend before low" feature with a preset low limit of 65?mg/dL. After exercise, frequent sample testing (FST) was conducted every 5?min if values were <70?mg/dL; every 15?min if 70-80?mg/dL; and every 30?min if >80?mg/dL. First-day performance of the Guardian? Sensor 3 glucose sensor and continuous glucose monitoring system was also evaluated.Activation of the "suspend before low" feature occurred in 79 of the 105 participants, 79.7% (63/79) did not result in SG falling below 65?mg/dL. Mean glucose at activation was 102?�?19?mg/dL and the initial insulin suspension duration was 87.5?�?32.7?min. Four hours after insulin resumption, mean reference glucose was 130?�?42?mg/dL. Mean absolute relative difference between the FST reference glucose and SG values on the first day of sensor wear was 11.4%. For the 26 participants in whom the "suspend before low" feature did not activate, none involved a reference glucose value ?65?mg/dL, suggesting that the PLGM algorithm performed as intended.In children aged 7-13 years with T1D, the "suspend before low" feature of the MiniMed 670G system demonstrated a hypoglycemia prevention rate of nearly 80% after exercise and did not involve rebound hyperglycemia. There were no events of severe hypoglycemia during the evaluation.

View details for PubMedID 30299976
Predictive Low-Glucose Suspend Reduces Hypoglycemia in Adults, Adolescents, and Children With Type 1 Diabetes in an At-Home Randomized Crossover Study: Results of the PROLOG Trial DIABETES CARE Forlenza, G. P., Li, Z., Buckingham, B. A., Pinsker, J. E., Cengiz, E., Wadwa, R., Ekhlaspour, L., Church, M., Weinzimer, S. A., Jost, E., Marcal, T., Andre, C., Carria, L., Swanson, V., Lum, J. W., Kollman, C., Woodall, W., Beck, R. W. 2018; 41 (10): 2155?61
Abstract

This study evaluated a new insulin delivery system designed to reduce insulin delivery when trends in continuous glucose monitoring (CGM) glucose concentrations predict future hypoglycemia.Individuals with type 1 diabetes (n = 103, age 6-72 years, mean HbA1c 7.3% [56 mmol/mol]) participated in a 6-week randomized crossover trial to evaluate the efficacy and safety of a Tandem Diabetes Care t:slim X2 pump with Basal-IQ integrated with a Dexcom G5 sensor and a predictive low-glucose suspend algorithm (PLGS) compared with sensor-augmented pump (SAP) therapy. The primary outcome was CGM-measured time <70 mg/dL.Both study periods were completed by 99% of participants; median CGM usage exceeded 90% in both arms. Median time <70 mg/dL was reduced from 3.6% at baseline to 2.6% during the 3-week period in the PLGS arm compared with 3.2% in the SAP arm (difference [PLGS - SAP] = -0.8%, 95% CI -1.1 to -0.5, P < 0.001). The corresponding mean values were 4.4%, 3.1%, and 4.5%, respectively, represent-ing a 31% reduction in the time <70 mg/dL with PLGS. There was no increase in mean glucose concentration (159 vs. 159 mg/dL, P = 0.40) or percentage of time spent >180 mg/dL (32% vs. 33%, P = 0.12). One severe hypoglycemic event occurred in the SAP arm and none in the PLGS arm. Mean pump suspension time was 104 min/day.The Tandem Diabetes Care Basal-IQ PLGS system significantly reduced hypoglycemia without rebound hyperglycemia, indicating that the system can benefit adults and youth with type 1 diabetes in improving glycemic control.

View details for PubMedID 30089663
ISPAD Clinical Practice Consensus Guidelines 2018: Insulin treatment in children and adolescents with diabetes Danne, T., Phillip, M., Buckingham, B. A., Jarosz-Chobot, P., Saboo, B., Urakami, T., Battelino, T., Hanas, R., Codner, E. WILEY. 2018: 115?35
View details for PubMedID 29999222
Psychosocial and Human Factors During a Trial of a Hybrid Closed Loop System for Type 1 Diabetes Management. Diabetes technology & therapeutics Adams, R. N., Tanenbaum, M. L., Hanes, S. J., Ambrosino, J. M., Ly, T. T., Maahs, D. M., Naranjo, D., Walders-Abramson, N., Weinzimer, S. A., Buckingham, B. A., Hood, K. K. 2018
Abstract

BACKGROUND: Hybrid closed loop (HCL) systems are designed to automate insulin delivery to improve type 1 diabetes (T1D) outcomes and reduce user burden and distress. Because the systems only automate some aspects of diabetes care, psychosocial and human factors remain an important consideration in their use. Thus, we examined whether psychosocial and human factors (i.e., distress related to diabetes management, fear of hypoglycemia, and technology attitudes) would (1) change after using the system and (2) predict glycemic outcomes during the trial.SUBJECTS AND METHODS: Fourteen adults and 15 adolescents with T1D participated in a multisite clinical trial of an investigational version of the MiniMed 670G system (Medtronic, Northridge, CA) over 4 to 5 days in a semisupervised outpatient setting. Users completed surveys assessing psychosocial and human factors before beginning the HCL system and at the conclusion of the study. t-Tests and regression analyses were conducted to examine whether these factors changed following trial exposure to the HCL system and predicted glycemic outcomes during the trial.RESULTS: Diabetes management distress decreased and diabetes technology attitudes became more positive over the trial period. Fear of hypoglycemia did not change over the trial period. There was a trend toward greater pretrial management distress predicting less time in range during the trial, controlling for time in range before the trial.CONCLUSIONS: Results suggest that this system is promising for enhancing technology attitudes and reducing management distress. Psychosocial factors, such as management distress, may negatively impact glycemic outcomes and should be a priority area for further investigation.

View details for PubMedID 30239219
Psychosocial and Human Factors During a Trial of a Hybrid Closed Loop System for Type 1 Diabetes Management DIABETES TECHNOLOGY & THERAPEUTICS Adams, R. N., Tanenbaum, M. L., Hanes, S. J., Ambrosino, J. M., Ly, T. T., Maahs, D. M., Naranjo, D., Walders-Abramson, N., Weinzimer, S. A., Buckingham, B. A., Hood, K. K. 2018; 20 (10): 648?53
View details for DOI 10.1089/dia.2018.0174

View details for Web of Science ID 000445347300001
Performance of the Omnipod Personalized Model Predictive Control Algorithm with Meal Bolus Challenges in Adults with Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B. A., Christiansen, M. P., Forlenza, G. P., Wadwa, R., Peyser, T. A., Lee, J., O'Connor, J., Dassau, E., Huyett, L. M., Layne, J. E., Ly, T. T. 2018; 20 (9): 585?95
View details for DOI 10.1089/dia.2018.0138

View details for Web of Science ID 000442600400003
Performance of the Omnipod Personalized Model Predictive Control Algorithm with Meal Bolus Challenges in Adults with Type 1 Diabetes. Diabetes technology & therapeutics Buckingham, B. A., Christiansen, M. P., Forlenza, G. P., Wadwa, R. P., Peyser, T. A., Lee, J. B., O'Connor, J., Dassau, E., Huyett, L. M., Layne, J. E., Ly, T. T. 2018
Abstract

BACKGROUND: This study assessed the safety and performance of the Omnipod personalized model predictive control (MPC) algorithm using an investigational device in adults with type 1 diabetes in response to overestimated and missed meal boluses and extended boluses for high-fat meals.MATERIALS AND METHODS: A supervised 54-h hybrid closed-loop (HCL) study was conducted in a hotel setting after a 7-day outpatient open-loop run-in phase. Adults aged 18-65 years with type 1 diabetes and HbA1c 6.0%-10.0% were eligible. Primary endpoints were percentage time in hypoglycemia <70mg/dL and hyperglycemia ?250mg/dL. Glycemic responses for 4h to a 130% overestimated bolus and a missed meal bolus were compared with a 100% bolus for identical meals, respectively. The 12-h postprandial responses to a high-fat meal were compared using either a standard or extended bolus.RESULTS: Twelve subjects participated in the study, with (mean�standard deviation): age 35.4�14.1 years, diabetes duration 16.5�9.3 years, HbA1c 7.7�0.9%, and total daily dose 0.58�0.19U/kg. Outcomes for the 54-h HCL period were mean glucose 153�15mg/dL, percentage time <70mg/dL [median (interquartile range)]: 0.0% (0.0-1.2%), 70-180mg/dL: 76.1%�8.0%, and ?250mg/dL: 4.5%�3.6%. After both the 100% and 130% boluses, postprandial percentage time <70mg/dL was 0.0% (0.0-0.0%) (P=0.50). After the 100% and missed boluses, postprandial percentage time ?250mg/dL was 0.2%�0.6% and 10.3%�16.5%, respectively (P=0.06). Postprandial percentages time ?250 mg/dL and <70mg/dL were similar with standard or extended boluses for a high-fat meal.CONCLUSIONS: The Omnipod personalized MPC algorithm performed well and was safe during day and night use in response to overestimated, missed, and extended meal boluses in adults with type 1 diabetes.

View details for PubMedID 30070928
Sustained Continuous Glucose Monitor Use in Low-Income Youth with Type 1 Diabetes Following Insurance Coverage Supports Expansion of Continuous Glucose Monitor Coverage for All. Diabetes technology & therapeutics Prahalad, P., Addala, A., Buckingham, B., Wilson, D. M., Maahs, D. M. 2018
View details for PubMedID 30020810
Sustained Continuous Glucose Monitor Use in Low-Income Youth with Type 1 Diabetes Following Insurance Coverage Supports Expansion of Continuous Glucose Monitor Coverage for All DIABETES TECHNOLOGY & THERAPEUTICS Prahalad, P., Addala, A., Buckingham, B., Wilson, D. M., Maahs, D. M. 2018; 20 (9): 632?34
View details for DOI 10.1089/dia.2018.0204

View details for Web of Science ID 000439550100001
Persistence of abnormalities in white matter in children with type 1 diabetes DIABETOLOGIA Fox, L. A., Hershey, T., Mauras, N., Arbelaez, A., Tamborlane, W. V., Buckingham, B., Tsalikian, E., Englert, K., Raman, M., Jo, B., Shen, H., Reiss, A., Mazaika, P., Diabet Res Children Network Direct 2018; 61 (7): 1538?47
Abstract

Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes.One hundred and eighteen children, aged 4 to <10�years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18�months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA1c levels were obtained every 3�months.Axial diffusivity was lower in children with diabetes at baseline (p?=?0.022) and at 18�months (p?=?0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p?=?0.037). Fractional anisotropy was positively correlated with performance (p?
View details for PubMedID 29654376

View details for PubMedCentralID PMC5991628
A Feasibility Study to Detect Neonatal Hypoglycemia Using Real-Time Continuous Glucose Monitoring Nally, L. M., Bondy, N. W., Doiev, J., Buckingham, B., Wilson, D. AMER DIABETES ASSOC. 2018
View details for DOI 10.2337/db18-906-P

View details for Web of Science ID 000462825102177
Large Changes in Brain Volume Observed in an Asymptomatic Young Child With Type 1 Diabetes DIABETES CARE Mazaika, P. K., Aye, T., Reiss, A. L., Buckingham, B. A. 2018; 41 (7): 1535?37
View details for DOI 10.2337/dc17-2503

View details for Web of Science ID 000435926000040
Advances in Care for Insulin-Requiring Patients Without Closed Loop. Diabetes technology & therapeutics Lal, R. A., Buckingham, B., Maahs, D. M. 2018; 20 (S2): S285?S291
View details for PubMedID 29916743
Advances in Care for Insulin-Requiring Patients Without Closed Loop DIABETES TECHNOLOGY & THERAPEUTICS Lal, R. A., Buckingham, B., Maahs, D. M. 2018; 20: 85?91
View details for DOI 10.1089/dia.2018.0084

View details for Web of Science ID 000435570300012
Need for Regulatory Change to Incorporate Beyond A1C Glycemic Metrics DIABETES CARE Alexander, C. M., Amiel, S., Beck, R., Bergenstal, R. M., Bloomgarden, Z., Brown, A., Buckingham, B., Cefalu, W. T., Close, K. L., Chin, I., Danne, T., DeSalvo, D., Dickinson, J. K., Fitts, E., Frier, B., Gabbay, R. A., Grunberger, G., Hirsch, I., Home, P., Kowalski, A., Laffel, L., McCall, A., Parkin, C. G., Peters, A. L., Ratner, R., Van der Schueren, B., Wood, R., Beyond A1C Writing Grp 2018; 41 (6): E92?E94
View details for DOI 10.2337/dci18-0010

View details for Web of Science ID 000432673000005

View details for PubMedID 29784704
Predictive hyperglycemia and hypoglycemia minimization: In-home double-blind randomized controlled evaluation in children and young adolescents PEDIATRIC DIABETES Forlenza, G. P., Raghinaru, D., Cameron, F., Bequette, B., Chase, H., Wadwa, R., Maahs, D. M., Jost, E., Ly, T. T., Wilson, D. M., Norlander, L., Ekhlaspour, L., Min, H., Clinton, P., Njeru, N., Lum, J. W., Kollman, C., Beck, R. W., Buckingham, B. A., In-Home Closed-Loop IHCL Study Grp 2018; 19 (3): 420?28
Abstract

The primary objective of this trial was to evaluate the feasibility, safety, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system vs predictive low glucose suspension (PLGS) alone in optimizing overnight glucose control in children 6 to 14 years old.Twenty-eight participants 6 to 14 years old with T1D duration ?1?year with daily insulin therapy ?12 months and on insulin pump therapy for ?6?months were randomized per night into PHHM mode or PLGS-only mode for 42 nights. The primary outcome was percentage of time in sensor-measured range 70 to 180?mg/dL in the overnight period.The addition of automated insulin delivery with PHHM increased time in target range (70-180?mg/dL) from 66?�?11% during PLGS nights to 76?�?9% during PHHM nights (P<.001), without increasing hypoglycemia as measured by time below various thresholds. Average morning blood glucose improved from 176?�?28?mg/dL following PLGS nights to 154?�?19?mg/dL following PHHM nights (P<.001).The PHHM system was effective in optimizing overnight glycemic control, significantly increasing time in range, lowering mean glucose, and decreasing glycemic variability compared to PLGS alone in children 6 to 14 years old.

View details for PubMedID 29159870
Fully Closed-Loop Multiple Model Probabilistic Predictive Controller Artificial Pancreas Performance in Adolescents and Adults in a Supervised Hotel Setting DIABETES TECHNOLOGY & THERAPEUTICS Forlenza, G. P., Cameron, F. M., Ly, T. T., Lam, D., Howsmon, D. P., Baysal, N., Kulina, G., Messer, L., Clinton, P., Levister, C., Patek, S. D., Levy, C. J., Wadwa, R., Maahs, D. M., Bequette, B., Buckingham, B. A. 2018; 20 (5): 335?43
Abstract

Initial Food and Drug Administration-approved artificial pancreas (AP) systems will be hybrid closed-loop systems that require prandial meal announcements and will not eliminate the burden of premeal insulin dosing. Multiple model probabilistic predictive control (MMPPC) is a fully closed-loop system that uses probabilistic estimation of meals to allow for automated meal detection. In this study, we describe the safety and performance of the MMPPC system with announced and unannounced meals in a supervised hotel setting.The Android phone-based AP system with remote monitoring was tested for 72?h in six adults and four adolescents across three clinical sites with daily exercise and meal challenges involving both three announced (manual bolus by patient) and six unannounced (no bolus by patient) meals. Safety criteria were predefined. Controller aggressiveness was adapted daily based on prior hypoglycemic events.Mean 24-h continuous glucose monitor (CGM) was 157.4?�?14.4?mg/dL, with 63.6?�?9.2% of readings between 70 and 180?mg/dL, 2.9?�?2.3% of readings <70?mg/dL, and 9.0?�?3.9% of readings >250?mg/dL. Moderate hyperglycemia was relatively common with 24.6?�?6.2% of readings between 180 and 250?mg/dL, primarily within 3?h after a meal. Overnight mean CGM was 139.6?�?27.6?mg/dL, with 77.9?�?16.4% between 70 and 180?mg/dL, 3.0?�?4.5% <70?mg/dL, 17.1?�?14.9% between 180 and 250?mg/dL, and 2.0?�?4.5%> 250?mg/dL. Postprandial hyperglycemia was more common for unannounced meals compared with announced meals (4-h postmeal CGM 197.8?�?44.1 vs. 140.6?�?35.0?mg/dL; P?
View details for PubMedID 29658779

View details for PubMedCentralID PMC5963546
Glucose sensor-augmented continuous subcutaneous insulin infusion in patients with diabetic gastroparesis: An open-label pilot prospective study PLOS ONE Calles-Escandon, J., Koch, K. L., Hasler, W. L., Van Natta, M. L., Pasricha, P. J., Tonascia, J., Parkman, H. P., Hamilton, F., Herman, W. H., Basina, M., Buckingham, B., Earle, K., Kirkeby, K., Hairston, K., Bright, T., Rothberg, A. E., Kraftson, A. T., Siraj, E. S., Subauste, A., Lee, L. A., Abell, T. L., McCallum, R. W., Sarosiek, I., Nguyen, L., Fass, R., Snape, W. J., Vaughn, I. A., Miriel, L. A., Farrugia, G., NIDDK Gastroparesis Clinical Re 2018; 13 (4): e0194759
Abstract

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85-1.64, P = 0.33). CGM time in hypoglycemia (<70 mg/dL) decreased from 3.9% to 1.8% (P<0.0001), time in euglycemia (70-180 mg/dL) increased from 44.0% to 52.0% (P = 0.02), time in severe hyperglycemia (>300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4�1.4% to 8.3�1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3�7.1 to 21.9�10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P?0.001). Quality-of-life scores improved from 2.4�1.1 to 3.1�1.1 (P<0.0001) and volumes of liquid nutrient meals tolerated increased from 420�258 to 487�312 mL (P = 0.05) at 24 weeks. In conclusion, CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis.

View details for PubMedID 29652893
HUMAN FACTORS DURING TRIAL OF A HYBRID CLOSED LOOP SYSTEM FOR TYPE 1 DIABETES MANAGEMENT Adams, R. N., Tanenbaum, M. L., Hanes, S. J., Ambrosino, J. M., Ly, T. T., Maahs, D. M., Naranjo, D., Walders-Abramson, N., Weinzimer, S. A., Buckingham, B. A., Hood, K. K. OXFORD UNIV PRESS INC. 2018: S718
View details for Web of Science ID 000431185202153
Safety and Feasibility of the OmniPod Hybrid Closed-Loop System in Adult, Adolescent, and Pediatric Patients with Type 1 Diabetes Using a Personalized Model Predictive Control Algorithm DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B. A., Forlenza, G. P., Pinsker, J. E., Christiansen, M. P., Wadwa, R., Schneider, J., Peyser, T. A., Dassau, E., Lee, J., O'Connor, J., Layne, J. E., Ly, T. T. 2018; 20 (4): 257?62
Abstract

The safety and feasibility of the OmniPod personalized model predictive control (MPC) algorithm in adult, adolescent, and pediatric patients with type 1 diabetes were investigated.This multicenter, observational trial included a 1-week outpatient sensor-augmented pump open-loop phase and a 36-h inpatient hybrid closed-loop (HCL) phase with announced meals ranging from 30 to 90?g of carbohydrates and limited physical activity. Patients aged 6-65 years with HbA1c between 6.0% and 10.0% were eligible. The investigational system included a modified version of OmniPod, the Dexcom G4 505 Share� AP System, and the personalized MPC algorithm running on a tablet computer. Primary endpoints included sensor glucose percentage of time in hypoglycemia <70?mg/dL and hyperglycemia >250?mg/dL. Additional glycemic targets were assessed.The percentage of time <70?mg/dL during the 36-h HCL phase was mean (standard deviation): 0.7 (1.7) in adults receiving 80% meal bolus (n?=?24), and 0.7 (1.2) in adults (n?=?10), 2.0 (2.4) in adolescents (n?=?12), and 2.0 (2.6) in pediatrics (n?=?12) receiving 100% meal bolus. The overall hypoglycemia rate was 0.49 events/24?h. The percentage of time >250?mg/dL was 8.0 (7.5), 3.6 (3.7), 4.9 (6.3), and 6.7 (5.6) in the study groups, respectively. Percentage of time in the target range of 70-180?mg/dL was 69.5 (14.4), 73.0 (15.0), 72.6 (15.5), and 70.1 (12.3), respectively.The OmniPod personalized MPC algorithm performed well and was safe during day and night use in adult, adolescent, and pediatric patients with type 1 diabetes. Longer term studies will assess the safety and performance of the algorithm under free living conditions with extended use.

View details for DOI 10.1089/dia.2017.0346

View details for Web of Science ID 000424848600001

View details for PubMedID 29431513

View details for PubMedCentralID PMC5910038
The dawn of automated insulin delivery: A new clinical framework to conceptualize insulin administration PEDIATRIC DIABETES Messer, L. H., Forlenza, G. P., Wadwa, R., Weinzimer, S. A., Sherr, J. L., Hood, K. K., Buckingham, B. A., Slover, R. H., Maahs, D. M. 2018; 19 (1): 14?17
View details for PubMedID 28656656
Overnight Hypoglycemia and Hyperglycemia Mitigation for Individuals with Type 1 Diabetes HOW RISKS CAN BE REDUCED IEEE CONTROL SYSTEMS MAGAZINE Bequette, B., Cameron, F., Buckingham, B. A., Maahs, D. M., Lum, J. 2018; 38 (1): 125?34
View details for DOI 10.1109/MCS.2017.2767119

View details for Web of Science ID 000423203300013
Large Changes in Brain Volume Observed in an Asymptomatic Young Child With Type 1 Diabetes. Diabetes care Mazaika, P. K., Aye, T., Reiss, A. L., Buckingham, B. A. 2018; 41 (7): 1535?37
View details for PubMedID 29934482
Impact of Early Diabetic Ketoacidosis on the Developing Brain. Diabetes care Aye, T., Mazaika, P. K., Mauras, N., Marzelli, M. J., Shen, H., Hershey, T., Cato, A., Weinzimer, S. A., White, N. H., Tsalikian, E., Jo, B., Reiss, A. L. 2018
Abstract

This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes.Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to <10 years, who participated in an observational study of the Diabetes Research in Children Network (DirecNet). Participants were grouped according to history of DKA severity (none/mild or moderate/severe). Each participant had unsedated MRI scans and cognitive testing at baseline and 18 months.In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants who had a history of moderate/severe DKA compared with none/mild DKA were observed to have significantly lower Full Scale Intelligence Quotient scores, cognitive performance on the Detectability and Commission subtests of the Conners' Continuous Performance Test II, and the Dot Locations subtest of the Children's Memory Scale.A single episode of moderate/severe DKA in young children at diagnosis is associated with lower cognitive scores and altered brain growth. Further studies are needed to assess whether earlier diagnosis of type 1 diabetes and prevention of DKA may reduce the long-term effect of ketoacidosis on the developing brain.

View details for DOI 10.2337/dc18-1405

View details for PubMedID 30573652
Glycemic Variability Percentage: A Novel Method for Assessing Glycemic Variability from Continuous Glucose Monitor Data DIABETES TECHNOLOGY & THERAPEUTICS Peyser, T. A., Balo, A. K., Buckingham, B. A., Hirsch, I. B., Garcia, A. 2018; 20 (1): 6?16
Abstract

High levels of glycemic variability are still observed in most patients with diabetes with severe insulin deficiency. Glycemic variability may be an important risk factor for acute and chronic complications. Despite its clinical importance, there is no consensus on the optimum method for characterizing glycemic variability.We developed a simple new metric, the glycemic variability percentage (GVP), to assess glycemic variability by analyzing the length of the continuous glucose monitoring (CGM) temporal trace normalized to the duration under evaluation. The GVP is similar to other recently proposed glycemic variability metrics, the distance traveled, and the mean absolute glucose (MAG) change. We compared results from distance traveled, MAG, GVP, standard deviation (SD), and coefficient of variation (CV) applied to simulated CGM traces accentuating the difference between amplitude and frequency of oscillations. The GVP metric was also applied to data from clinical studies for the Dexcom G4 Platinum CGM in subjects without diabetes, with type 2 diabetes, and with type 1 diabetes (adults, adolescents, and children).In contrast to other metrics, such as CV and SD, the distance traveled, MAG, and GVP all captured both the amplitude and frequency of glucose oscillations. The GVP metric was also able to differentiate between diabetic and nondiabetic subjects and between subjects with diabetes with low, moderate, and high glycemic variability based on interquartile analysis.A new metric for the assessment of glycemic variability has been shown to capture glycemic variability due to fluctuations in both the amplitude and frequency of glucose given by CGM data.

View details for PubMedID 29227755

View details for PubMedCentralID PMC5846572
Real-Time Detection of Infusion Site Failures in a Closed-Loop Artificial Pancreas. Journal of diabetes science and technology Howsmon, D. P., Baysal, N., Buckingham, B. A., Forlenza, G. P., Ly, T. T., Maahs, D. M., Marcal, T., Towers, L., Mauritzen, E., Deshpande, S., Huyett, L. M., Pinsker, J. E., Gondhalekar, R., Doyle, F. J., Dassau, E., Hahn, J., Bequette, B. W. 2018; 12 (3): 599?607
Abstract

BACKGROUND: As evidence emerges that artificial pancreas systems improve clinical outcomes for patients with type 1 diabetes, the burden of this disease will hopefully begin to be alleviated for many patients and caregivers. However, reliance on automated insulin delivery potentially means patients will be slower to act when devices stop functioning appropriately. One such scenario involves an insulin infusion site failure, where the insulin that is recorded as delivered fails to affect the patient's glucose as expected. Alerting patients to these events in real time would potentially reduce hyperglycemia and ketosis associated with infusion site failures.METHODS: An infusion site failure detection algorithm was deployed in a randomized crossover study with artificial pancreas and sensor-augmented pump arms in an outpatient setting. Each arm lasted two weeks. Nineteen participants wore infusion sets for up to 7 days. Clinicians contacted patients to confirm infusion site failures detected by the algorithm and instructed on set replacement if failure was confirmed.RESULTS: In real time and under zone model predictive control, the infusion site failure detection algorithm achieved a sensitivity of 88.0% (n = 25) while issuing only 0.22 false positives per day, compared with a sensitivity of 73.3% (n = 15) and 0.27 false positives per day in the SAP arm (as indicated by retrospective analysis). No association between intervention strategy and duration of infusion sets was observed ( P = .58).CONCLUSIONS: As patient burden is reduced by each generation of advanced diabetes technology, fault detection algorithms will help ensure that patients are alerted when they need to manually intervene. Clinical Trial Identifier: www.clinicaltrials.gov,NCT02773875.

View details for PubMedID 29390915
Optimizing Hybrid Closed-Loop Therapy in Adolescents and Emerging Adults Using the MiniMed 670G System. Diabetes care Messer, L. H., Forlenza, G. P., Sherr, J. L., Wadwa, R. P., Buckingham, B. A., Weinzimer, S. A., Maahs, D. M., Slover, R. H. 2018; 41 (4): 789?96
Abstract

The MiniMed 670G System is the first commercial hybrid closed-loop (HCL) system for management of type 1 diabetes. Using data from adolescent and young adult participants, we compared insulin delivery patterns and time-in-range metrics in HCL (Auto Mode) and open loop (OL). System alerts, usage profiles, and operational parameters were examined to provide suggestions for optimal clinical use of the system.Data from 31 adolescent and young adult participants (14-26 years old) at three clinical sites in the 670G pivotal trial were analyzed. Participants had a 2-week run-in period in OL, followed by a 3-month in-home study phase with HCL functionality enabled. Data were compared between baseline OL and HCL use after 1 week, 1 month, 2 months, and 3 months.Carbohydrate-to-insulin (C-to-I) ratios were more aggressive for all meals with HCL compared with baseline OL. Total daily insulin dose and basal-to-bolus ratio did not change during the trial. Time in range increased 14% with use of Auto Mode after 3 months (P< 0.001), and HbA1cdecreased 0.75%. Auto Mode exits were primarily due to sensor/insulin delivery alerts and hyperglycemia. The percentage of time in Auto Mode gradually declined from 87%, with a final use rate of 72% (-15%).In transitioning young patients to the 670G system, providers should anticipate immediate C-to-I ratio adjustments while also assessing active insulin time. Users should anticipate occasional Auto Mode exits, which can be reduced by following system instructions and reliably bolusing for meals. Unique 670G system functionality requires ongoing clinical guidance and education from providers.

View details for PubMedID 29444895
A Practical Approach to Using Trend Arrows on the Dexcom G5 CGM System to Manage Children and Adolescents With Diabetes JOURNAL OF THE ENDOCRINE SOCIETY Laffel, L. M., Aleppo, G., Buckingham, B. A., Forlenza, G. P., Rasbach, L. E., Tsalikian, E., Weinzimer, S. A., Harris, D. R. 2017; 1 (12): 1461?76
Abstract

After assessing previously published methods, we developed a practical approach to adjusting insulin doses using rtCGM trend arrows in pediatric patients with diabetes.

View details for PubMedID 29344578
Application of Glycemic Variability Percentage: Implications for Continuous Glucose Monitor Utilization and Analysis of Artificial Pancreas Data DIABETES TECHNOLOGY & THERAPEUTICS Garcia, A., Balo, A. K., Buckingham, B. A., Hirsch, I. B., Peyser, T. A. 2017; 19 (12): 699?706
View details for DOI 10.1089/dia.2017.0188

View details for Web of Science ID 000418152000002
Trust in hybrid closed loop among people with diabetes: Perspectives of experienced system users. Journal of health psychology Tanenbaum, M. L., Iturralde, E., Hanes, S. J., Suttiratana, S. C., Ambrosino, J. M., Ly, T. T., Maahs, D. M., Naranjo, D., Walders-Abramson, N., Weinzimer, S. A., Buckingham, B. A., Hood, K. K. 2017: 1359105317718615
Abstract

Automated closed loop systems will greatly change type 1 diabetes management; user trust will be essential for acceptance of this new technology. This qualitative study explored trust in 32 individuals following a hybrid closed loop trial. Participants described how context-, system-, and person-level factors influenced their trust in the system. Participants attempted to override the system when they lacked trust, while trusting the system decreased self-management burdens and decreased stress. Findings highlight considerations for fostering trust in closed loop systems. Systems may be able to engage users by offering varying levels of controls to match trust preferences.

View details for PubMedID 28810490
Application of Zone Model Predictive Control Artificial Pancreas During Extended Use of Infusion Set and Sensor: A Randomized Crossover-Controlled Home-Use Trial. Diabetes care Forlenza, G. P., Deshpande, S., Ly, T. T., Howsmon, D. P., Cameron, F., Baysal, N., Mauritzen, E., Marcal, T., Towers, L., Bequette, B. W., Huyett, L. M., Pinsker, J. E., Gondhalekar, R., Doyle, F. J., Maahs, D. M., Buckingham, B. A., Dassau, E. 2017
Abstract

As artificial pancreas (AP) becomes standard of care, consideration of extended use of insulin infusion sets (IIS) and continuous glucose monitors (CGMs) becomes vital. We conducted an outpatient randomized crossover study to test the safety and efficacy of a zone model predictive control (zone-MPC)-based AP system versus sensor augmented pump (SAP) therapy in which IIS and CGM failures were provoked via extended wear to 7 and 21 days, respectively.A smartphone-based AP system was used by 19 adults (median age 23 years [IQR 10], mean 8.0 � 1.7% HbA1c) over 2 weeks and compared with SAP therapy for 2 weeks in a crossover, unblinded outpatient study with remote monitoring in both study arms.AP improved percent time 70-140 mg/dL (48.1 vs. 39.2%; P = 0.016) and time 70-180 mg/dL (71.6 vs. 65.2%; P = 0.008) and decreased median glucose (141 vs. 153 mg/dL; P = 0.036) and glycemic variability (SD 52 vs. 55 mg/dL; P = 0.044) while decreasing percent time <70 mg/dL (1.3 vs. 2.7%; P = 0.001). AP also improved overnight control, as measured by mean glucose at 0600 h (140 vs. 158 mg/dL; P = 0.02). IIS failures (1.26 � 1.44 vs. 0.78 � 0.78 events; P = 0.13) and sensor failures (0.84 � 0.6 vs. 1.1 � 0.73 events; P = 0.25) were similar between AP and SAP arms. Higher percent time in closed loop was associated with better glycemic outcomes.Zone-MPC significantly and safely improved glycemic control in a home-use environment despite prolonged CGM and IIS wear. This project represents the first home-use AP study attempting to provoke and detect component failure while successfully maintaining safety and effective glucose control.

View details for DOI 10.2337/dc17-0500

View details for PubMedID 28584075
A Simple Composite Metric for the Assessment of Glycemic Status from Continuous Glucose Monitoring Data: Implications for Clinical Practice and the Artificial Pancreas DIABETES TECHNOLOGY & THERAPEUTICS Hirsch, I. B., Balo, A. K., Sayer, K., Garcia, A., Buckingham, B. A., Peyser, T. A. 2017; 19: S38?S48
Abstract

The potential clinical benefits of continuous glucose monitoring (CGM) have been recognized for many years, but CGM is used by a small fraction of patients with diabetes. One obstacle to greater use of the technology is the lack of simplified tools for assessing glycemic control from CGM data without complicated visual displays of data.We developed a simple new metric, the personal glycemic state (PGS), to assess glycemic control solely from continuous glucose monitoring data. PGS is a composite index that assesses four domains of glycemic control: mean glucose, glycemic variability, time in range and frequency and severity of hypoglycemia. The metric was applied to data from six clinical studies for the G4 Platinum continuous glucose monitoring system (Dexcom, San Diego, CA). The PGS was also applied to data from a study of artificial pancreas comparing results from open loop and closed loop in adolescents and in adults.The new metric for glycemic control, PGS, was able to characterize the quality of glycemic control in a wide range of study subjects with various mean glucose, minimal, moderate, and excessive glycemic variability and subjects on open loop versus closed loop control.A new composite metric for the assessment of glycemic control based on CGM data has been defined for use in assessing glycemic control in clinical practice and research settings. The new metric may help rapidly identify problems in glycemic control and may assist with optimizing diabetes therapy during time-constrained physician office visits.

View details for PubMedID 28585873

View details for PubMedCentralID PMC5467104
Outpatient Closed-Loop Control with Unannounced Moderate Exercise in Adolescents Using Zone Model Predictive Control. Diabetes technology & therapeutics Huyett, L. M., Ly, T. T., Forlenza, G. P., Reuschel-DiVirgilio, S., Messer, L. H., Wadwa, R. P., Gondhalekar, R., Doyle, F. J., Pinsker, J. E., Maahs, D. M., Buckingham, B. A., Dassau, E. 2017
Abstract

The artificial pancreas (AP) has the potential to improve glycemic control in adolescents. This article presents the first evaluation in adolescents of the Zone Model Predictive Control and Health Monitoring System (ZMPC+HMS) AP algorithms, and their first evaluation in a supervised outpatient setting with frequent exercise.Adolescents with type 1 diabetes underwent 3 days of closed-loop control (CLC) in a hotel setting with the ZMPC+HMS algorithms on the Diabetes Assistant platform. Subjects engaged in twice-daily exercise, including soccer, tennis, and bicycling. Meal size (unrestricted) was estimated and entered into the system by subjects to trigger a bolus, but exercise was not announced.Ten adolescents (11.9-17.7 years) completed 72?h of CLC, with data on 95?�?14?h of sensor-augmented pump (SAP) therapy before CLC as a comparison to usual therapy. The percentage of time with continuous glucose monitor (CGM) 70-180?mg/dL was 71%?�?10% during CLC, compared to 57%?�?16% during SAP (P?=?0.012). Nocturnal control during CLC was safe, with 0% (0%, 0.6%) of time with CGM <70?mg/dL compared to 1.1% (0.0%, 14%) during SAP. Despite large meals (estimated up to 120?g carbohydrate), only 8.0%?�?6.9% of time during CLC was spent with CGM >250?mg/dL (16%?�?14% during SAP). The system remained connected in CLC for 97%?�?2% of the total study time. No adverse events or severe hypoglycemia occurred.The use of the ZMPC+HMS algorithms is feasible in the adolescent outpatient environment and achieved significantly more time in the desired glycemic range than SAP in the face of unannounced exercise and large announced meal challenges.

View details for DOI 10.1089/dia.2016.0399

View details for PubMedID 28459617
Pivotal Trial of a Hybrid-Closed Loop System in Type 1 Dabetes Burkett, L., Lee, S. W., Shin, J., Kaufman, F. R., Buckingham, B. A., Slover, R., Weinzimer, S. ELSEVIER SCIENCE INC. 2017: 106
View details for DOI 10.1016/j.pedn.2017.02.023

View details for Web of Science ID 000403734400034
Stabilization of glycemic control and improved quality of life using a shared medical appointment model in adolescents with type 1 diabetes in suboptimal control PEDIATRIC DIABETES Floyd, B. D., Block, J. M., Buckingham, B. B., Ly, T., Foster, N., Wright, R., Mueller, C. L., Hood, K. K., Shah, A. C. 2017; 18 (3): 204-212
Abstract

Declining glycemic control in type 1 diabetes (T1D) during adolescence persists despite treatment advances. Non-adherence, peer relations, diabetes burnout, risk taking, transition to autonomy, family conflict, and poor quality of life (QOL) are recognized barriers. Shared medical appointments (SMAs) in adolescent T1D may offer benefits, but data are limited. Our objective was to determine whether SMAs, with multi-component interventions utilizing multidisciplinary teams, improve glycemic control and psychosocial outcomes in poorly controlled adolescent T1D.SMAs focused on self-management, communication skills, goal setting, glucose pattern recognition, and peer/diabetes team support. SMAs included: individual history and physical, labs, surveys, multidisciplinary educational ice breakers, group session, and individual wrap up. Outcomes were QOL, adherence, and retrospective and prospective glycemic control. Three to six subjects and families came to 3 SMAs and 1 individual appointment every 3 months over 9 months.A total of 37 English speaking subjects, ages 12-16?yrs, with T1D ? 1 year, and hemoglobin A1c (HbA1c) 7.5-11% enrolled. Thirty-two subjects attended 75% of visits, meeting inclusion criteria.HbA1c worsened in the 9 months before study (?HbA1c= 0.7?�?1.2; p??0.05). There were significant improvements in overall QOL (p?=?0.005), school function (p?=?0.006), psychosocial function (p?=?0.008), barriers (p?=?0.02), adherence (p?=?0.01), and communication (p?=?0.02). Improvements in school function and communication reached clinical significance.SMAs are feasible replacements to individual appointments in adolescent T1D, stabilizing glycemic control and improving QOL. Randomized controlled trials with optimizations are needed to further explore and refine this intervention.

View details for DOI 10.1111/pedi.12373

View details for Web of Science ID 000399353400005
Expectations and Attitudes of Individuals With Type 1 Diabetes After Using a Hybrid Closed Loop System DIABETES EDUCATOR Iturralde, E., Tanenbaum, M. L., Hanes, S. J., Suttiratana, S. C., Ambrosino, J. M., Ly, T. T., Maahs, D. M., Naranjo, D., Walders-Abramson, N., Weinzimer, S. A., Buckingham, B. A., Hood, K. K. 2017; 43 (2): 223-232
Abstract

Purpose The first hybrid closed loop (HCL) system, which automates insulin delivery but requires user inputs, was approved for treatment of type 1 diabetes (T1D) by the US Food and Drug Administration in September 2016. The purpose of this study was to explore the benefits, expectations, and attitudes of individuals with T1D following a clinical trial of an HCL system. Methods Thirty-two individuals with T1D (17 adults, 15 adolescents) participated in focus groups after 4 to 5 days of system use. Content analysis generated themes regarding perceived benefits, hassles, and limitations. Results Some participants felt misled by terms such as "closed loop" and "artificial pancreas," which seemed to imply a more "hands-off" experience. Perceived benefits were improved glycemic control, anticipated reduction of long-term complications, better quality of life, and reduced mental burden of diabetes. Hassles and limitations included unexpected tasks for the user, difficulties wearing the system, concerns about controlling highs, and being reminded of diabetes. Conclusion Users are willing to accept some hassles and limitations if they also perceive health and quality-of-life benefits beyond current self-management. It is important for clinicians to provide a balanced view of positives and negatives to help manage expectations.

View details for DOI 10.1177/0145721717697244

View details for PubMedID 28340542
Predictive Hyperglycemia and Hypoglycemia Minimization: In-Home Evaluation of Safety, Feasibility, and Efficacy in Overnight Glucose Control in Type 1 Diabetes. Diabetes care Spaic, T., Driscoll, M., Raghinaru, D., Buckingham, B. A., Wilson, D. M., Clinton, P., Chase, H. P., Maahs, D. M., Forlenza, G. P., Jost, E., Hramiak, I., Paul, T., Bequette, B. W., Cameron, F., Beck, R. W., Kollman, C., Lum, J. W., Ly, T. T. 2017; 40 (3): 359-366
Abstract

The objective of this study was to determine the safety, feasibility, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system compared with predictive low-glucose insulin suspension (PLGS) alone in overnight glucose control.A 42-night trial was conducted in 30 individuals with type 1 diabetes in the age range 15-45 years. Participants were randomly assigned each night to either PHHM or PLGS and were blinded to the assignment. The system suspended the insulin pump on both the PHHM and PLGS nights for predicted hypoglycemia but delivered correction boluses for predicted hyperglycemia on PHHM nights only. The primary outcome was the percentage of time spent in a sensor glucose range of 70-180 mg/dL during the overnight period.The addition of automated insulin delivery with PHHM increased the time spent in the target range (70-180 mg/dL) from 71 � 10% during PLGS nights to 78 � 10% during PHHM nights (P < 0.001). The average morning blood glucose concentration improved from 163 � 23 mg/dL after PLGS nights to 142 � 18 mg/dL after PHHM nights (P < 0.001). Various sensor-measured hypoglycemic outcomes were similar on PLGS and PHHM nights. All participants completed 42 nights with no episodes of severe hypoglycemia, diabetic ketoacidosis, or other study- or device-related adverse events.The addition of a predictive hyperglycemia minimization component to our existing PLGS system was shown to be safe, feasible, and effective in overnight glucose control.

View details for DOI 10.2337/dc16-1794

View details for PubMedID 28100606
Compensatory Hyperconnectivity in Developing Brains of Young Children With Type 1 Diabetes DIABETES Saggar, M., Tsalikian, E., Mauras, N., Mazaika, P., White, N. H., Weinzimer, S., Buckingham, B., Hershey, T., Reiss, A. L. 2017; 66 (3): 754-762
Abstract

Sustained dysregulation of blood glucose (hyper or hypoglycemia) associated with type 1 diabetes (T1D) has been linked to cognitive deficits and altered brain anatomy and connectivity. However, a significant gap remains with respect to how T1D affects spontaneous at-rest connectivity in young developing brains. Here, using a large multi-site study, resting state functional Magnetic Resonance Imaging (rsfMRI) data were examined in young children with T1D (N=57, mean age=7.88 years; 27F) as compared to age-matched non-diabetic controls (N=26, mean age=7.43 years; 14F). Using both model-driven seed-based analysis and model-free independent component analysis (ICA) and controlling for age, site and sex, converging results were obtained suggesting increased connectivity in young children with T1D as compared to non-diabetic controls. Further, increased connectivity in children with T1D was observed to be positively associated with cognitive functioning. The observed positive association of connectivity with cognitive functioning in T1D, without overall group differences in cognitive function, suggests a putative compensatory role of hyper-intrinsic connectivity in the brain in children with this condition. Altogether, our study attempts to fill a critical gap in knowledge regarding how dysglycemia in T1D might affect the brain's intrinsic connectivity at very young ages.

View details for DOI 10.2337/db16-0414

View details for Web of Science ID 000394634100020
Evaluation of a Predictive Low-Glucose Management System In-Clinic. Diabetes technology & therapeutics Buckingham, B. A., Bailey, T. S., Christiansen, M., Garg, S., Weinzimer, S., Bode, B., Anderson, S. M., Brazg, R., Ly, T., Kaufman, F. R. 2017
Abstract

Predictions based on continuous glucose monitoring (CGM) data are the basis for automatic suspension and resumption of insulin delivery by a predictive low-glucose management feature termed "suspend before low," which is part of the Medtronic MiniMed(�) 640G combined insulin pump and CGM system. This study assessed the safety and performance characteristics of the system in an in-clinic setting at eight sites.In-clinic standardized increases in basal insulin delivery rates were used to induce nocturnal hypoglycemia in subjects (14-75 years) with type 1 diabetes wearing the MiniMed 640G system. The "suspend before low" feature was set at 65?mg/dL, and as a result, the predictive algorithm suspended insulin delivery when the forecasted glucose was predicted to be ?85?mg/dL in 30?min (a 20?mg/dL safety buffer). Reference plasma glucose values (Yellow Springs Instruments [YSI], Yellow Springs, OH) were used to establish hypoglycemia and were defined as ?2 consecutive values ?65?mg/dL.Eighty subjects were screened. Among the 69 successful completers, 27 experienced a hypoglycemic event and 42 did not, a prevention rate of 60%. The mean (�standard deviation) YSI value at the time of pump suspension was 101?�?18.5?mg/dL, and the mean duration of the 68 "suspend before low" events was 105?�?27?min. At 120?min after the start of the pump suspension events, the mean YSI value was 102?�?34.6?mg/dL.The MiniMed 640G "suspend before low" feature prevented 60% of induced predicted hypoglycemic events without significant rebound hyperglycemia.

View details for DOI 10.1089/dia.2016.0319

View details for PubMedID 28221823
Glucose Outcomes with the In-Home Use of a Hybrid Closed-Loop Insulin Delivery System in Adolescents and Adults with Type 1 Diabetes. Diabetes technology & therapeutics Garg, S. K., Weinzimer, S. A., Tamborlane, W. V., Buckingham, B. A., Bode, B. W., Bailey, T. S., Brazg, R. L., Ilany, J., Slover, R. H., Anderson, S. M., Bergenstal, R. M., Grosman, B., Roy, A., Cordero, T. L., Shin, J., Lee, S. W., Kaufman, F. R. 2017
Abstract

The safety and effectiveness of the in-home use of a hybrid closed-loop (HCL) system that automatically increases, decreases, and suspends insulin delivery in response to continuous glucose monitoring were investigated.Adolescents (n?=?30, ages 14-21 years) and adults (n?=?94, ages 22-75 years) with type 1 diabetes participated in a multicenter (nine sites in the United States, one site in Israel) pivotal trial. The Medtronic MiniMed(�) 670G system was used during a 2-week run-in phase without HCL control, or Auto Mode, enabled (Manual Mode) and, thereafter, with Auto Mode enabled during a 3-month study phase. A supervised hotel stay (6 days/5 nights) that included a 24-h frequent blood sample testing with a reference measurement (i-STAT) occurred during the study phase.Adolescents (mean?�?standard deviation [SD] 16.5?�?2.29 years of age and 7.7?�?4.15 years of diabetes) used the system for a median 75.8% (interquartile range [IQR] 68.0%-88.4%) of the time (2977 patient-days). Adults (mean?�?SD 44.6?�?12.79 years of age and 26.4?�?12.43 years of diabetes) used the system for a median 88.0% (IQR 77.6%-92.7%) of the time (9412 patient-days). From baseline run-in to the end of study phase, adolescent and adult HbA1c levels decreased from 7.7%?�?0.8% to 7.1%?�?0.6% (P?
View details for DOI 10.1089/dia.2016.0421

View details for PubMedID 28134564
Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial LANCET El-Khatib, F. H., Balliro, C., Hillard, M. A., Magyar, K. L., Ekhlaspour, L., Sinha, M., Mondesir, D., Esmaeili, A., Hartigan, C., Thompson, M. J., Malkani, S., Lock, J. P., Harlan, D. M., Clinton, P., Frank, E., Wilson, D. M., DeSalvo, D., Norlander, L., Ly, T., Buckingham, B. A., Diner, J., Dezube, M., Young, L. A., Goley, A., Kirkman, M. S., Buse, J. B., Zheng, H., Selagamsetty, R. R., Damiano, E. R., Russell, S. J. 2017; 389 (10067): 369-380
Abstract

The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity.We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3�3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220.We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7�8 mmol/L (SD 0�6) in the bionic pancreas period versus 9�0 mmol/L (1�6) in the comparator period (difference 1�1 mmol/L, 95% CI 0�7-1�6; p<0�0001), and the mean time with CGM glucose concentration less than 3�3 mmol/L was 0�6% (0�6) in the bionic pancreas period versus 1�9% (1�7) in the comparator period (difference 1�3%, 95% CI 0�8-1�8; p<0�0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0�52 [SD 0�83]) than in the comparator period (0�05 [0�17]; difference 0�47, 95% CI 0�21-0�73; p=0�0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study.Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas.National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

View details for DOI 10.1016/S0140-6736(16)32567-3

View details for PubMedID 28007348
Application of Glycemic Variability Percentage: Implications for Continuous Glucose Monitor Utilization and Analysis of Artificial Pancreas Data. Diabetes technology & therapeutics Garcia, A., Balo, A. K., Buckingham, B. A., Hirsch, I. B., Peyser, T. A. 2017; 19 (12): 699?706
Abstract

The problem of glycemic variability has been widely acknowledged in patients with diabetes with severe insulin deficiency. In a companion article, we proposed a novel metric, the glycemic variability percentage (GVP), for assessing glycemic variability that accounts for both the amplitude and frequency of glycemic fluctuations.We applied the new metric, the GVP, to a previously reported case of a subject using an earlier generation continuous glucose monitoring (CGM) device, in which successive periods of use were associated with an apparent decrease in glycemic variability. Results were compared with histogram distributions for the rate of change of glucose as well. The GVP was also applied to data from a published study of a bihormonal artificial pancreas system comparing results from open loop and closed loop in adolescents and in adults.The GVP was able to quantify the changes in glycemic variability during successive periods of CGM use. Application of the GVP to a published study of a bihormonal artificial pancreas found an increase in glycemic variability compared with other accepted metrics which suggested a decrease in glycemic variability.The GVP may be a clinically useful tool in characterizing the change in glycemic variability in subjects using CGM devices. Compared with metrics, such as the standard deviation, that focus solely on the amplitude of oscillations, the GVP, which measures both frequency and amplitude, may also be a more useful tool in assessing the true level of glycemic variability in artificial pancreas studies.

View details for PubMedID 29243959
GLUCOSE CONTROL IN ADOLESCENTS WITH T1D DURING THE MEDTRONIC HYBRID CLOSED-LOOP PIVOTAL TRIAL Sherr, J., Weinzimer, S. A., Slover, R. H., Buckingham, B. A., Criego, A. B., Anderson, S. M., Bailey, T. S., Bode, B. W., Brazg, R. L., Garg, S. K., Ilany, J., Shin, J., Lee, S. W., Cordero, T., Kaufman, F. R. KARGER. 2017: 46?47
View details for Web of Science ID 000412595401085
Measures from Nonlinear Dynamics Reflect Glucose Current Sensor Degradation Mauritzen, E., Mandell, A., Tallman, D., Buckingham, B., In, Longhini, P., Palacios, A. SPRINGER INTERNATIONAL PUBLISHING AG. 2017: 189?93
View details for DOI 10.1007/978-3-319-52621-8_17

View details for Web of Science ID 000425537400017
Feasibility of Long-Term Closed-Loop Control: A Multicenter 6-Month Trial of 24/7 Automated Insulin Delivery DIABETES TECHNOLOGY & THERAPEUTICS Kovatchev, B., Cheng, P., Anderson, S. M., Pinsker, J. E., Boscari, F., Buckingham, B. A., Doyle, F. J., Hood, K. K., Brown, S. A., Breton, M. D., Chernavvsky, D., Bevier, W. C., Bradley, P. K., Bruttomesso, D., Del Favero, S., Calore, R., Cobelli, C., Avogaro, A., Ly, T. T., Shanmugham, S., Dassau, E., Kollman, C., Lum, J. W., Beck, R. W. 2017; 19 (1): 18-?
Abstract

In the past few years, the artificial pancreas-the commonly accepted term for closed-loop control (CLC) of blood glucose in diabetes-has become a hot topic in research and technology development. In the summer of 2014, we initiated a 6-month trial evaluating the safety of 24/7 CLC during free-living conditions.Following an initial 1-month Phase 1, 14 individuals (10 males/4 females) with type 1 diabetes at three clinical centers in the United States and one in Italy continued with a 5-month Phase 2, which included 24/7 CLC using the wireless portable Diabetes Assistant (DiAs) developed at the University of Virginia Center for Diabetes Technology. Median subject characteristics were age 45 years, duration of diabetes 27 years, total daily insulin 0.53?U/kg/day, and baseline HbA1c 7.2% (55?mmol/mol).Compared with the baseline observation period, the frequency of hypoglycemia below 3.9?mmol/L during the last 3 months of CLC was lower: 4.1% versus 1.3%, P?
View details for DOI 10.1089/dia.2016.0333

View details for Web of Science ID 000392822900005

View details for PubMedID 27982707
Closed-Loop Control Without Meal Announcement in Type 1 Diabetes. Diabetes technology & therapeutics Cameron, F. M., Ly, T. T., Buckingham, B. A., Maahs, D. M., Forlenza, G. P., Levy, C. J., Lam, D., Clinton, P., Messer, L. H., Westfall, E., Levister, C., Xie, Y. Y., Baysal, N., Howsmon, D., Patek, S. D., Bequette, B. W. 2017; 19 (9): 527?32
Abstract

A fully closed-loop insulin-only system was developed to provide glucose control in patients with type 1 diabetes without requiring announcement of meals or activity. Our goal was to assess initial safety and efficacy of this system.The multiple model probabilistic controller (MMPPC) anticipates meals when the patient is awake. The controller used the subject's basal rates and total daily insulin dose for initialization. The system was tested at two sites on 10 patients in a 30-h inpatient study, followed by 15 subjects at three sites in a 54-h supervised hotel study, where the controller was challenged by exercise and unannounced meals. The system was implemented on the UVA DiAs system using a Roche Spirit Combo Insulin Pump and a Dexcom G4 Continuous Glucose Monitor.The mean overall (24-h basis) and nighttime (11 PM-7 AM) continuous glucose monitoring (CGM) values were 142 and 125?mg/dL during the inpatient study. The hotel study used a different daytime tuning and manual announcement, instead of automatic detection, of sleep and wake periods. This resulted in mean overall (24-h basis) and nighttime CGM values of 152 and 139?mg/dL for the hotel study and there was also a reduction in hypoglycemia events from 1.6 to 0.91 events/patient/day.The MMPPC system achieved a mean glucose that would be particularly helpful for people with an elevated A1c as a result of frequent missed meal boluses. Current full closed loop has a higher risk for hypoglycemia when compared with algorithms using meal announcement.

View details for PubMedID 28767276

View details for PubMedCentralID PMC5647490
International Consensus on Use of Continuous Glucose Monitoring. Diabetes care Danne, T., Nimri, R., Battelino, T., Bergenstal, R. M., Close, K. L., DeVries, J. H., Garg, S., Heinemann, L., Hirsch, I., Amiel, S. A., Beck, R., Bosi, E., Buckingham, B., Cobelli, C., Dassau, E., Doyle, F. J., Heller, S., Hovorka, R., Jia, W., Jones, T., Kordonouri, O., Kovatchev, B., Kowalski, A., Laffel, L., Maahs, D., Murphy, H. R., N�rgaard, K., Parkin, C. G., Renard, E., Saboo, B., Scharf, M., Tamborlane, W. V., Weinzimer, S. A., Phillip, M. 2017; 40 (12): 1631?40
Abstract

Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1ctesting and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1cmeasurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.

View details for PubMedID 29162583
Continuous Glucose Monitoring Enables the Detection of Losses in Infusion Set Actuation (LISAs) SENSORS Howsmon, D. P., Cameron, F., Baysal, N., Ly, T. T., Forlenza, G. P., Maahs, D. M., Buckingham, B. A., Hahn, J., Bequette, B. W. 2017; 17 (1)
Abstract

Reliable continuous glucose monitoring (CGM) enables a variety of advanced technology for the treatment of type 1 diabetes. In addition to artificial pancreas algorithms that use CGM to automate continuous subcutaneous insulin infusion (CSII), CGM can also inform fault detection algorithms that alert patients to problems in CGM or CSII. Losses in infusion set actuation (LISAs) can adversely affect clinical outcomes, resulting in hyperglycemia due to impaired insulin delivery. Prolonged hyperglycemia may lead to diabetic ketoacidosis-a serious metabolic complication in type 1 diabetes. Therefore, an algorithm for the detection of LISAs based on CGM and CSII signals was developed to improve patient safety. The LISA detection algorithm is trained retrospectively on data from 62 infusion set insertions from 20 patients. The algorithm collects glucose and insulin data, and computes relevant fault metrics over two different sliding windows; an alarm sounds when these fault metrics are exceeded. With the chosen algorithm parameters, the LISA detection strategy achieved a sensitivity of 71.8% and issued 0.28 false positives per day on the training data. Validation on two independent data sets confirmed that similar performance is seen on data that was not used for training. The developed algorithm is able to effectively alert patients to possible infusion set failures in open-loop scenarios, with limited evidence of its extension to closed-loop scenarios.

View details for DOI 10.3390/s17010161

View details for Web of Science ID 000393021000160

View details for PubMedID 28098839

View details for PubMedCentralID PMC5298734
Algorithms for a Single Hormone Closed-Loop Artificial Pancreas: Challenges Pertinent to Chemical Process Operations and Control PROCESSES Bequette, B., Cameron, F., Baysal, N., Howsmon, D. P., Buckingham, B. A., Maahs, D. M., Levy, C. J. 2016; 4 (4)
Abstract

The development of a closed-loop artificial pancreas to regulate the blood glucose concentration of individuals with type 1 diabetes has been a focused area of research for over 50 years, with rapid progress during the past decade. The daily control challenges faced by someone with type 1 diabetes include asymmetric objectives and risks, and one-sided manipulated input action with frequent relatively fast disturbances. The major automation steps toward a closed-loop artificial pancreas include (i) monitoring and overnight alarms for hypoglycemia (low blood glucose); (ii) overnight low glucose suspend (LGS) systems to prevent hypoglycemia; and (iii) fully closed-loop systems that adjust insulin (and perhaps glucagon) to maintain desired blood glucose levels day and night. We focus on the steps that we used to develop and test a probabilistic, risk-based, model predictive control strategy for a fully closed-loop artificial pancreas. We complete the paper by discussing ramifications of lessons learned for chemical process systems applications.

View details for PubMedID 30740333
Early Detection of Infusion Set Failure During Insulin Pump Therapy in Type 1 Diabetes. Journal of diabetes science and technology Cescon, M., DeSalvo, D. J., Ly, T. T., Maahs, D. M., Messer, L. H., Buckingham, B. A., Doyle, F. J., Dassau, E. 2016; 10 (6): 1268-1276
Abstract

Insulin infusion set failure resulting in prolonged hyperglycemia or diabetic ketoacidosis can occur with pump therapy in type 1 diabetes. Set failures are frequently characterized by variable and unpredictable patterns of increasing glucose values despite increased insulin infusion. Early detection may minimize the risk of prolonged hyperglycemia, an important consideration for automated insulin delivery and closed-loop applications.A novel algorithm designed to alert the patient to the onset of infusion set failure was developed based upon continuous glucose sensor values and insulin delivered from an insulin pump. The method was calibrated on 12 weeks of infusion set wear without failures recorded by 4 patients in ambulatory conditions and prospectively validated on 18 weeks of infusion set wear with and without failures belonging to 9 other subjects in ambulatory conditions.The algorithm, evaluated retrospectively, identified a failure 2.52 � 1.91 days ahead of the actual event as recorded by the clinical team, corresponding to 50% sensitivity, 66% specificity and 55% accuracy. If set failure alarms had been activated in real time, the average time >180 mg/dl would be reduced from 82.7 � 40.9 hours/week/subject (without alarm) to 58.8 � 31.1 hours/week/subject (with alarm), corresponding to a potential 29% reduction in time spent >180mg/dl.The proposed method for early detection of infusion set failure based on glucose sensor and insulin data demonstrated favorable results on retrospective data and may be implemented as an additional safeguard in a future fully automated closed-loop system.

View details for PubMedID 27621142
Altered Integration of Structural Covariance Networks in Young Children With Type 1 Diabetes. Human brain mapping Hosseini, S. M., Mazaika, P., Mauras, N., Buckingham, B., Weinzimer, S. A., Tsalikian, E., White, N. H., Reiss, A. L. 2016; 37 (11): 4034-4046
Abstract

Type 1 diabetes mellitus (T1D), one of the most frequent chronic diseases in children, is associated with glucose dysregulation that contributes to an increased risk for neurocognitive deficits. While there is a bulk of evidence regarding neurocognitive deficits in adults with T1D, little is known about how early-onset T1D affects neural networks in young children. Recent data demonstrated widespread alterations in regional gray matter and white matter associated with T1D in young children. These widespread neuroanatomical changes might impact the organization of large-scale brain networks. In the present study, we applied graph-theoretical analysis to test whether the organization of structural covariance networks in the brain for a cohort of young children with T1D (N?=?141) is altered compared to healthy controls (HC; N?=?69). While the networks in both groups followed a small world organization-an architecture that is simultaneously highly segregated and integrated-the T1D network showed significantly longer path length compared with HC, suggesting reduced global integration of brain networks in young children with T1D. In addition, network robustness analysis revealed that the T1D network model showed more vulnerability to neural insult compared with HC. These results suggest that early-onset T1D negatively impacts the global organization of structural covariance networks and influences the trajectory of brain development in childhood. This is the first study to examine structural covariance networks in young children with T1D. Improving glycemic control for young children with T1D might help prevent alterations in brain networks in this population. Hum Brain Mapp, 2016. � 2016 Wiley Periodicals, Inc.

View details for DOI 10.1002/hbm.23293

View details for PubMedID 27339089
Characteristics of youth with type 1 diabetes (T1D) with and without a parent with T1D in the T1D exchange clinic registry. Journal of diabetes Fox, L. A., Mubasher, M., Wolfsdorf, J. I., Buckingham, B. A., Peters, A. L., Tamborlane, W. V., Schatz, D. A., Maahs, D. M., Miller, K. M., Beck, R. W. 2016; 8 (6): 834-838
Abstract

The aim of the present study was to compare characteristics and diabetes management in children and adolescents with and without at least one parent with type 1 diabetes (T1D).In all, 12 890 participants aged <18?years at enrollment in the T1D Exchange Registry were included in the present study. Statistical comparisons between those with and without parental T1D were conducted using a univariate generalized linear mixed model.Of the study participants, 1056 (8.2%) registrants had at least one parent with T1D. Those with parental T1D were slightly, albeit significantly, younger (6.3 vs 6.9?years; P?<�0.001) and less likely to have diabetic ketoacidosis (DKA) at diagnosis (24% vs 41%; P?<�0.001) than those without parental T1D. There were no differences between groups in HbA1c, use of continuous glucose monitoring or insulin pump therapy, or the development of severe hypoglycemia or DKA. In addition, there were no differences found when comparing characteristics or diabetes management in those with a mother versus those with a father with T1D.Children and adolescents with parental T1D tend to be diagnosed earlier. Diabetes management, glycemic control, and acute complications are similar in those with and without parental T1D.

View details for DOI 10.1111/1753-0407.12363

View details for PubMedID 26663683
Efficacy of an Overnight Predictive Low-Glucose Suspend System in Relation to Hypoglycemia Risk Factors in Youth and Adults With Type 1 Diabetes. Journal of diabetes science and technology Calhoun, P. M., Buckingham, B. A., Maahs, D. M., Hramiak, I., Wilson, D. M., Aye, T., Clinton, P., Chase, P., Messer, L., Kollman, C., Beck, R. W., Lum, J. 2016; 10 (6): 1216-1221
Abstract

We developed a system to suspend insulin pump delivery overnight when the glucose trend predicts hypoglycemia. This predictive low-glucose suspend (PLGS) system substantially reduces nocturnal hypoglycemia without an increase in morning ketosis. Evaluation of hypoglycemia risk factors that could potentially influence the efficacy of the system remains critical for understanding possible problems with the system and identifying patients that may have the greatest benefit when using the system.The at-home randomized trial consisted of 127 study participants with hemoglobin A1c (A1C) of ?8.5% (mmol/mol) for patients aged 4-14 years and ?8.0% for patient aged 15-45 years. Factors assessed included age, gender, A1C, diabetes duration, daily percentage basal insulin, total daily dose of insulin (units/kg-day), bedtime BG, bedtime snack, insulin on board, continuous glucose monitor (CGM) rate of change (ROC), day of the week, time system activated, daytime exercise intensity, and daytime CGM-measured hypoglycemia.The PLGS system was effective in preventing hypoglycemia for each factor subgroup. There was no evidence that the PLGS system was more or less effective in preventing hypoglycemia in any one subgroup compared with the other subgroups based on that factor. In addition, the effect of the system on overnight hyperglycemia did not differ in subgroups.The PLGS system tested in this study effectively reduced hypoglycemia without a meaningful increase in hyperglycemia across a variety of factors.

View details for PubMedID 27207890
Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bergenstal, R. M., Garg, S., Weinzimer, S. A., Buckingham, B. A., Bode, B. W., Tamborlane, W. V., Kaufman, F. R. 2016; 316 (13): 1407?8
View details for PubMedID 27629148
Compensatory Hyper-Connectivity in Developing Brains of Young Children with Type 1 Diabetes. Diabetes Saggar, M., Tsalikian, E., Mauras, N., Mazaika, P., White, N. H., Weinzimer, S., Buckingham, B., Hershey, T., Reiss, A. L. 2016
Abstract

Sustained dysregulation of blood glucose (hyper or hypoglycemia) associated with type 1 diabetes (T1D) has been linked to cognitive deficits and altered brain anatomy and connectivity. However, a significant gap remains with respect to how T1D affects spontaneous at-rest connectivity in young developing brains. Here, using a large multi-site study, resting state functional Magnetic Resonance Imaging (rsfMRI) data were examined in young children with T1D (N=57, mean age=7.88 years; 27F) as compared to age-matched non-diabetic controls (N=26, mean age=7.43 years; 14F). Using both model-driven seed-based analysis and model-free independent component analysis (ICA) and controlling for age, site and sex, converging results were obtained suggesting increased connectivity in young children with T1D as compared to non-diabetic controls. Further, increased connectivity in children with T1D was observed to be positively associated with cognitive functioning. The observed positive association of connectivity with cognitive functioning in T1D, without overall group differences in cognitive function, suggests a putative compensatory role of hyper-intrinsic connectivity in the brain in children with this condition. Altogether, our study attempts to fill a critical gap in knowledge regarding how dysglycemia in T1D might affect the brain's intrinsic connectivity at very young ages.

View details for PubMedID 27702833
Continuous Glucose Sensor Survival and Accuracy Over 14 Consecutive Days DIABETES CARE DeSalvo, D. J., Ly, T. T., Wadwa, R., Messer, L., Westfall, E., Gopisetty, D., Hanes, S., von Eyben, R., Maahs, D. M., Buckingham, B. A. 2016; 39 (8): E112?E113
View details for PubMedID 27222506

View details for PubMedCentralID PMC4955929
Improving Patient Experience With Insulin Infusion Sets: Practical Guidelines and Future Directions. Diabetes educator Evert, A. B., Bode, B. W., Buckingham, B. A., Nardacci, E., Verderese, C. A., Wolff-McDonagh, P., Walsh, J., Hirsch, I. B. 2016; 42 (4): 470-484
Abstract

Insulin infusion sets (IISs) are an essential component of safe and effective insulin pump therapy. Establishing best practices for their use has been impeded by a lack of formal study and limited resources for clinician and patient education. Recent innovations in IIS science promise to change this status quo by increasing awareness of such problems as unexplained hyperglycemia and infusion set occlusion.In August 2015, a panel of diabetologists and certified diabetes educators from various disciplines was convened to reconsider IIS-related complications of pump therapy, to better characterize infusion set factors affecting patient experience, and to update priorities for optimizing current technologies. Actionable guidelines were provided for addressing common issues, including skin reactions, site rotation and set changes, dislodgment of the infusion set, and partial or complete blockage of the catheter. These issues may underlie episodes of IIS failure and/or unexplained hyperglycemia.Development of practical tools and standardized guidelines for empowering patients to prevent, diagnose, and troubleshoot IIS problems that contribute to unexplained hyperglycemia will be necessary to realize the full benefit of insulin pump therapy along the continuum of diabetes education.

View details for DOI 10.1177/0145721716642526

View details for PubMedID 27056594
Day-and-Night Closed-Loop Control Using the Unified Safety System in Adolescents With Type 1 Diabetes at Camp DIABETES CARE Ly, T. T., Buckingham, B. A., DeSalvo, D. J., Shanmugham, S., Satin-Smith, M., DeBoer, M. D., Oliveri, M. C., Schertz, E., Breton, M. D., Chernavvsky, D. R. 2016; 39 (8): E106?E107
View details for PubMedID 27271182

View details for PubMedCentralID PMC5878678
Ketone production in children with type 1 diabetes, ages 4-14 years, with and without nocturnal insulin pump suspension. Pediatric diabetes Wadwa, R. P., Chase, H. P., Raghinaru, D., Buckingham, B. A., Hramiak, I., Maahs, D. M., Messer, L., Ly, T., Aye, T., Clinton, P., Kollman, C., Beck, R. W., Lum, J. 2016
Abstract

To compare the frequency of elevated morning blood ketone levels according to age in 4-14 year olds with type 1 diabetes following overnight use of an automated low glucose insulin suspension system, or following control nights when the system was not used.For 28 children ages 4-9 years and 54 youth ages 10-14 years, elevation of morning blood ketone levels was assessed using the Precision Xtra Ketone meter following 1155 and 2345 nights, respectively. Repeated measures logistic regression models were used to compare age groups for blood ketone level elevation following control nights (system not activated) and following intervention nights with and without insulin suspension.Elevated morning blood ketones (?0.6 mmol/L) were present following 10% of 580 control nights in the 4-9 year olds compared with 2% of 1162 control nights in 10-14 year olds (P < 0.001). Likewise, the frequency was greater following intervention nights in the younger age group (13% of 575 nights vs 2% of 1183 nights, P < 0.001). A longer duration of pump suspension resulted in a higher percentage of mornings with elevated blood ketones in the younger age group (P = 0.002), but not in the older age group (P = 0.63). The presence of elevated morning ketone levels did not progress to ketoacidosis in any subject.Elevated morning blood ketones are more common in younger children with type 1 diabetes with or without nocturnal insulin suspension. Care providers need to be aware of the differences in ketogenesis in younger age children relative to various clinical situations.

View details for DOI 10.1111/pedi.12410

View details for PubMedID 27402452
Duration of Infusion Set Survival in Lipohypertrophy Versus Nonlipohypertrophied Tissue in Patients with Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Karlin, A. W., Ly, T. T., Pyle, L., Forlenza, G. P., Messer, L., Wadwa, R. P., DeSalvo, D. J., Payne, S. L., Hanes, S., Clinton, P., Maahs, D. M., Buckingham, B. 2016; 18 (7): 429-435
Abstract

Improved insulin infusion set survival and faster insulin action are important issues for pump users and for the development of an artificial pancreas. The current recommendation is to change infusion sets every 3 days. Our objectives were to determine the effect of lipohypertrophy (LH) on infusion set survival and continuous glucose monitoring glucose levels.In this multicenter crossover trial, we recruited 20 subjects (age 28.1?�?9.0 years) with type 1 diabetes (duration 17.5?�?8.8 years) and an area of lipohypertrophied tissue >3?cm. Subjects alternated weekly wearing a Teflon infusion set in an area of either LH or non-LH for 4 weeks. Sets were changed after (a) failure or (b) surviving 7 days of use.The least-squares mean duration of infusion set survival for sets that lasted <7 days in lipohypertrophied tissue was 4.31 days compared with 4.12 days in nonlipohypertrophied tissue (P?=?0.71). The average duration of set survival for individual subjects ranged from 2.2 to 7.0 days. Infusion sets in lipohypertrophied tissue failed due to hyperglycemia in 35% of subjects compared with 23% in nonlipohypertrophied tissue (P?=?0.22). Both lipohypertrophied and nonlipohypertrophied tissues displayed a general increase in mean daily glucose after the third day of infusion set wear, but daily mean glucose did not differ by tissue type (P?>?0.38 on each day).LH did not significantly affect infusion set survival or mean glucose. Achieving optimal infusion set performance requires research into factors affecting set survival. Additionally, the recommendation for duration of set change may need to be individualized.

View details for DOI 10.1089/dia.2015.0432

View details for Web of Science ID 000379497600006

View details for PubMedID 27227290

View details for PubMedCentralID PMC4931738
Multinational Home Use of Closed-Loop Control Is Safe and Effective. Diabetes care Anderson, S. M., Raghinaru, D., Pinsker, J. E., Boscari, F., Renard, E., Buckingham, B. A., Nimri, R., Doyle, F. J., Brown, S. A., Keith-Hynes, P., Breton, M. D., Chernavvsky, D., Bevier, W. C., Bradley, P. K., Bruttomesso, D., Del Favero, S., Calore, R., Cobelli, C., Avogaro, A., Farret, A., Place, J., Ly, T. T., Shanmugham, S., Phillip, M., Dassau, E., Dasanayake, I. S., Kollman, C., Lum, J. W., Beck, R. W., Kovatchev, B. 2016; 39 (7): 1143-1150
Abstract

To evaluate the efficacy of a portable, wearable, wireless artificial pancreas system (the Diabetes Assistant [DiAs] running the Unified Safety System) on glucose control at home in overnight-only and 24/7 closed-loop control (CLC) modes in patients with type 1 diabetes.At six clinical centers in four countries, 30 participants 18-66 years old with type 1 diabetes (43% female, 96% non-Hispanic white, median type 1 diabetes duration 19 years, median A1C 7.3%) completed the study. The protocol included a 2-week baseline sensor-augmented pump (SAP) period followed by 2 weeks of overnight-only CLC and 2 weeks of 24/7 CLC at home. Glucose control during CLC was compared with the baseline SAP.Glycemic control parameters for overnight-only CLC were improved during the nighttime period compared with baseline for hypoglycemia (time <70 mg/dL, primary end point median 1.1% vs. 3.0%; P < 0.001), time in target (70-180 mg/dL: 75% vs. 61%; P < 0.001), and glucose variability (coefficient of variation: 30% vs. 36%; P < 0.001). Similar improvements for day/night combined were observed with 24/7 CLC compared with baseline: 1.7% vs. 4.1%, P < 0.001; 73% vs. 65%, P < 0.001; and 34% vs. 38%, P < 0.001, respectively.CLC running on a smartphone (DiAs) in the home environment was safe and effective. Overnight-only CLC reduced hypoglycemia and increased time in range overnight and increased time in range during the day; 24/7 CLC reduced hypoglycemia and increased time in range both overnight and during the day. Compared with overnight-only CLC, 24/7 CLC provided additional hypoglycemia protection during the day.

View details for DOI 10.2337/dc15-2468

View details for PubMedID 27208316
Outcome Measures for Artificial Pancreas Clinical Trials: A Consensus Report. Diabetes care Maahs, D. M., Buckingham, B. A., Castle, J. R., Cinar, A., Damiano, E. R., Dassau, E., DeVries, J. H., Doyle, F. J., Griffen, S. C., Haidar, A., Heinemann, L., Hovorka, R., Jones, T. W., Kollman, C., Kovatchev, B., Levy, B. L., Nimri, R., O'Neal, D. N., Philip, M., Renard, E., Russell, S. J., Weinzimer, S. A., Zisser, H., Lum, J. W. 2016; 39 (7): 1175-1179
Abstract

Research on and commercial development of the artificial pancreas (AP) continue to progress rapidly, and the AP promises to become a part of clinical care. In this report, members of the JDRF Artificial Pancreas Project Consortium in collaboration with the wider AP community 1) advocate for the use of continuous glucose monitoring glucose metrics as outcome measures in AP trials, in addition to HbA1c, and 2) identify a short set of basic, easily interpreted outcome measures to be reported in AP studies whenever feasible. Consensus on a broader range of measures remains challenging; therefore, reporting of additional metrics is encouraged as appropriate for individual AP studies or study groups. Greater consistency in reporting of basic outcome measures may facilitate the interpretation of study results by investigators, regulatory bodies, health care providers, payers, and patients themselves, thereby accelerating the widespread adoption of AP technology to improve the lives of people with type 1 diabetes.

View details for DOI 10.2337/dc15-2716

View details for PubMedID 27330126
Automated Overnight Closed-Loop Control Using a Proportional-Integral-Derivative Algorithm with Insulin Feedback in Children and Adolescents with Type 1 Diabetes at Diabetes Camp DIABETES TECHNOLOGY & THERAPEUTICS Ly, T. T., Keenan, D. B., Roy, A., Han, J., Grosman, B., Cantwell, M., Kurtz, N., von Eyben, R., Clinton, P., Wilson, D. M., Buckingham, B. A. 2016; 18 (6): 377-384
Abstract

This study determined the feasibility and efficacy of an automated proportional-integral-derivative with insulin feedback (PID-IFB) controller in overnight closed-loop (OCL) control of children and adolescents with type 1 diabetes over multiple days in a diabetes camp setting.The Medtronic (Northridge, CA) Android? (Google, Mountain View, CA)-based PID-IFB system consists of the Medtronic Minimed Revel? 2.0 pump and Enlite? sensor, a control algorithm residing on an Android phone, a translator, and remote monitoring capabilities. An inpatient study was completed for 16 participants to determine feasibility. For the camp study, subjects with type 1 diabetes were randomized to either OCL or sensor-augmented pump therapy (control conditions) per night for up to 6 nights at diabetes camp.During the camp study, 21 subjects completed 50 OCL nights and 52 control nights. Based on intention to treat, the median time spent in range, from 70 to 150?mg/dL, was greater during OCL at 66.4% (n?=?55) versus 50.6% (n?=?52) during the control period (P?=?0.004). A per-protocol analysis allowed for assessment of algorithm performance with the median percentage time in range, 70-150?mg/dL, being 75.5% (n?=?37) for OCL versus 47.6% (n?=?32) for the control period (P?
View details for DOI 10.1089/dia.2015.0431

View details for PubMedID 27183197
Changes in beta cell function during the proximate post-diagnosis period in persons with type 1 diabetes PEDIATRIC DIABETES Dimeglio, L. A., Cheng, P., Beck, R. W., Kollman, C., Ruedy, K. J., Slover, R., Aye, T., Weinzimer, S. A., Bremer, A. A., Buckingham, B. 2016; 17 (4): 237-243
Abstract

Prior studies examining beta-cell preservation in type 1 diabetes have predominantly assessed stimulated C-peptide concentrations approximately 10?wk after diagnosis. We examined whether earlier assessments might aid in prediction of beta cell function over time.Using data from a multi-center randomized trial assessing the effect of intensive diabetes management initiated within 1?wk of diagnosis, we assessed which clinical factors predicted 90-min mixed-meal tolerance test (MMTT) stimulated C-peptide values obtained 2 and 6?wk after diagnosis. We also studied associations of these factors with C-peptide values at 1- and 2-year post-diagnosis. Data from intervention and control groups were pooled.Among 67 study participants (mean age 13.3?�?5.7?yr, range 7.8-45.7?yr) in multivariable analyses, C-peptide increased from baseline to 2?wks and then 6?wk. C-peptide levels at these times were significantly correlated with 1- and 2-yr C-peptide concentrations (all p?
View details for DOI 10.1111/pedi.12271

View details for Web of Science ID 000379831900001

View details for PubMedID 25720763
Automated hybrid closed-loop control with a proportional-integral-derivative based system in adolescents and adults with type 1 diabetes: individualizing settings for optimal performance. Pediatric diabetes Ly, T. T., Weinzimer, S. A., Maahs, D. M., Sherr, J. L., Roy, A., Grosman, B., Cantwell, M., Kurtz, N., Carria, L., Messer, L., von Eyben, R., Buckingham, B. A. 2016
Abstract

Automated insulin delivery systems, utilizing a control algorithm to dose insulin based upon subcutaneous continuous glucose sensor values and insulin pump therapy, will soon be available for commercial use. The objective of this study was to determine the preliminary safety and efficacy of initialization parameters with the Medtronic hybrid closed-loop controller by comparing percentage of time in range, 70-180 mg/dL (3.9-10 mmol/L), mean glucose values, as well as percentage of time above and below target range between sensor-augmented pump therapy and hybrid closed-loop, in adults and adolescents with type 1 diabetes.We studied an initial cohort of 9 adults followed by a second cohort of 15 adolescents, using the Medtronic hybrid closed-loop system with the proportional-integral-derivative with insulin feed-back (PID-IFB) algorithm. Hybrid closed-loop was tested in supervised hotel-based studies over 4-5 days.The overall mean percentage of time in range (70-180 mg/dL, 3.9-10 mmol/L) during hybrid closed-loop was 71.8% in the adult cohort and 69.8% in the adolescent cohort. The overall percentage of time spent under 70 mg/dL (3.9 mmol/L) was 2.0% in the adult cohort and 2.5% in the adolescent cohort. Mean glucose values were 152 mg/dL (8.4 mmol/L) in the adult cohort and 153 mg/dL (8.5 mmol/L) in the adolescent cohort.Closed-loop control using the Medtronic hybrid closed-loop system enables adaptive, real-time basal rate modulation. Initializing hybrid closed-loop in clinical practice will involve individualizing initiation parameters to optimize overall glucose control.

View details for DOI 10.1111/pedi.12399

View details for PubMedID 27191182
In-home nighttime predictive low glucose suspend experience in children and adults with type 1 diabetes. Pediatric diabetes Messer, L. H., Calhoun, P., Buckingham, B., Wilson, D. M., Hramiak, I., Ly, T. T., Driscoll, M., Clinton, P., Maahs, D. M. 2016: -?
Abstract

Overnight predictive low glucose suspend (PLGS) reduces hypoglycemia across all ages; however, there are no reports on behavior or experience differences across age groups, especially in pediatrics. As run-in for a subsequent randomized clinical trial (RCT), 127 subjects (50% male) ages 4-45?yr utilized the experimental PLGS system nightly for 5-10 nights (PLGS active phase). We analyzed the number of blood glucose (BG) checks and boluses given per age group. During the subsequent 42 night RCT phase, we analyzed sensor use, skin reactions, errors, and reasons why the experimental system was not used. In 821 nights of active PLGS, subjects ages 4-6?yr (and their parents) tested BG levels 75% of nights compared with 65% of nights (7-10?yr), 53% of nights (11-14?yr), 33% of nights (15-25?yr), and 28% of nights (26-45?yr), respectively (p?270 at bedtime (study requirement) were primary contributors to non-system use. Understanding the different use patterns and challenges in pediatrics and adolescence is needed to direct patient education to optimize use of PLGS and future artificial pancreas systems.

View details for DOI 10.1111/pedi.12395

View details for PubMedID 27125223

View details for PubMedCentralID PMC5086306
Longitudinal Evaluation of Cognitive Functioning in Young Children with Type 1 Diabetes over 18 Months. Journal of the International Neuropsychological Society Cato, M. A., Mauras, N., Mazaika, P., Kollman, C., Cheng, P., Aye, T., Ambrosino, J., Beck, R. W., Ruedy, K. J., Reiss, A. L., Tansey, M., White, N. H., Hershey, T. 2016; 22 (3): 293-302
Abstract

Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D.A total of 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 years; mean age of onset 4.1 years) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes.Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function.The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (Verbal IQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned.

View details for DOI 10.1017/S1355617715001289

View details for PubMedID 26786245
Closed-loop control in type 1 diabetes. The lancet. Diabetes & endocrinology Buckingham, B., Ly, T. 2016; 4 (3): 191-193
View details for DOI 10.1016/S2213-8587(16)00015-2

View details for PubMedID 26850708
Stabilization of glycemic control and improved quality of life using a shared medical appointment model in adolescents with type 1 diabetes in suboptimal control. Pediatric diabetes Floyd, B. D., Block, J. M., Buckingham, B. B., Ly, T., Foster, N., Wright, R., Mueller, C. L., Hood, K. K., Shah, A. C. 2016
Abstract

Declining glycemic control in type 1 diabetes (T1D) during adolescence persists despite treatment advances. Non-adherence, peer relations, diabetes burnout, risk taking, transition to autonomy, family conflict, and poor quality of life (QOL) are recognized barriers. Shared medical appointments (SMAs) in adolescent T1D may offer benefits, but data are limited. Our objective was to determine whether SMAs, with multi-component interventions utilizing multidisciplinary teams, improve glycemic control and psychosocial outcomes in poorly controlled adolescent T1D.SMAs focused on self-management, communication skills, goal setting, glucose pattern recognition, and peer/diabetes team support. SMAs included: individual history and physical, labs, surveys, multidisciplinary educational ice breakers, group session, and individual wrap up. Outcomes were QOL, adherence, and retrospective and prospective glycemic control. Three to six subjects and families came to 3 SMAs and 1 individual appointment every 3 months over 9 months.A total of 37 English speaking subjects, ages 12-16?yrs, with T1D ? 1 year, and hemoglobin A1c (HbA1c) 7.5-11% enrolled. Thirty-two subjects attended 75% of visits, meeting inclusion criteria.HbA1c worsened in the 9 months before study (?HbA1c= 0.7?�?1.2; p??0.05). There were significant improvements in overall QOL (p?=?0.005), school function (p?=?0.006), psychosocial function (p?=?0.008), barriers (p?=?0.02), adherence (p?=?0.01), and communication (p?=?0.02). Improvements in school function and communication reached clinical significance.SMAs are feasible replacements to individual appointments in adolescent T1D, stabilizing glycemic control and improving QOL. Randomized controlled trials with optimizations are needed to further explore and refine this intervention.

View details for DOI 10.1111/pedi.12373

View details for PubMedID 26919322
Progress in Diabetes Technology: Developments in Insulin Pumps, Continuous Glucose Monitors, and Progress towards the Artificial Pancreas JOURNAL OF PEDIATRICS Forlenza, G. P., Buckingham, B., Maahs, D. M. 2016; 169: 13-20
View details for DOI 10.1016/j.jpeds.2015.10.015

View details for Web of Science ID 000368595300006

View details for PubMedID 26547403
Diabetes Technology and the Human Factor DIABETES TECHNOLOGY & THERAPEUTICS Liberman, A., Buckingham, B. 2016; 18: S101-S111
View details for DOI 10.1089/dia.2016.2510

View details for Web of Science ID 000369672600012

View details for PubMedID 26836423
Variations in Brain Volume and Growth in Young Children With Type 1 Diabetes. Diabetes Mazaika, P. K., Weinzimer, S. A., Mauras, N., Buckingham, B., White, N. H., Tsalikian, E., Hershey, T., Cato, A., Aye, T., Fox, L., Wilson, D. M., Tansey, M. J., Tamborlane, W., Peng, D., Raman, M., Marzelli, M., Reiss, A. L. 2016; 65 (2): 476-485
Abstract

Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4-10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (�SD) HbA1c level was 7.9 � 0.9% (63 � 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.

View details for DOI 10.2337/db15-1242

View details for PubMedID 26512024
Effects of Frequency of Sensor-Augmented Pump Use on HbA1c and C-Peptide Levels in the First Year of Type 1 Diabetes. Diabetes care Triolo, T. M., Maahs, D. M., Pyle, L., Slover, R., Buckingham, B., Cheng, P., DiMeglio, L. A., Bremer, A. A., Weinzimer, S. A., Chase, H. P., Diabetes Research in Children Network (DirecNet) and Type 1 Diabetes TrialNet Study Groups 2016; 39 (4): e61?2
View details for PubMedID 26895885
Effect of Lipohypertrophy on Accuracy of Continuous Glucose Monitoring in Patients With Type 1 Diabetes DIABETES CARE DeSalvo, D. J., Maahs, D. M., Messer, L., Wadwa, R., Payne, S., Ly, T. T., Buckingham, B. A. 2015; 38 (10): E166?E167
View details for PubMedID 26307604

View details for PubMedCentralID PMC4876738
Effect of Acetaminophen on CGM Glucose in an Outpatient Setting DIABETES CARE Maahs, D. M., DeSalvo, D., Pyle, L., Trang Ly, Messer, L., Clinton, P., Westfall, E., Wadwa, R., Buckingham, B. 2015; 38 (10): E158?E159
View details for PubMedID 26269199

View details for PubMedCentralID PMC4876736
Erratum. Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis. Diabetes Care 2015;38:1197-1204. Diabetes care Buckingham, B. A., Raghinaru, D., Cameron, F., Bequette, B. W., Chase, H. P., Maahs, D. M., Slover, R., Wadwa, R. P., Wilson, D. M., Ly, T., Aye, T., Hramiak, I., Clarson, C., Stein, R., Gallego, P. H., Lum, J., Sibayan, J., Kollman, C., Beck, R. W. 2015; 38 (9): 1813-?
View details for DOI 10.2337/dc15-er09

View details for PubMedID 26294776
Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis DIABETES CARE Buckingham, B. A., Raghinaru, D., Cameron, F., Bequette, B. W., Chase, H. P., Maahs, D. M., Slover, R., Wadwa, R. P., Wilson, D. M., Ly, T., Aye, T., Hramiak, I., Clarson, C., Stein, R., Gallego, P. H., Lum, J., Sibayan, J., Kollman, C., Beck, R. W. 2015; 38 (7): 1197-1204
Abstract

Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor-based overnight predictive low-glucose suspend (PLGS) system.In two age-groups of children with type 1 diabetes (11-14 and 4-10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight.Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11-14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4-10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 � 18 vs. 152 � 19 mg/dL [P < 0.001] and 153 � 14 vs. 160 � 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 � 29 vs. 176 � 28 mg/dL (P < 0.001) in the 11-14-year-olds and 154 � 25 vs. 158 � 22 mg/dL (P = 0.11) in the 4-10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis.In 4-14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

View details for DOI 10.2337/dc14-3053

View details for PubMedID 26049549
Day and Night Closed-Loop Control Using the Integrated Medtronic Hybrid Closed-Loop System in Type 1 Diabetes at Diabetes Camp DIABETES CARE Ly, T. T., Roy, A., Grosman, B., Shin, J., Campbell, A., Monirabbasi, S., Liang, B., von Eyben, R., Shanmugham, S., Clinton, P., Buckingham, B. A. 2015; 38 (7): 1205-1211
Abstract

To evaluate the feasibility and efficacy of a fully integrated hybrid closed-loop (HCL) system (Medtronic MiniMed Inc., Northridge, CA), in day and night closed-loop control in subjects with type 1 diabetes, both in an inpatient setting and during 6 days at diabetes camp.The Medtronic MiniMed HCL system consists of a fourth generation (4S) glucose sensor, a sensor transmitter, and an insulin pump using a modified proportional-integral-derivative (PID) insulin feedback algorithm with safety constraints. Eight subjects were studied over 48 h in an inpatient setting. This was followed by a study of 21 subjects for 6 days at diabetes camp, randomized to either the closed-loop control group using the HCL system or to the group using the Medtronic MiniMed 530G with threshold suspend (control group).The overall mean sensor glucose percent time in range 70-180 mg/dL was similar between the groups (73.1% vs. 69.9%, control vs. HCL, respectively) (P = 0.580). Meter glucose values between 70 and 180 mg/dL were also similar between the groups (73.6% vs. 63.2%, control vs. HCL, respectively) (P = 0.086). The mean absolute relative difference of the 4S sensor was 10.8 � 10.2%, when compared with plasma glucose values in the inpatient setting, and 12.6 � 11.0% compared with capillary Bayer CONTOUR NEXT LINK glucose meter values during 6 days at camp.In the first clinical study of this fully integrated system using an investigational PID algorithm, the system did not demonstrate improved glucose control compared with sensor-augmented pump therapy alone. The system demonstrated good connectivity and improved sensor performance.

View details for DOI 10.2337/dc14-3073

View details for Web of Science ID 000356933600013

View details for PubMedID 26049550
Factors Associated with Nocturnal Hypoglycemia in At-Risk Adolescents and Young Adults with Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Wilson, D. M., Calhoun, P. M., Maahs, D. M., Chase, H. P., Messer, L., Buckingham, B. A., Aye, T., Clinton, P. K., Hramiak, I., Kollman, C., Beck, R. W. 2015; 17 (6): 385-391
Abstract

Hypoglycemia remains an impediment to good glycemic control, with nocturnal hypoglycemia being particularly dangerous. Information on major contributors to nocturnal hypoglycemia remains critical for understanding and mitigating risk.Continuous glucose monitoring (CGM) data for 855 nights were studied, generated by 45 subjects 15-45 years of age with hemoglobin A1c (HbA1c) levels of ?8.0% who participated in a larger randomized study. Factors assessed for potential association with nocturnal hypoglycemia (CGM measurement of <60?mg/dL for ?30?min) included bedtime blood glucose (BG), exercise intensity, bedtime snack, insulin on board, day of the week, previous daytime hypoglycemia, age, gender, HbA1c level, diabetes duration, daily basal insulin, and daily insulin dose.Hypoglycemia occurred during 221 of 885 (25%) nights and was more frequent with younger age (P<0.001), lower HbA1c levels (P=0.006), medium/high-intensity exercise during the preceding day (P=0.003), and the occurrence of antecedent daytime hypoglycemia (P=0.001). There was a trend for lower bedtime BG levels to be associated with more frequent nocturnal hypoglycemia (P=0.10). Bedtime snack, before bedtime insulin bolus, weekend versus weekday, gender, and daily basal and bolus insulin were not associated with nocturnal hypoglycemia.Awareness that HbA1c level, exercise, bedtime BG level, and daytime hypoglycemia are all modifiable factors associated with nocturnal hypoglycemia may help patients and providers decrease the risk of hypoglycemia at night. Risk for nocturnal hypoglycemia increased in a linear fashion across the range of variables, with no clear-cut thresholds to guide clinicians or patients for any particular night.

View details for DOI 10.1089/dia.2014.0342

View details for PubMedID 25761202
CGM-measured glucose values have a strong correlation with C-peptide, HbA(1c) and IDAAC, but do poorly in predicting C-peptide levels in the two years following onset of diabetes DIABETOLOGIA Buckingham, B., Cheng, P., Beck, R. W., Kollman, C., Ruedy, K. J., Weinzimer, S. A., Slover, R., Bremer, A. A., Fuqua, J., Tamborlane, W. 2015; 58 (6): 1167-1174
Abstract

The aim of this work was to assess the association between continuous glucose monitoring (CGM) data, HbA1c, insulin-dose-adjusted HbA1c (IDAA1c) and C-peptide responses during the first 2�years following diagnosis of type 1 diabetes.A secondary analysis was conducted of data collected from a randomised trial assessing the effect of intensive management initiated within 1�week of diagnosis of type 1 diabetes, in which mixed-meal tolerance tests were performed at baseline and at eight additional time points through 24�months. CGM data were collected at each visit.Among 67 study participants (mean age [� SD] 13.3?�?5.7�years), HbA1c was inversely correlated with C-peptide at each time point (p?
View details for DOI 10.1007/s00125-015-3559-y

View details for Web of Science ID 000353893000005

View details for PubMedID 25773405

View details for PubMedCentralID PMC4416994
Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children With Type 1 Diabetes: Association With Hyperglycemia DIABETES Mauras, N., Mazaika, P., Buckingham, B., Weinzimer, S., White, N. H., Tsalikian, E., Hershey, T., Cato, A., Cheng, P., Kollman, C., Beck, R. W., Ruedy, K., Aye, T., Fox, L., Arbelaez, A. M., Wilson, D., Tansey, M., Tamborlane, W., Peng, D., Marzelli, M., Winer, K. K., Reiss, A. L. 2015; 64 (5): 1770-1779
Abstract

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.

View details for DOI 10.2337/db14-1445

View details for PubMedID 25488901
Body Mass Index Changes in Youth in the First Year after Type 1 Diabetes Diagnosis JOURNAL OF PEDIATRICS Gregg, B., Connor, C. G., Ruedy, K. J., Beck, R. W., Kollman, C., Schatz, D., Cengiz, E., Harris, B., Tamborlane, W. V., Klingensmith, G. J., Lee, J. M. 2015; 166 (5): 1265-U494
Abstract

To describe changes in weight and body mass index (BMI) during the first year following diagnosis of type 1 diabetes (T1D) and associations with demographic and clinical characteristics.The Pediatric Diabetes Consortium includes 7 US centers with prospective longitudinal data from initial T1D diagnosis. This analysis includes 530 youth with diabetes duration of ?1�year and measures of BMI at 3 and 12�months after diagnosis. BMI trajectory of participants and relationships between the change in BMI z-score from baseline (3�months) to 12�months with demographic characteristics, hemoglobin A1c at baseline, and insulin delivery mode at baseline were evaluated.As a group, BMI z-scores increased sharply from diagnosis for 1-3�months but remained relatively stable from +0.51 at 3�months to +0.48 at 12�months. Children aged 2-<5�years experienced a significant positive change in BMI z-score between 3 and 12�months, and there was a similar trend among girls that did not reach statistical significance. No significant differences were found for race, socioeconomic status, or insulin delivery mode.These data suggest that increased BMI during the first year of treatment of most youth with T1D reflects regain of weight lost before diagnosis. There is, however, a propensity toward additional weight gain in younger children and girls.

View details for DOI 10.1016/j.jpeds.2015.02.036

View details for PubMedID 25919735
Diabetes technology and the human factor. Diabetes technology & therapeutics Liberman, A., Phillip, M., Buckingham, B. 2015; 17: S109-18
View details for DOI 10.1089/dia.2015.1513

View details for PubMedID 25679421
Diabetes Technology and the Human Factor DIABETES TECHNOLOGY & THERAPEUTICS Liberman, A., Phillip, M., Buckingham, B. 2015; 17: S109-S118
View details for DOI 10.1089/dia.2015.1513

View details for Web of Science ID 000349317800015

View details for PubMedID 25679421
The impact of accelerometer use in exercise-associated hypoglycemia prevention in type 1 diabetes. Journal of diabetes science and technology Stenerson, M., Cameron, F., Payne, S. R., Payne, S. L., Ly, T. T., Wilson, D. M., Buckingham, B. A. 2015; 9 (1): 80-85
Abstract

Exercise-associated hypoglycemia is a common adverse event in people with type 1 diabetes. Previous in silico testing by our group demonstrated superior exercise-associated hypoglycemia mitigation when a predictive low glucose suspend (PLGS) algorithm was augmented to incorporate activity data. The current study investigates the effectiveness of an accelerometer-augmented PLGS algorithm in an outpatient exercise protocol. Subjects with type 1 diabetes on insulin pump therapy participated in two structured soccer sessions, one utilizing the algorithm and the other using the subject's regular basal insulin rate. Each subject wore their own insulin pump and a Dexcom G4? Platinum continuous glucose monitor (CGM); subjects on-algorithm also wore a Zephyr BioHarness? 3 accelerometer. The algorithm utilized a Kalman filter with a 30-minute prediction horizon. Activity and CGM readings were manually entered into a spreadsheet and at five-minute intervals, the algorithm indicated whether the basal insulin infusion should be on or suspended; any changes were then implemented by study staff. The rate of hypoglycemia during and after exercise (until the following morning) was compared between groups. Eighteen subjects (mean age 13.4 � 3.7 years) participated in two separate sessions 7-22 days apart. The difference in meter blood glucose levels between groups at each rest period did not achieve statistical significance at any time point. Hypoglycemia during the session was recorded in three on-algorithm subjects, compared to six off-algorithm subjects. In the postexercise monitoring period, hypoglycemia occurred in two subjects who were on-algorithm during the session and four subjects who were off-algorithm. The accelerometer-augmented algorithm failed to prevent exercise-associated hypoglycemia compared to subjects on their usual basal rates. A larger sample size may have achieved statistical significance. Further research involving an automated system, a larger sample size, and an algorithm design that favors longer periods of pump suspension is necessary.

View details for DOI 10.1177/1932296814551045

View details for PubMedID 25231116
A novel method to detect pressure-induced sensor attenuations (PISA) in an artificial pancreas. Journal of diabetes science and technology Baysal, N., Cameron, F., Buckingham, B. A., Wilson, D. M., Chase, H. P., Maahs, D. M., Bequette, B. W. 2014; 8 (6): 1091-1096
Abstract

Continuous glucose monitors (CGMs) provide real-time interstitial glucose concentrations that are essential for automated treatment of individuals with type 1 diabetes. Miscalibration, noise spikes, dropouts, or pressure applied to the site (e.g., lying on the site while sleeping) can cause inaccurate glucose signals, which could lead to inappropriate insulin dosing decisions. These studies focus on the problem of pressure-induced sensor attenuations (PISAs) that occur overnight and can cause undesirable pump shut-offs in a predictive low glucose suspend system. The algorithm presented here uses real-time CGM readings without knowledge of meals, insulin doses, activity, sensor recalibrations, or fingerstick measurements. The real-time PISA detection technique was tested on outpatient "in-home" data from a predictive low-glucose suspend trial with over 1125 nights of data. A total of 178 sets were created by using different parameters for the PISA detection algorithm to illustrate its range of available performance. The tracings were reviewed via a web-based analysis tool by an engineer with an extensive expertise on analyzing clinical datasets and ~3% of the CGM readings were marked as PISA events which were used as the gold standard. It is shown that 88.34% of the PISAs were successfully detected by the algorithm, and the percentage of false detections could be reduced to 1.70% by altering the algorithm parameters. Use of the proposed PISA detection method can result in a significant decrease in undesirable pump suspensions overnight, and may lead to lower overnight mean glucose levels while still achieving a low risk of hypoglycemia.

View details for DOI 10.1177/1932296814553267

View details for PubMedID 25316716
Inpatient Trial of an Artificial Pancreas Based on Multiple Model Probabilistic Predictive Control with Repeated Large Unannounced Meals DIABETES TECHNOLOGY & THERAPEUTICS Cameron, F., Niemeyer, G., Wilson, D. M., Bequette, B. W., Benassi, K. S., Clinton, P., Buckingham, B. A. 2014; 16 (11): 728-734
Abstract

Closed-loop control of blood glucose levels in people with type 1 diabetes offers the potential to reduce the incidence of diabetes complications and reduce the patients' burden, particularly if meals do not need to be announced. We therefore tested a closed-loop algorithm that does not require meal announcement.A multiple model probabilistic predictive controller (MMPPC) was assessed on four patients, revised to improve performance, and then assessed on six additional patients. Each inpatient admission lasted for 32?h with five unannounced meals containing approximately 1?g/kg of carbohydrate per admission. The system used an Abbott Diabetes Care (Alameda, CA) Navigator(�) continuous glucose monitor (CGM) and Insulet (Bedford, MA) Omnipod(�) insulin pump, with the MMPPC implemented through the artificial pancreas system platform. The controller was initialized only with the patient's total daily dose and daily basal pattern.On a 24-h basis, the first cohort had mean reference and CGM readings of 179 and 167?mg/dL, respectively, with 53% and 62%, respectively, of readings between 70 and 180?mg/dL and four treatments for glucose values <70?mg/dL. The second cohort had mean reference and CGM readings of 161 and 142?mg/dL, respectively, with 63% and 78%, respectively, of the time spent euglycemic. There was one controller-induced hypoglycemic episode. For the 30 unannounced meals in the second cohort, the mean reference and CGM premeal, postmeal maximum, and 3-h postmeal values were 139 and 132, 223 and 208, and 168 and 156?mg/dL, respectively.The MMPPC, tested in-clinic against repeated, large, unannounced meals, maintained reasonable glycemic control with a mean blood glucose level that would equate to a mean glycated hemoglobin value of 7.2%, with only one controller-induced hypoglycemic event occurring in the second cohort.

View details for DOI 10.1089/dia.2014.0093

View details for Web of Science ID 000343419900006

View details for PubMedID 25259939

View details for PubMedCentralID PMC4201242
Multicenter Closed-Loop/Hybrid Meal Bolus Insulin Delivery with Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Chase, H. P., Doyle, F. J., Zisser, H., Renard, E., Nimri, R., Cobelli, C., Buckingham, B. A., Maahs, D. M., Anderson, S., Magni, L., Lum, J., Calhoun, P., Kollman, C., Beck, R. W. 2014; 16 (10): 623-632
Abstract

This study evaluated meal bolus insulin delivery strategies and associated postprandial glucose control while using an artificial pancreas (AP) system.This study was a multicenter trial in 53 patients, 12-65 years of age, with type 1 diabetes for at least 1 year and use of continuous subcutaneous insulin infusion for at least 6 months. Four different insulin bolus strategies were assessed: standard bolus delivered with meal (n=51), standard bolus delivered 15 min prior to meal (n=40), over-bolus of 30% delivered with meal (n=40), and bolus purposely omitted (n=46). Meal carbohydrate (CHO) intake was 1 g of CHO/kg of body weight up to a maximum of 100 g for the first three strategies or up to a maximum of 50 g for strategy 4.Only three of 177 meals (two with over-bolus and one with standard bolus 15 min prior to meal) had postprandial blood glucose values of <60 mg/dL. Postprandial hyperglycemia (blood glucose level >180 mg/dL) was prolonged for all four bolus strategies but was shorter for the over-bolus (41% of the 4-h period) than the two standard bolus strategies (73% for each). Mean postprandial blood glucose level was 15.9 mg/dL higher for the standard bolus with meal compared with the prebolus (baseline-adjusted, P=0.07 for treatment effect over the 4-h period).The AP handled the four bolus situations safely, but at the expense of having elevated postprandial glucose levels in most subjects. This was most likely secondary to suboptimal performance of the algorithm.

View details for DOI 10.1089/dia.2014.0050

View details for Web of Science ID 000342561100003

View details for PubMedID 25188375

View details for PubMedCentralID PMC4183919
Multicenter Closed-Loop Insulin Delivery Study Points to Challenges for Keeping Blood Glucose in a Safe Range by a Control Algorithm in Adults and Adolescents with Type 1 Diabetes from Various Sites DIABETES TECHNOLOGY & THERAPEUTICS Zisser, H., Renard, E., Kovatchev, B., Cobelli, C., Avogaro, A., Nimri, R., Magni, L., Buckingham, B. A., Chase, H. P., Doyle, F. J., Lum, J., Calhoun, P., Kollman, C., Dassau, E., Farret, A., Place, J., Breton, M., Anderson, S. M., Dalla Man, C., Del Favero, S., Bruttomesso, D., Filippi, A., Scotton, R., Phillip, M., Atlas, E., Muller, I., Miller, S., Toffanin, C., Raimondo, D. M., De Nicolao, G., Beck, R. W. 2014; 16 (10): 613-622
Abstract

The Control to Range Study was a multinational artificial pancreas study designed to assess the time spent in the hypo- and hyperglycemic ranges in adults and adolescents with type 1 diabetes while under closed-loop control. The controller attempted to keep the glucose ranges between 70 and 180 mg/dL. A set of prespecified metrics was used to measure safety.We studied 53 individuals for approximately 22 h each during clinical research center admissions. Plasma glucose level was measured every 15-30 min (YSI clinical laboratory analyzer instrument [YSI, Inc., Yellow Springs, OH]). During the admission, subjects received three mixed meals (1 g of carbohydrate/kg of body weight; 100 g maximum) with meal announcement and automated insulin dosing by the controller.For adults, the mean of subjects' mean glucose levels was 159 mg/dL, and mean percentage of values 71-180 mg/dL was 66% overall (59% daytime and 82% overnight). For adolescents, the mean of subjects' mean glucose levels was 166 mg/dL, and mean percentage of values in range was 62% overall (53% daytime and 82% overnight). Whereas prespecified criteria for safety were satisfied by both groups, they were met at the individual level in adults only for combined daytime/nighttime and for isolated nighttime. Two adults and six adolescents failed to meet the daytime criterion, largely because of postmeal hyperglycemia, and another adolescent failed to meet the nighttime criterion.The control-to-range system performed as expected: faring better overnight than during the day and performing with variability between patients even after individualization based on patients' prior settings. The system had difficulty preventing postmeal excursions above target range.

View details for DOI 10.1089/dia.2014.0066

View details for Web of Science ID 000342561100002

View details for PubMedID 25003311

View details for PubMedCentralID PMC4183913
Accuracy evaluation of blood glucose monitoring systems in children on overnight closed-loop control. Journal of diabetes science and technology DeSalvo, D. J., Shanmugham, S., Ly, T. T., Wilson, D. M., Buckingham, B. A. 2014; 8 (5): 969-973
Abstract

This pilot study evaluated the difference in accuracy between the Bayer Contour� Next (CN) and HemoCue� (HC) glucose monitoring systems in children with type 1 diabetes participating in overnight closed-loop studies. Subjects aged 10-18 years old were admitted to a clinical research center and glucose values were obtained every 30 minutes overnight. Glucose values were measured using whole blood samples for CN and HC readings and results were compared to Yellow Springs Instrument (YSI) reference values obtained with plasma from the same sample. System accuracy was compared using mean absolute relative difference (MARD) and International Organization for Standardization (ISO) accuracy standards. A total of 28 subjects were enrolled in the study. Glucose measurements were evaluated at 457 time points. CN performed better than HC with an average MARD of 3.13% compared to 10.73% for HC (P < .001). With a limited sample size, CN met ISO criteria (2003 and 2013) at all glucose ranges while HC did not. CN performed very well, and would make an excellent meter for future closed-loop studies outside of a research center.

View details for DOI 10.1177/1932296814532238

View details for PubMedID 24876427
Overnight glucose control with an automated, unified safety system in children and adolescents with type 1 diabetes at diabetes cAMP. Diabetes care Ly, T. T., Breton, M. D., Keith-Hynes, P., De Salvo, D., Clinton, P., Benassi, K., Mize, B., Chernavvsky, D., Place, J., Wilson, D. M., Kovatchev, B. P., Buckingham, B. A. 2014; 37 (8): 2310-2316
Abstract

To determine the safety and efficacy of an automated unified safety system (USS) in providing overnight closed-loop (OCL) control in children and adolescents with type 1 diabetes attending diabetes summer camps.RESEARCH DESIGN AND METHODS: The Diabetes Assistant (DIAS) USS used the Dexcom G4P glucose sensor (Dexcom) and t:slim insulin pump (Tandem Diabetes Care). An initial inpatient study was completed for 12 participants to evaluate safety. For the main camp study, 20 participants with type 1 diabetes were randomized to either OCL or sensor-augmented therapy (control conditions) per night over the course of a 5- to 6-day diabetes camp.RESULTS: Subjects completed 54 OCL nights and 52 control nights. On an intention-to-treat basis, with glucose data analyzed regardless of system status, the median percent time in range, from 70-150 mg/dL, was 62% (29, 87) for OCL nights versus 55% (25, 80) for sensor-augmented pump therapy (P = 0.233). A per-protocol analysis allowed for assessment of algorithm performance. The median percent time in range, from 70-150 mg/dL, was 73% (50, 89) for OCL nights (n = 41) versus 52% (24, 83) for control conditions (n = 39) (P = 0.037). There was less time spent in the hypoglycemic range <50, <60, and <70 mg/dL during OCL compared with the control period (P = 0.019, P = 0.009, and P = 0.023, respectively).CONCLUSIONS: The DIAS USS algorithm is effective in improving time spent in range as well as reducing nocturnal hypoglycemia during the overnight period in children and adolescents with type 1 diabetes in a diabetes camp setting.

View details for DOI 10.2337/dc14-0147

View details for PubMedID 24879841
A Randomized Trial of a Home System to Reduce Nocturnal Hypoglycemia in Type 1 Diabetes DIABETES CARE Maahs, D. M., Calhoun, P., Buckingham, B. A., Chase, H. P., Hramiak, I., Lum, J., Cameron, F., Bequette, B. W., Aye, T., Paul, T., Slover, R., Wadwa, R. P., Wilson, D. M., Kollman, C., Beck, R. W. 2014; 37 (7): 1885-1891
Abstract

Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels.Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15-45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ?1 CGM glucose values ?60 mg/dL occurred.Overnight hypoglycemia with at least one CGM value ?60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43-0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm.Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

View details for DOI 10.2337/dc13-2159

View details for Web of Science ID 000338020400022

View details for PubMedCentralID PMC4067393
A randomized trial of a home system to reduce nocturnal hypoglycemia in type 1 diabetes. Diabetes care Maahs, D. M., Calhoun, P., Buckingham, B. A., Chase, H. P., Hramiak, I., Lum, J., Cameron, F., Bequette, B. W., Aye, T., Paul, T., Slover, R., Wadwa, R. P., Wilson, D. M., Kollman, C., Beck, R. W. 2014; 37 (7): 1885-1891
Abstract

Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels.Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15-45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ?1 CGM glucose values ?60 mg/dL occurred.Overnight hypoglycemia with at least one CGM value ?60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43-0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm.Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

View details for DOI 10.2337/dc13-2159

View details for PubMedID 24804697
Evolution of abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the first 2 years after diagnosis. Diabetes care Sherr, J., Tsalikian, E., Fox, L., Buckingham, B., Weinzimer, S., Tamborlane, W. V., White, N. H., Arbelaez, A. M., Kollman, C., Ruedy, K. J., Cheng, P., Beck, R. W. 2014; 37 (6): 1741-1744
Abstract

To examine the evolution of the dysregulated glucagon responses to mixed-meal tolerance tests (MMTTs) in youth with recent-onset type 1 diabetes (T1D).MMTTs were performed in 25 youth (9-18 years of age) with 1.5-12 months disease duration (year 1); 22 subjects were restudied 1 year later (year 2). Twenty nondiabetic (ND) control children were also studied.In T1D children, MMTT-stimulated increases in glucagon were significantly greater than that in ND children (median increments: year 1, 21 pg/mL [16-30]; year 2, 25 pg/mL [16-30]; ND, 9 pg/mL [5-16]; P = 0.001 and P < 0.001, respectively).In comparison with ND control children, exaggerated plasma glucagon responses to mixed-meal feedings are observed in youth with T1D within the first 2 years of diagnosis. Further studies to determine whether suppression of these abnormal responses may help to improve glycemic control are warranted.

View details for DOI 10.2337/dc13-2612

View details for PubMedID 24696460
Effect of Lipohypertrophy on Dexcom G4p Continuous Glucose Sensor Desalvo, D. J., Ly, T., Clinton, P., Shanmugham, S., Buckingham, B. A. AMER DIABETES ASSOC. 2014: A221
View details for Web of Science ID 000359481601197
Effect of Shared Medical Appointments in Youth with Type 1 Diabetes in Poor Control Shah, A. C., Block, J. M., Floyd, B. D., Evans-Behnke, D., Hendry, D., Buckingham, B. A. AMER DIABETES ASSOC. 2014: A327
View details for Web of Science ID 000359481601580
Pediatric Diabetes Consortium Type 1 Diabetes New Onset (NeOn) Study: factors associated with HbA1c levels one year after diagnosis PEDIATRIC DIABETES Redondo, M. J., Connor, C. G., Ruedy, K. J., Beck, R. W., Kollman, C., Wood, J. R., Buckingham, B., Klingensmith, G. J., Silverstein, J., Tamborlane, W. V. 2014; 15 (4): 294-302
Abstract

To identify determinants of hemoglobin A1c (HbA1c) levels 1 yr after the diagnosis of type 1 diabetes (T1D) in participants in the Pediatric Diabetes Consortium (PDC) T1D New Onset (NeOn) Study.Diabetes-specific as well as socioeconomic factors during the first year following diagnosis were analyzed in 857 participants (mean age 9.1?yrs, 51% female, 66% non-Hispanic White) not participating in an intervention study who had an HbA1c value at 12?months.Mean � SD HbA1c at 1 yr was 62?�?16?mmol/mol (7.8%?�?1.5). In univariate and multivariate analyses, clinical center, non-Hispanic White race, private health insurance, living with both parents, higher frequency of self-monitoring of blood glucose (SMBG), and lower insulin requirements were associated with lower HbA1c concentrations at 1 yr (p?
View details for DOI 10.1111/pedi.12061

View details for Web of Science ID 000337560400005

View details for PubMedID 23889707

View details for PubMedCentralID PMC3858510
Frequency of Morning Ketosis After Overnight Insulin Suspension Using an Automated Nocturnal Predictive Low Glucose Suspend System DIABETES CARE Beck, R. W., Raghinaru, D., Wadwa, R. P., Chase, H. P., Maahs, D. M., Buckingham, B. A. 2014; 37 (5): 1224-1229
Abstract

To assess the effect of overnight insulin pump suspension in an automated predictive low glucose suspend system on morning blood glucose and ketone levels in an attempt to determine whether routine measurement of ketone levels is useful when a closed-loop system that suspends insulin delivery overnight is being used.Data from an in-home randomized trial of 45 individuals with type 1 diabetes (age range 15-45 years) were analyzed, evaluating an automated predictive low glucose pump suspension system in which blood glucose, blood ketone, and urine ketone levels were measured on 1,954 mornings.One or more pump suspensions occurred during 744 of the 977 intervention nights (76%). The morning blood ketone level was ?0.6 mmol/L after 11 of the 744 nights (1.5%) during which a pump suspension occurred and 2 of the 233 nights (0.9%) during which there was no suspension compared with 11 of 977 control nights (1.1%). The morning blood ketone level was ?0.6 mmol/L after only 2 of 159 nights (1.3%) with a pump suspension exceeding 2 h. Morning fasting blood glucose level was not a good predictor of the presence of blood ketones.Routine measurement of blood or urine ketones during use of an automated pump suspension system using continuous glucose monitoring, whether threshold based or predictive, is not necessary. Recommendations for checking ketone levels should be no different when a patient is using a system with automated insulin suspension than it is for conventional diabetes self-management.

View details for DOI 10.2337/dc13-2775

View details for Web of Science ID 000334840100034

View details for PubMedID 24757229

View details for PubMedCentralID PMC3994933
Hypoglycemia Begets Hypoglycemia: The Order Effect in the ASPIRE In-Clinic Study. Diabetes technology & therapeutics Garg, S. K., Brazg, R. L., Bailey, T. S., Buckingham, B. A., Slover, R. H., Klonoff, D. C., Shin, J., Welsh, J. B., Kaufman, F. R. 2014; 16 (3): 125-130
Abstract

Abstract Background: The ASPIRE in-clinic study established that automatic suspension of insulin with the threshold suspend (TS) feature reduces the duration of induced hypoglycemia. The study's crossover design allowed the effects of antecedent hypoglycemia to be studied. Subjects and Methods: The study enrolled 50 subjects who exercised until plasma glucose (YSI glucose and lactate analyzer; YSI, Inc., Yellow Springs, OH) reached ?85?mg/dL. Hypoglycemia was evaluated after the YSI value reached <70?mg/dL. In TS experiments, insulin was stopped for 2?h once a sensor glucose (SG) value of ?70?mg/dL was detected; in control experiments, basal insulin delivery continued. Subjects were randomly assigned to Group A (TS in Period 1; control in Period 2) or Group B (control in Period 1; TS in Period 2). Experiments were separated by 3-10 days. Results: Hypoglycemia was 63.7?min shorter in Period 1 TS experiments (no preceding control experiment) than in Period 2 TS experiments (one or more preceding control experiment(s)) (P<0.01). The number of experiments prior to a successful TS experiment was lower for Period 1 than for Period 2 (0.36�0.64 vs. 1.57�0.84; P<0.001), as was the cumulative duration of antecedent hypoglycemia (16.6?min vs. 204.6 min; P<0.001). The between-groups difference in hypoglycemia duration was not attributable to differences in SG rates of change, the duration of exercise, or area under the curve of <70?mg/dL�min in the 2 days before the successful experiment (all P>0.3). Conclusions: The TS feature's ability to mitigate hypoglycemia was decreased by an episode or episodes of prolonged antecedent hypoglycemia, suggesting hypoglycemia begets hypoglycemia. The effect of antecedent hypoglycemia should be taken into consideration in the design of future experiments assessing strategies to reduce hypoglycemia.

View details for DOI 10.1089/dia.2013.0219

View details for PubMedID 24405492
Blunted glucagon but not epinephrine responses to hypoglycemia occurs in youth with less than 1 yr duration of type 1 diabetes mellitus PEDIATRIC DIABETES Arbelaez, A. M., Xing, D., Cryer, P. E., Kollman, C., Beck, R. W., Sherr, J., Ruedy, K. J., Tamborlane, W. V., Mauras, N., Tsalikian, E., Wilson, D. M., White, N. H. 2014; 15 (2): 127-134
Abstract

Glycemic control is limited by the barrier of hypoglycemia. Recurrent hypoglycemia impairs counterregulatory (CR) hormone responses to subsequent hypoglycemia.To determine the glucagon and epinephrine responses to insulin-induced hypoglycemia in adolescents with recent-onset type 1 diabetes mellitus (T1DM).We assessed the CR responses to hypoglycemia by performing a hyperinsulinemic (2.0 mU/kg/min), euglycemic (BG 90 mg/dL; 5.0 mmol/L)-hypoglycemic (BG 55 mg/dL; 3.0 mmol/L) clamp in 25 recent-onset (<1 yr duration) patients 9-18 yr old (mean � SD: 13.4 � 2.7) with T1DM and 16 non-diabetic controls 19-25 yr old (mean � SD 23.3 � 1.8). Twenty of the T1DM subjects were retested 1-yr (53 � 3 wk) later.At the initial and 1-yr studies, peak glucagon (pGON) and incremental glucagon (?GON) during hypoglycemia were lower in the T1DM subjects [median pGON = 47 pg/mL (quartiles: 34, 72), ?GON?= 16 (4, 27) initially and pGON?= 50 pg/mL (42, 70), ?GON?= 12 (9, 19) at 1-yr] than in controls [pGON?= 93 pg/mL (60, 111); ?GON?= 38 pg/mL (19, 66), p = 0.01 and p = 0.004 for ?GON at initial and 1-yr study, respectively]. In contrast, peak epinephrine (pEPI) and incremental epinephrine (?EPI) levels were similar in the T1DM (pEPI = 356 pg/mL (174, 797) and ?EPI?= 322 pg/mL (143, 781) initially and pEPI = 469 pg/mL (305, 595) and ?EPI?= 440 pg/mL (285, 574) at 1 yr) and in controls (pEPI?= 383 pg/mL (329, 493) and ?EPI?= 336 pg/mL (298, 471) p = 0.97 and 0.21 for ?EPI at initial and 1-yr study, respectively).Even within the first year of T1DM, glucagon responses to hypoglycemia are blunted but epinephrine responses are not, suggesting that the mechanisms involved in the loss of these hormonal responses, which are key components in pathophysiology of hypoglycemia-associated autonomic failure, are different.

View details for DOI 10.1111/pedi.12070

View details for Web of Science ID 000333060300007

View details for PubMedID 23992543

View details for PubMedCentralID PMC3858506
Alterations in white matter structure in young children with type 1 diabetes. Diabetes care Barnea-Goraly, N., Raman, M., Mazaika, P., Marzelli, M., Hershey, T., Weinzimer, S. A., Aye, T., Buckingham, B., Mauras, N., White, N. H., Fox, L. A., Tansey, M., Beck, R. W., Ruedy, K. J., Kollman, C., Cheng, P., Reiss, A. L. 2014; 37 (2): 332-340
Abstract

To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

View details for DOI 10.2337/dc13-1388

View details for PubMedID 24319123

View details for PubMedCentralID PMC3898758
Cognitive functioning in young children with type 1 diabetes. Journal of the International Neuropsychological Society Cato, M. A., Mauras, N., Ambrosino, J., Bondurant, A., Conrad, A. L., Kollman, C., Cheng, P., Beck, R. W., Ruedy, K. J., Aye, T., Reiss, A. L., White, N. H., Hershey, T. 2014; 20 (2): 238-247
Abstract

The aim of this study was to assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10 years across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data, and T1D glycemic history since diagnosis were collected. The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5 years and average onset age was 4 years. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < .001). Learning and memory (p = .46) and processing speed (p = .25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time. (JINS, 2014, 20, 238-247).

View details for DOI 10.1017/S1355617713001434

View details for PubMedID 24512675
Diabetes technology and the human factor. Diabetes technology & therapeutics Liberman, A., Buckingham, B., Phillip, M. 2014; 16: S110-8
View details for DOI 10.1089/dia.2014.1513

View details for PubMedID 24479592

View details for PubMedCentralID PMC3920750
Remote Glucose Monitoring in Camp Setting Reduces the Risk of Prolonged Nocturnal Hypoglycemia DIABETES TECHNOLOGY & THERAPEUTICS DeSalvo, D. J., Keith-Hynes, P., Peyser, T., Place, J., Caswell, K., Wilson, D. M., Harris, B., Clinton, P., Kovatchev, B., Buckingham, B. A. 2014; 16 (1): 1-7
Abstract

This study tested the feasibility and effectiveness of remote continuous glucose monitoring (CGM) in a diabetes camp setting.Twenty campers (7-21 years old) with type 1 diabetes were enrolled at each of three camp sessions lasting 5-6 days. On alternating nights, 10 campers were randomized to usual wear of a Dexcom (San Diego, CA) G4? PLATINUM CGM system, and 10 were randomized to remote monitoring with the Dexcom G4 PLATINUM communicating with the Diabetes Assistant, a cell phone platform, to allow wireless transmission of CGM values. Up to 15 individual graphs and sensor values could be displayed on a single remote monitor or portable tablet. An alarm was triggered for values <70?mg/dL, and treatment was given for meter-confirmed hypoglycemia. The primary end point was to decrease the duration of hypoglycemic episodes <50?mg/dL.There were 320 nights of CGM data and 197 hypoglycemic events. Of the remote monitoring alarms, 79% were true (meter reading of <70?mg/dL). With remote monitoring, 100% of alarms were responded to, whereas without remote monitoring only 54% of alarms were responded to. The median duration of hypoglycemic events <70?mg/dL was 35?min without remote monitoring and 30?min with remote monitoring (P=0.078). Remote monitoring significantly decreased prolonged hypoglycemic events, eliminating all events <50?mg/dL lasting longer than 30?min as well as all events <70?mg/dL lasting more than 2?h.Remote monitoring is feasible at diabetes camps and effective in reducing the risk of prolonged nocturnal hypoglycemia. This technology will facilitate forthcoming studies to evaluate the efficacy of automated closed-loop systems in the camp setting.

View details for DOI 10.1089/dia.2013.0139

View details for PubMedID 24168317
The Impact of Accelerometer and Heart Rate Data on Hypoglycemia Mitigation in Type 1 Diabetes. Journal of diabetes science and technology Stenerson, M., Cameron, F., Wilson, D. M., Harris, B., Payne, S., Bequette, B. W., Buckingham, B. A. 2014; 8 (1): 64-69
Abstract

Aerobic exercise can lower blood glucose levels and alter insulin sensitivity both during and several hours after exercise, creating challenges for a closed-loop artificial pancreas. Predictive low glucose suspend (PLGS) algorithms are a first step toward an artificial pancreas, but few of these have been successfully applied to exercise. This study incorporates physical activity measurements from a combined accelerometer/heart rate monitor (HRM) to improve the performance of an existing PLGS algorithm at mitigating exercise-associated hypoglycemia in participants with type 1 diabetes. In all, 22 subjects with type 1 diabetes on insulin pump therapy were provided a combined accelerometer/HRM and (if not already using one) a continuous glucose monitor (CGM), then instructed to go about their everyday lives while wearing the devices. After the monitoring period, each subject's insulin pump, CGM, and accelerometer/HRM were downloaded and the data were used to augment an existing PLGS algorithm to incorporate activity. Using a computer simulator, the accelerometer-augmented algorithm was compared to the HRM-augmented algorithm to determine which was most effective at mitigating hypoglycemia. Mean length of monitoring was 4.9 days. Across all subjects, 11 061 CGM readings were recorded during the monitoring period. In the simulator analysis, the PLGS algorithm reduced hypoglycemia by 62%, compared to 71% and 74% reductions for the HRM-augmented and accelerometer-augmented algorithms, respectively; combined accelerometer and HRM augmentation provided a 76% reduction. In a simulated setting, the accelerometer-augmented pump suspension algorithm decreases the incidence of exercise-related hypoglycemia by a meaningful amount compared to the PLGS algorithm alone. Results also failed to justify the additional user burden of a HRM.

View details for PubMedID 24876539
Alterations in white matter structure in young children with type 1 diabetes mellitus DIABETES CARE Barnea-Goraly, N., Raman, M., Mazaika, P., Marzelli, M., et al 2014: 332?40
Abstract

To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

View details for DOI 10.2337/dc13-1388

View details for PubMedCentralID PMC3898758
Randomized Trial of Infusion Set Function: Steel Versus Teflon DIABETES TECHNOLOGY & THERAPEUTICS Patel, P. J., Benasi, K., Ferrari, G., Evans, M. G., Shanmugham, S., Wilson, D. M., Buckingham, B. A. 2014; 16 (1): 15-19
Abstract

This study compared infusion set function for up to 1 week using either a Teflon(�) (Dupont(?), Wilmington, DE) catheter or a steel catheter for insulin pump therapy in type 1 diabetes mellitus.Twenty subjects participating in a randomized, open-labeled, crossover study were asked to wear two Quick-Set(�) and two Sure-T(�) infusion sets (both from Medtronic Minimed, Northridge, CA) until the infusion set failed or was worn for 1 week. All subjects wore a MiniMed continuous glucose monitoring system for the duration of the study.One subject withdrew from the study. There were 38 weeks of Sure-T wear and 39 weeks of Quick-Set wear with no difference in the survival curves of the infusion sets. There was, however, a 15% initial failure rate with the Teflon infusion set. After 7 days, both types of infusion sets had a 64% failure rate. Overall, 30% failed because of hyperglycemia and a failed correction dose, 13% were removed for pain, 10% were pulled out by accident, 10% had erythema and/or induration of>10?mm, 5% fell out because of loss of adhesion, and 4% were removed for infection. The main predictor of length of wear was the individual subject. There was no increase in hyperglycemia or daily insulin requirements when an infusion set was successfully used for 7 days (n=25 of 77 weeks).We found no difference between steel and Teflon infusion sets in their function over 7 days, although 15% of Teflon sets failed because of kinking on insertion. The strongest predictor of prolonged 7-day infusion set function was the individual subject, not the type of infusion set.

View details for DOI 10.1089/dia.2013.0119

View details for Web of Science ID 000329298500003

View details for PubMedID 24090124

View details for PubMedCentralID PMC3887416
Neuroanatomical correlates of dysglycemia in young children with type 1 diabetes. Diabetes Marzelli, M. J., Mazaika, P. K., Barnea-Goraly, N., Hershey, T., Tsalikian, E., Tamborlane, W., Mauras, N., White, N. H., Buckingham, B., Beck, R. W., Ruedy, K. J., Kollman, C., Cheng, P., Reiss, A. L. 2014; 63 (1): 343-353
Abstract

Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 � 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development.

View details for DOI 10.2337/db13-0179

View details for PubMedID 24170697
Effectiveness of Early Intensive Therapy on beta-Cell Preservation in Type 1 Diabetes DIABETES CARE Buckingham, B., Beck, R. W., Ruedy, K. J., Cheng, P., Kollman, C., Weinzimer, S. A., Dimeglio, L. A., Bremer, A. A., Slover, R., Tamborlane, W. V. 2013; 36 (12): 4030-4035
Abstract

To assess effectiveness of inpatient hybrid closed-loop control (HCLC) followed by outpatient sensor-augmented pump (SAP) therapy initiated within 7 days of diagnosis of type 1 diabetes on the preservation of ?-cell function at 1 year.Sixty-eight individuals (mean age 13.3 � 5.7 years; 35% female, 92% Caucasian) were randomized to HCLC followed by SAP therapy (intensive group; N = 48) or to the usual-care group treated with multiple daily injections or insulin pump therapy (N = 20). Primary outcome was C-peptide concentrations during mixed-meal tolerance tests at 12 months.Intensive-group participants initiated HCLC a median of 6 days after diagnosis for a median duration of 71.3 h, during which median participant mean glucose concentration was 140 mg/dL (interquartile range 134-153 mg/dL). During outpatient SAP, continuous glucose monitor (CGM) use decreased over time, and at 12 months, only 33% of intensive participants averaged sensor use ?6 days/week. In the usual-care group, insulin pump and CGM use were initiated prior to 12 months by 15 and 5 participants, respectively. Mean HbA1c levels were similar in both groups throughout the study. At 12 months, the geometric mean (95% CI) of C-peptide area under the curve was 0.43 (0.34-0.52) pmol/mL in the intensive group and 0.52 (0.32-0.75) pmol/mL in the usual-care group (P = 0.49). Thirty-seven (79%) intensive and 16 (80%) usual-care participants had a peak C-peptide concentration ?0.2 pmol/mL (P = 0.30).In new-onset type 1 diabetes, HCLC followed by SAP therapy did not provide benefit in preserving ?-cell function compared with current standards of care.

View details for DOI 10.2337/dc13-1074

View details for Web of Science ID 000327211500053

View details for PubMedID 24130350
Race, Socioeconomic Status, and Treatment Center Are Associated with Insulin Pump Therapy in Youth in the First Year Following Diagnosis of Type 1 Diabetes DIABETES TECHNOLOGY & THERAPEUTICS Lin, M. H., Connor, C. G., Ruedy, K. J., Beck, R. W., Kollman, C., Buckingham, B., Redondo, M. J., Schatz, D., Haro, H., Lee, J. M., Tamborlane, W. V., Wood, J. R. 2013; 15 (11): 929-934
Abstract

Increasing numbers of children and adolescents with type 1 diabetes (T1D) have been placed on insulin pump therapy. Nevertheless, data are limited regarding patterns of pump use during the first year of treatment and the clinical and socioeconomic factors associated with early use of pump therapy. Therefore, we sought to determine factors associated with pump therapy within the first year of diagnosis in youth enrolled in the Pediatric Diabetes Consortium (PDC) T1D New-Onset (NeOn) Study.The NeOn Study includes youth <19 years old at T1D diagnosis who have been followed from the time of diagnosis at seven U.S. pediatric diabetes centers. Cox regression was used to determine factors associated with transition from injection to pump therapy during the first year of T1D in 1,012 participants.Twenty-seven percent (n=254) of participants began pump therapy within the first year of diagnosis, ranging from 18% to 59% among the seven centers. After adjusting for center effect, factors associated with pump use in multivariate analysis included private health insurance (37% vs. 7%; P<0.001), having annual household income over $100,000 (50% vs. 15%; P<0.001), and non-Hispanic white race (36% vs. 11%; P<0.001). The hemoglobin A1c level did not appear to influence the decision to initiate pump use.Participants of non-Hispanic white race and higher socioeconomic status were more likely to be placed on pumps during the first year. Further investigations are needed to gain a better understanding of barriers to use of pumps in youth with T1D, especially in disadvantaged and minority families.

View details for DOI 10.1089/dia.2013.0132

View details for Web of Science ID 000326401400005

View details for PubMedID 23869706

View details for PubMedCentralID PMC3817890
DiAs web monitoring: a real-time remote monitoring system designed for artificial pancreas outpatient trials. Journal of diabetes science and technology Place, J., Robert, A., Ben Brahim, N., Keith-Hynes, P., Farret, A., Pelletier, M., Buckingham, B., Breton, M., Kovatchev, B., Renard, E. 2013; 7 (6): 1427-1435
Abstract

Developments in an artificial pancreas (AP) for patients with type 1 diabetes have allowed a move toward performing outpatient clinical trials. "Home-like" environment implies specific protocol and system adaptations among which the introduction of remote monitoring is meaningful. We present a novel tool allowing multiple patients to monitor AP use in home-like settings.We investigated existing systems, performed interviews of experienced clinical teams, listed required features, and drew several mockups of the user interface. The resulting application was tested on the bench before it was used in three outpatient studies representing 3480 h of remote monitoring.Our tool, called DiAs Web Monitoring (DWM), is a web-based application that ensures reception, storage, and display of data sent by AP systems. Continuous glucose monitoring (CGM) and insulin delivery data are presented in a colored chart to facilitate reading and interpretation. Several subjects can be monitored simultaneously on the same screen, and alerts are triggered to help detect events such as hypoglycemia or CGM failures. In the third trial, DWM received approximately 460 data per subject per hour: 77% for log messages, 5% for CGM data. More than 97% of transmissions were achieved in less than 5 min.Transition from a hospital setting to home-like conditions requires specific AP supervision to which remote monitoring systems can contribute valuably. DiAs Web Monitoring worked properly when tested in our outpatient studies. It could facilitate subject monitoring and even accelerate medical and technical assessment of the AP. It should now be adapted for long-term studies with an enhanced notification feature.

View details for PubMedID 24351169
Continuous glucose monitoring: current use and future directions. Current diabetes reports DeSalvo, D., Buckingham, B. 2013; 13 (5): 657-662
Abstract

Continuous glucose monitoring (CGM) is an emerging technology that provides a continuous measure of interstitial glucose levels. In addition to providing a more complete pattern of glucose excursions, CGMs utilize real-time alarms for thresholds and predictions of hypo- and hyperglycemia, as well as rate of change alarms for rapid glycemic excursions. CGM users have been able to improve glycemic control without increasing their risk of hypoglycemia. Sensor accuracy, reliability, and wearability are important challenges to CGM success and are critical to the development of an artificial pancreas (or closed-loop system).

View details for DOI 10.1007/s11892-013-0398-4

View details for PubMedID 23943230
Outpatient Safety Assessment of an In-Home Predictive Low-Glucose Suspend System with Type 1 Diabetes Subjects at Elevated Risk of Nocturnal Hypoglycemia DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B. A., Cameron, F., Calhoun, P., Maahs, D. M., Wilson, D. M., Chase, H. P., Bequette, B. W., Lum, J., Sibayan, J., Beck, R. W., Kollman, C. 2013; 15 (8): 622-627
Abstract

Abstract Objective: Nocturnal hypoglycemia is a common problem with type 1 diabetes. In the home setting, we conducted a pilot study to evaluate the safety of a system consisting of an insulin pump and continuous glucose monitor communicating wirelessly with a bedside computer running an algorithm that temporarily suspends insulin delivery when hypoglycemia is predicted. Research Design and Methods: After the run-in phase, a 21-night randomized trial was conducted in which each night was randomly assigned 2:1 to have either the predictive low-glucose suspend (PLGS) system active (intervention night) or inactive (control night). Three predictive algorithm versions were studied sequentially during the study for a total of 252 intervention and 123 control nights. The trial included 19 participants 18-56 years old with type 1 diabetes (hemoglobin A1c level of 6.0-7.7%) who were current users of the MiniMed Paradigm(�) REAL-Time Revel? System and Sof-sensor(�) glucose sensor (Medtronic Diabetes, Northridge, CA). Results: With the final algorithm, pump suspension occurred on 53% of 77 intervention nights. Mean morning glucose level was 144�48?mg/dL on the 77 intervention nights versus 133�57?mg/dL on the 37 control nights, with morning blood ketones >0.6 mmol/L following one intervention night. Overnight hypoglycemia was lower on intervention than control nights, with at least one value ?70?mg/dL occurring on 16% versus 30% of nights, respectively, with the final algorithm. Conclusions: This study demonstrated that the PLGS system in the home setting is safe and feasible. The preliminary efficacy data appear promising with the final algorithm reducing nocturnal hypoglycemia by almost 50%.

View details for DOI 10.1089/dia.2013.0040

View details for PubMedID 23883408
Lack of Association Between Residual Insulin Production and Glucagon Response to Hypoglycemia in Youth With Short Duration of Type 1 Diabetes DIABETES CARE Sherr, J., Xing, D., Ruedy, K. J., Beck, R. W., Kollman, C., Buckingham, B., White, N. H., Fox, L., Tsalikian, E., Weinzimer, S., Arbelaez, A. M., Tamborlane, W. V. 2013; 36 (6): 1470-1476
Abstract

To examine the loss of glucagon response to hypoglycemia and its relationship with residual ?-cell function early in the course of type 1 diabetes (T1D) in youth.Twenty-one youth with T1D duration <1 year (ages 8-18 years, T1D duration 6-52 weeks) underwent mixed-meal tolerance tests (MMTTs) to assess residual ?-cell function and hypoglycemic clamps to assess glucagon responses to hypoglycemia. Glucagon responses to hypoglycemia in T1D subjects were compared with those in 12 nondiabetic young adults (ages 19-25 years).Peak MMTT-stimulated C-peptide levels (range 0.12-1.43) were ? 0.2 nmol/L in all but one T1D subject. As expected, the median of glucagon responses to hypoglycemia in the T1D subjects (18 pg/mL [interquartile range 7-32]) was significantly reduced compared with the responses in nondiabetic control subjects (38 pg/mL [19-66], P = 0.02). However, there was no correlation between the incremental increase in plasma glucagon during the hypoglycemic clamp and the incremental increase and peak plasma C-peptide level during the MMTT. Similarly, the seven T1D subjects who failed to achieve an increase in glucagon ? 12 pg/mL (i.e., 3 SD above baseline values) had C-peptide response ? 0.2 nmol/L (0.54-1.12), and the one T1D subject with peak stimulated <0.2 nmol/L had a 14 pg/mL increase in plasma glucagon in response to hypoglycemia.Impaired plasma glucagon responses to hypoglycemia are evident in youth with T1D during the first year of the disease. Moreover, defective and absent glucagon responses to hypoglycemia were observed in patients who retained clinically important residual endogenous ?-cell function.

View details for DOI 10.2337/dc12-1697

View details for Web of Science ID 000321472600007

View details for PubMedID 23288858

View details for PubMedCentralID PMC3661789
The Effects of Inpatient Hybrid Closed-Loop Therapy Initiated Within 1 Week of Type 1 Diabetes Diagnosis DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B. A., Beck, R. W., Ruedy, K. J., Cheng, P., Kollman, C., Weinzimer, S. A., Dimeglio, L. A., Bremer, A. A., Slover, R., Cantwell, M., Tsalikian, E., Tansey, M. J., Coffey, J., Cabbage, J., Salamati, S., Mauras, N., Fox, L. A., Englert, K., Permuy, J., Sikes, K., Buckingham, B. A., Wilson, D. M., Clinton, P., Caswell, K., Weinzimer, S. A., Tamborlane, W. V., Sherr, J., Steffen, A., Weyman, K., Zgorski, M., Tichy, E., White, N. H., Arbelaez, A. M., Levandoski, L., Starnes, A., Skyler, J. S., Greenbaum, C. J., Kenyon, N. S., Rafkin, L., Santiago, I., Sosenko, J. M. 2013; 15 (5): 401-408
View details for DOI 10.1089/dia.2013.0002

View details for Web of Science ID 000318477700007
The effects of inpatient hybrid closed-loop therapy initiated within 1 week of type 1 diabetes diagnosis. Diabetes technology & therapeutics Buckingham, B. A., Beck, R. W., Ruedy, K. J., Cheng, P., Kollman, C., Weinzimer, S. A., Dimeglio, L. A., Bremer, A. A., Slover, R., Cantwell, M. 2013; 15 (5): 401-408
Abstract

This article describes our experience with inpatient hybrid closed-loop control (HCLC) initiated shortly after the diagnosis of type 1 diabetes in a randomized trial designed to assess the effectiveness of inpatient HCLC followed by outpatient sensor-augmented pump (SAP) therapy on the preservation of ?-cell function.Forty-eight individuals with newly diagnosed type 1 diabetes and positive pancreatic autoantibodies (7.8-37.7 years old) received inpatient HCLC therapy for up to 93 h, initiated within 7 days of diagnosis.On initiation of HCLC, mean glucose concentration was 240�100 mg/dL. During the first day of HCLC, median of the participant's mean glucose concentrations fell rapidly to 146 mg/dL, a level of control that was sustained on Days 2 and 3 (138 mg/dL and 139 mg/dL, respectively). By Day 3, the median percentage of glucose values >250 and <60 mg/dL was <1%. During the first 2 weeks of SAP treatment at home, the median participant mean glucose level was 126 mg/dL (interquartile range, 117, 137 mg/dL), and the median percentage of values between 71 and 180 mg/dL was 85% (interquartile range, 80%, 90%).Inpatient HCLC followed by outpatient SAP therapy can provide a safe and effective means to rapidly reverse glucose toxicity and establish near-normal glycemic control in patients with newly diagnosed type 1 diabetes.

View details for DOI 10.1089/dia.2013.0002

View details for PubMedID 23570538
Recommendations for Standardizing Glucose Reporting and Analysis to Optimize Clinical Decision Making in Diabetes: The Ambulatory Glucose Profile (AGP) DIABETES TECHNOLOGY & THERAPEUTICS Bergenstal, R. M., Ahmann, A. J., Bailey, T., Beck, R. W., Bissen, J., Buckingham, B., Deeb, L., Dolin, R. H., Garg, S. K., Goland, R., Hirsch, I. B., Klonoff, D. C., Kruger, D. F., Matfin, G., Mazze, R. S., Olson, B. A., Parkin, C., Peters, A., Powers, M. A., Rodriguez, H., Southerland, P., Strock, E. S., Tamborlane, W., Wesley, D. M. 2013; 15 (3): 198-211
Abstract

Abstract Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardization of analysis and presentation of glucose monitoring data, with the initial focus on data derived from CGM systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile (AGP), and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This paper provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients.

View details for DOI 10.1089/dia.2013.0051

View details for Web of Science ID 000316064500004

View details for PubMedID 23448694
DOES INTENSIVE METABOLIC CONTROL AT THE ONSET OF DIABETES FOLLOWED BY ONE YEAR OF SENSOR AUGMENTED PUMP THERAPY IMPROVE C-PEPTIDE LEVELS ONE YEAR POST DIAGNOSIS? Buckingham, B., Ruedy, K., Chase, H. P., Weinzimer, S., DiMeglio, L., Russell, W., Wilson, D., Tamborlane, W., Bremer, A., Sherr, J., Slover, R., KOLLMAN, C., Cheng, P., Beck, R. MARY ANN LIEBERT INC. 2013: A137?A137
View details for Web of Science ID 000315467200379
RANDOMIZED TRIAL OF REMOTE NOCTURNAL CONTINUOUS GLUCOSE MONITORING AT DIABETES CAMPS USING THE DEXCOM G4 PLATINUM AND DIAS Buckingham, B., Keith-Hynes, P., PEYSER, T., DeSalvo, D., Caswell, K., Ferrari, G., Wilson, D., Anjo, B., Harris, B., Clinton, P., Place, J., Mize, L. B., Kovatchev, B. MARY ANN LIEBERT INC. 2013: A56?A56
View details for Web of Science ID 000315467200153
Diabetes Technology and the Human Factor DIABETES TECHNOLOGY & THERAPEUTICS Liberman, A., Buckingham, B., Phillip, M. 2013; 15: S117-S125
View details for DOI 10.1089/dia.2013.1513

View details for Web of Science ID 000315467200402

View details for PubMedID 23441700
RACE AND SOCIOECONOMIC STATUS ARE ASSOCIATED WITH INSULIN PUMP THERAPY IN YOUTH IN THE FIRST YEAR FOLLOWING DIAGNOSIS OF TYPE 1 DIABETES Wood, J., Lin, M., Connor, C., Ruedy, K., Beck, R., KOLLMAN, C., Buckingham, B., Redondo, M. J., Schatz, D., Haro, H., Lee, J., Tamborlane, W. MARY ANN LIEBERT INC. 2013: A25?A26
View details for Web of Science ID 000315467200071
USING ACTIVITY MONITORS TO IMPROVE CGM SENSOR ANOMALY DETECTION BAYSAL, N., Cameron, F., Stenerson, M., Buckingham, B. A., Wilson, D. M., Mayer-Davis, E. J., Maahs, D. M., Bequette, B. W. MARY ANN LIEBERT INC. 2013: A2?A2
View details for Web of Science ID 000315467200005
BENEFITS OF ACCELEROMETER AND HEART RATE DATA FOR HYPOGLYCEMIA MITIGATION Cameron, F., Stenerson, M., Wilson, D. M., Maahs, D. M., Mayer-Davis, E. J., Bequette, B. W., Buckingham, B. A. MARY ANN LIEBERT INC. 2013: A93?A93
View details for Web of Science ID 000315467200257
Acceptability and utility of the mySentry remote glucose monitoring system. Journal of diabetes science and technology Kaiserman, K., Buckingham, B. A., Prakasam, G., Gunville, F., Slover, R. H., Wang, Y., Nguyen, X., Welsh, J. B. 2013; 7 (2): 356-361
Abstract

The mySentry system (Medtronic Inc.) is the first to amplify and relay continuous glucose monitoring (CGM) and insulin pump data to a remote site within the house. Its usability and acceptability were evaluated in families having a child with type 1 diabetes.Each enrolled family included a child (age 7-17 years) who used a Paradigm REAL-Time Revel sensor-augmented insulin pump (Medtronic). After a 1-week run-in phase, families set up and used the mySentry system for a 3-week study phase. Opinion surveys were completed by parents, and pump and CGM data were collected and analyzed retrospectively. No formal hypothesis testing was performed, and the study was not powered to detect changes in nocturnal glycemia.Thirty-five families completed the study. Enrolled children (61.1% female) had a mean (� standard deviation) age of 11.9 � 2.70 years and a mean age at initiation of pump therapy of 7.1 � 3.19 years. Baseline survey results indicated that most parents were fearful of their unawareness of their children's nocturnal glucose excursions. The mySentry system met the predefined acceptability criteria for general experience, product usability, and training materials. There were no unanticipated device-related adverse effects. Among children who experienced nocturnal hypo- or hyperglycemic episodes in both phases of the study, there was a trend toward less frequent and less prolonged episodes during mySentry use.The mySentry system met all predefined criteria for acceptability and did not demonstrate safety issues. Alerting parents to abnormal glucose values or trends may attenuate nocturnal hypoglycemia and hyperglycemia by prompting appropriate and timely intervention.

View details for PubMedID 23566993
Detecting Sensor and Insulin Infusion Set Anomalies in an Artificial Pancreas American Control Conference (ACC) Baysal, N., Cameron, F., Buckingham, B. A., Wilson, D. M., Bequette, B. W. IEEE. 2013: 2929?2933
View details for Web of Science ID 000327210203018
White Matter Structural Differences in Young Children With Type 1 Diabetes: A Diffusion Tensor Imaging Study DIABETES CARE Aye, T., Barnea-Goraly, N., Ambler, C., Hoang, S., Schleifer, K., Park, Y., Drobny, J., Wilson, D. M., Reiss, A. L., Buckingham, B. A. 2012; 35 (11): 2167-2173
Abstract

To detect clinical correlates of cognitive abilities and white matter (WM) microstructural changes using diffusion tensor imaging (DTI) in young children with type 1 diabetes.Children, ages 3 to <10 years, with type 1 diabetes (n = 22) and age- and sex-matched healthy control subjects (n = 14) completed neurocognitive testing and DTI scans.Compared with healthy controls, children with type 1 diabetes had lower axial diffusivity (AD) values (P = 0.046) in the temporal and parietal lobe regions. There were no significant differences between groups in fractional anisotropy and radial diffusivity (RD). Within the diabetes group, there was a significant, positive correlation between time-weighted HbA(1c) and RD (P = 0.028). A higher, time-weighted HbA(1c) value was significantly correlated with lower overall intellectual functioning measured by the full-scale intelligence quotient (P = 0.03).Children with type 1 diabetes had significantly different WM structure (as measured by AD) when compared with controls. In addition, WM structural differences (as measured by RD) were significantly correlated with their HbA(1c) values. Additional studies are needed to determine if WM microstructural differences in young children with type 1 diabetes predict future neurocognitive outcome.

View details for DOI 10.2337/dc12-0017

View details for PubMedID 22966090
Inpatient studies of a Kalman-filter-based predictive pump shutoff algorithm. Journal of diabetes science and technology Cameron, F., Wilson, D. M., Buckingham, B. A., Arzumanyan, H., Clinton, P., Chase, H. P., Lum, J., Maahs, D. M., Calhoun, P. M., Bequette, B. W. 2012; 6 (5): 1142-1147
Abstract

An insulin pump shutoff system can prevent nocturnal hypoglycemia and is a first step on the pathway toward a closed-loop artificial pancreas. In previous pump shutoff studies using a voting algorithm and a 1 min continuous glucose monitor (CGM), 80% of induced hypoglycemic events were prevented.The pump shutoff algorithm used in previous studies was revised to a single Kalman filter to reduce complexity, incorporate CGMs with different sample times, handle sensor signal dropouts, and enforce safety constraints on the allowable pump shutoff time.Retrospective testing of the new algorithm on previous clinical data sets indicated that, for the four cases where the previous algorithm failed (minimum reference glucose less than 60 mg/dl), the mean suspension start time was 30 min earlier than the previous algorithm. Inpatient studies of the new algorithm have been conducted on 16 subjects. The algorithm prevented hypoglycemia in 73% of subjects. Suspension-induced hyperglycemia is not assessed, because this study forced excessive basal insulin infusion rates.The new algorithm functioned well and is flexible enough to handle variable sensor sample times and sensor dropouts. It also provides a framework for handling sensor signal attenuations, which can be challenging, particularly when they occur overnight.

View details for PubMedID 23063041

View details for PubMedCentralID PMC3570849
Feasibility of prolonged continuous glucose monitoring in toddlers with type 1 diabetes. Pediatric diabetes Tsalikian, E., Fox, L., Weinzimer, S., Buckingham, B., White, N. H., Beck, R., Kollman, C., Xing, D., Ruedy, K. 2012; 13 (4): 301-307
Abstract

To examine the feasibility of continuous glucose monitoring (CGM) use in very young children with type 1 diabetes (T1D).Twenty-three children less than 4 yr of age with T1D were provided with a FreeStyle Navigator(�) (n = 21) or a Paradigm(�) (n = 2) CGM device. At baseline, mean age was 3.0 � 0.8 yr, mean hemoglobin A1c (HbA1c) was 8.0 � 0.8%, 10 were using an insulin pump and 13 were on multiple daily injections. CGM use was evaluated over a 6-month period.Three children dropped out of the study before the end of 6 months. Among the 20 children who completed 6 months of follow-up, CGM use in month 6 was ?6 d/wk in 9 (45%), 4 ? 6 d/wk in 2 (10%), and <4 d/wk in 9 (45%). Skin reactions were minimal. Although there was no detectable change in mean HbA1c between baseline and 6 months (7.9 and 8.0%, respectively), there was a high degree of parental satisfaction with CGM as measured on the CGM satisfaction scale questionnaire. A high percentage of glucose values were in the hyperglycemic range, and biochemical hypoglycemia was infrequent.More than 40% of very young children were able to safely use CGM on a near-daily basis after 6 months. CGM demonstrated frequent hyperglycemic excursions, with a large variability in glucose readings. Although improvement in glycemic control was not detected in the group as a whole, parental satisfaction with CGM was high.

View details for DOI 10.1111/j.1399-5448.2011.00837.x

View details for PubMedID 22151826
Transient False Positive Elevations of Antibody Markers of Celiac Disease at the Onset of Diabetes Shanmugham, S., Buckingham, B. AMER DIABETES ASSOC. 2012: A320
View details for Web of Science ID 000209842902396
Feasibility of prolonged continuous glucose monitoring in toddlers with type 1 diabetes PEDIATRIC DIABETES Tsalikian, E., Fox, L., Weinzimer, S., Buckingham, B., White, N., Beck, R., Kollman, C., Xing, D., Ruedy, K. 2012; 13 (4): 294-300
View details for DOI 10.1111/j.1399-5448.2011.00837.x

View details for Web of Science ID 000304597100002
Use of continuous glucose monitoring in children and adolescents PEDIATRIC DIABETES Phillip, M., Danne, T., Shalitin, S., Buckingham, B., Laffel, L., Tamborlane, W., Battelino, T. 2012; 13 (3): 215-228
View details for DOI 10.1111/j.1399-5448.2011.00849.x

View details for Web of Science ID 000303194000001

View details for PubMedID 22284160
Achievement of Target A1C Levels With Negligible Hypoglycemia and Low Glucose Variability in Youth With Short-Term Type 1 Diabetes and Residual beta-Cell Function DIABETES CARE Sherr, J., Tamborlane, W. V., Xing, D., Tsalikian, E., Mauras, N., Buckingham, B., White, N. H., Arbelaez, A. M., Beck, R. W., Kollman, C., Ruedy, K. 2012; 35 (4): 817-820
Abstract

To determine exposure to hyper- and hypoglycemia using blinded continuous glucose monitoring (CGM) profiles in youth with type 1 diabetes (T1D) with residual ?-cell function during the first year of insulin treatment.Blinded, 3-7 day CGM profiles were obtained in 16 short-term T1D patients (age 8-18 years, T1D duration 6-52 weeks) who had peak C-peptide levels ranging from 0.46 to 1.96 nmol/L during a mixed-meal tolerance test. Results in this short-term group were compared with those in 34 patients with well-controlled, longer-term T1D (duration ?5 years), matched for age and A1C with the short-term T1D group, and with those in 26 age-matched nondiabetic individuals.Despite matching for A1C, and therefore similar mean sensor glucose levels in the two T1D groups, short-term T1D participants had a lower frequency of hypoglycemia (0.3 vs. 7.6%, P < 0.001), a trend toward less hyperglycemia (17 vs. 32%, P = 0.15), and a greater percentage in the target range (median 77 vs. 60%, P = 0.02). Indeed, the percentage of sensor glucose levels ?70 mg/dL in the short-term T1D group (0.3%) did not differ from those in the nondiabetic group (1.7%, P = 0.73). The coefficient of variation of sensor glucose levels (an index of glucose variability) was lower in short-term vs. longer-term T1D participants (27 vs. 42%, respectively, P < 0.001).In youth with short-term T1D who retain residual ?-cell function, there is negligible exposure to hypoglycemia and lower glucose variability than in youth with well-controlled T1D of longer duration.

View details for DOI 10.2337/dc11-2190

View details for Web of Science ID 000301959600027

View details for PubMedID 22323414

View details for PubMedCentralID PMC3308298
Reduction in Duration of Hypoglycemia by Automatic Suspension of Insulin Delivery: The In-Clinic ASPIRE Study DIABETES TECHNOLOGY & THERAPEUTICS Garg, S., Brazg, R. L., Bailey, T. S., Buckingham, B. A., Slover, R. H., Klonoff, D. C., Shin, J., Welsh, J. B., Kaufman, F. R. 2012; 14 (3): 205-209
Abstract

The efficacy of automatic suspension of insulin delivery in induced hypoglycemia among subjects with type 1 diabetes was evaluated.In this randomized crossover study, subjects used a sensor-augmented insulin pump system with a low glucose suspend (LGS) feature that automatically stops insulin delivery for 2?h following a sensor glucose (SG) value ?70?mg/dL. Subjects fasted overnight and exercised until their plasma glucose (measured with the YSI 2300 STAT Plus? glucose and lactate analyzer [YSI Life Sciences, Yellow Springs, OH]) value reached ?85?mg/dL on different occasions separated by washout periods lasting 3-10 days. Exercise sessions were done with the LGS feature turned on (LGS-On) or with continued insulin delivery regardless of SG value (LGS-Off). The order of LGS-On and LGS-Off sessions was randomly assigned. YSI glucose data were used to compare the duration and severity of hypoglycemia from successful LGS-On and LGS-Off sessions and to estimate the risk of rebound hyperglycemia after pump suspension.Fifty subjects attempted 134 sessions, 98 of which were successful. The mean�SD hypoglycemia duration was less during LGS-On than during LGS-Off sessions (138.5�76.68 vs. 170.7�75.91?min, P=0.006). During LGS-On compared with LGS-Off sessions, mean nadir YSI glucose was higher (59.5�5.72 vs. 57.6�5.69?mg/dL, P=0.015), as was mean end-observation YSI glucose (91.4�41.84 vs. 66.2�13.48?mg/dL, P<0.001). Most (53.2%) end-observation YSI glucose values in LGS-On sessions were in the 70-180?mg/dL range, and none was >250?mg/dL.Automatic suspension of insulin delivery significantly reduced the duration and severity of induced hypoglycemia without causing rebound hyperglycemia.

View details for DOI 10.1089/dia.2011.0292

View details for Web of Science ID 000300845600003

View details for PubMedID 22316089
A Randomized Clinical Trial to Assess the Efficacy and Safety of Real-Time Continuous Glucose Monitoring in the Management of Type 1 Diabetes in Young Children Aged 4 to < 10 Years DIABETES CARE Mauras, N., Beck, R., Xing, D., Ruedy, K., Buckingham, B., Tansey, M., White, N. H., Weinzimer, S. A., Tamborlane, W., Kollman, C. 2012; 35 (2): 204-210
Abstract

Continuous glucose monitoring (CGM) has been demonstrated to improve glycemic control in adults with type 1 diabetes but less so in children. We designed a study to assess CGM benefit in young children aged 4 to 9 years with type 1 diabetes.After a run-in phase, 146 children with type 1 diabetes (mean age 7.5 � 1.7 years, 64% on pumps, median diabetes duration 3.5 years) were randomly assigned to CGM or to usual care. The primary outcome was reduction in HbA(1c) at 26 weeks by ?0.5% without the occurrence of severe hypoglycemia.The primary outcome was achieved by 19% in the CGM group and 28% in the control group (P = 0.17). Mean change in HbA(1c) was -0.1% in each group (P = 0.79). Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and change in HbA(1c) (r(s) = -0.09, P = 0.44). CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced.CGM in 4- to 9-year-olds did not improve glycemic control despite a high degree of parental satisfaction with CGM. We postulate that this finding may be related in part to limited use of the CGM glucose data in day-to-day management and to an unremitting fear of hypoglycemia. Overcoming the barriers that prevent integration of these critical glucose data into day-to-day management remains a challenge.

View details for DOI 10.2337/dc11-1746

View details for Web of Science ID 000299856000004

View details for PubMedID 22210571

View details for PubMedCentralID PMC3263860
Diabetes technology and the human factor. International journal of clinical practice. Supplement Liberman, A., Buckingham, B., Phillip, M. 2012: 79-84
View details for DOI 10.1111/j.1742-1241.2011.02858.x

View details for PubMedID 22308993
The interrelationships of glycemic control measures: HbA1c, glycated albumin, fructosamine, 1,5-anhydroglucitrol, and continuous glucose monitoring PEDIATRIC DIABETES Beck, R., Steffes, M., Xing, D., Ruedy, K., Mauras, N., Wilson, D. M., Kollman, C. 2011; 12 (8): 690-695
Abstract

To describe the interrelationships of glycemic control measures: hemoglobin A1c (HbA1c), glycated albumin, fructosamine, 1,5-anhydroglucitrol (1,5-AG), and continuous glucose monitoring (CGM) in children and adolescents with type 1 diabetes.In total, 26 subjects of age 4-17 had HbA1c measurement followed within 14 d by three laboratory measures of glycemia and the collection of CGM glucose data (N = 21).Glycated albumin and fructosamine levels had a higher correlation with each other than with HbA1c. The correlation of 1,5-AG with HbA1c was lower (absolute r value = 0.25). All four measures had a similar degree of correlation with CGM-measured mean glucose (absolute r value = 0.50-0.56) and with hyperglycemic area under the curve (AUC) at 180 mg/dL (0.50-0.60).Each of the four measures (i.e., HbA1c, glycated albumin, fructosamine, and 1,5-AG) had a similar correlation with mean glucose and hyperglycemic AUC-180. 1,5-AG did not correlate with hyperglycemic AUC-180 better than did HbA1c.

View details for DOI 10.1111/j.1399-5448.2011.00764.x

View details for Web of Science ID 000298170000004

View details for PubMedID 21496193

View details for PubMedCentralID PMC3193556
The ASPIRE study: design and methods of an in-clinic crossover trial on the efficacy of automatic insulin pump suspension in exercise-induced hypoglycemia. Journal of diabetes science and technology Brazg, R. L., Bailey, T. S., Garg, S., Buckingham, B. A., Slover, R. H., Klonoff, D. C., Nguyen, X., Shin, J., Welsh, J. B., Lee, S. W. 2011; 5 (6): 1466-1471
Abstract

The Paradigm�Veo? System includes a low glucose suspend (LGS) feature which suspends insulin delivery when a prespecified glucose threshold setting is reached by the associated continuous glucose monitoring (CGM) sensor. The ASPIRE (Automation to Simulate Pancreatic Insulin REsponse) study is a multicenter, in-clinic, randomized, crossover study to examine the efficacy of LGS in exercise-induced hypoglycemia.Insulin-pump users underwent two separate exercise sessions, one with the LGS feature set to suspend insulin (LGS-on) when the CGM-detected glucose concentration was ? 70 mg/dl and one with the LGS feature off. Exercise sessions were conducted after an overnight fast and with initial plasma glucose level as measured by the YSI 2300 STAT Plus glucose analyzer (YSI) of 100-140 mg/dl. Subjects exercised until their YSI value fell to ? 85 mg/dl; subsequent YSI values <70 mg/dl were recorded for up to 4 h to measure the duration and nadir of hypoglycemia. The protocol required that subjects with YSI values <50 or >300 mg/dl were rescued with carbohydrates or insulin, respectively, based on the provider's recommendation. The primary end point was comparison of duration and severity of hypoglycemia between LGS-on and LGS-off sessions. Secondary end points included areas under the glucose concentration curve, CGM sensor accuracy, and last YSI glucose. Device- and procedure-related adverse events and serious adverse events were recorded.Fifty adults and teenagers (17-58 years) with type 1 diabetes were randomized. Study completion is expected in November 2011.

View details for PubMedID 22226267
Continuous Glucose Monitoring: An Endocrine Society Clinical Practice Guideline JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Klonoff, D. C., Buckingham, B., Christiansen, J. S., Montori, V. M., Tamborlane, W. V., Vigersky, R. A., Wolpert, H. 2011; 96 (10): 2968-2979
Abstract

The aim was to formulate practice guidelines for determining settings where patients are most likely to benefit from the use of continuous glucose monitoring (CGM).The Endocrine Society appointed a Task Force of experts, a methodologist, and a medical writer.This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence.One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, the Diabetes Technology Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.The Task Force evaluated three potential uses of CGM: 1) real-time CGM in adult hospital settings; 2) real-time CGM in children and adolescent outpatients; and 3) real-time CGM in adult outpatients. The Task Force used the best available data to develop evidence-based recommendations about where CGM can be beneficial in maintaining target levels of glycemia and limiting the risk of hypoglycemia. Both strength of recommendations and quality of evidence were accounted for in the guidelines.

View details for DOI 10.1210/jc.2010-2756

View details for Web of Science ID 000295879600028

View details for PubMedID 21976745
Metabolic tests to determine risk for type 1 diabetes in clinical trials DIABETES-METABOLISM RESEARCH AND REVIEWS Greenbaum, C. J., Buckingham, B., Chase, H. P., Krischer, J. 2011; 27 (6): 584-589
Abstract

Evaluate the reproducibility and relationship of various metabolic tests conducted as part of the Diabetes Prevention Trial-type 1 diabetes.Coefficients of variation, intraclass correlation coefficients, and Pearson correlations between the same metabolic tests performed at different times as well as the different tests were determined.Fasting samples on the same day had a coefficient of variation of < 10 for C-peptide, 11 for insulin, and 2 for glucose. Testing on separate days approximately doubled the variance. Stimulated insulin values had less variance than fasting values and there was only a moderate correlation between fasting and stimulated values on each test. While highly correlated, C-peptide values from mixed meal tolerance tests are significantly lower than that obtained during oral glucose tolerance tests (OGTTs). Neither peak nor area under the curve C-peptide on the oral glucose tolerance test was different between those with abnormal and normal glucose tolerance. Those with abnormal as compared with normal glucose tolerance had lower 30-min C-peptide and a longer time to peak C-peptide.A large, multi-centre trial, with tests performed over a decade-long period, can provide robust data. C-peptide data from oral glucose tolerance tests and mixed meal tolerance tests differ; therefore, the same stimulation test should be used to evaluate changes in beta cell function over time. Worsening glucose tolerance is associated with lower C-peptide at 30 min and a delay in peak secretion on the oral glucose tolerance test. This Diabetes Prevention Trial-type 1 diabetes data can be used in planning parameters for future studies, including evaluation of new algorithms to determine risk of disease.

View details for DOI 10.1002/dmrr.1205

View details for Web of Science ID 000295176500008

View details for PubMedID 21488143
The Feasibility of Detecting Neuropsychologic and Neuroanatomic Effects of Type 1 Diabetes in Young Children DIABETES CARE Aye, T., Reiss, A. L., Kesler, S., Hoang, S., Drobny, J., Park, Y., Schleifer, K., Baumgartner, H., Wilson, D. M., Buckingham, B. A. 2011; 34 (7): 1458-1462
Abstract

To determine if frequent exposures to hypoglycemia and hyperglycemia during early childhood lead to neurocognitive deficits and changes in brain anatomy.In this feasibility, cross-sectional study, young children, aged 3 to 10 years, with type 1 diabetes and age- and sex-matched healthy control (HC) subjects completed neuropsychologic (NP) testing and magnetic resonance imaging (MRI) scans of the brain.NP testing and MRI scanning was successfully completed in 98% of the type 1 diabetic and 93% of the HC children. A significant negative relationship between HbA1c and Wechsler Intelligence Scale for Children (WISC) verbal comprehension was observed. WISC index scores were significantly reduced in type 1 diabetic subjects who had experienced seizures. White matter volume did not show the expected increase with age in children with type 1 diabetes compared with HC children (diagnosis by age interaction, P=0.005). A similar trend was detected for hippocampal volume. Children with type 1 diabetes who had experienced seizures showed significantly reduced gray matter and white matter volumes relative to children with type 1 diabetes who had not experienced seizures.It is feasible to perform MRI and NP testing in young children with type 1 diabetes. Further, early signs of neuroanatomic variation may be present in this population. Larger cross-sectional and longitudinal studies of neurocognitive function and neuroanatomy are needed to define the effect of type 1 diabetes on the developing brain.

View details for DOI 10.2337/dc10-2164

View details for PubMedID 21562318
The Use of Diffusion Tensor Imaging (DTI) in Young Children with Type 1 Diabetes Aye, T., Barnea-Goraly, N., Park, Y., Wilson, D. M., Reiss, A. L., Buckingham, B. A. AMER DIABETES ASSOC. 2011: A44?A45
View details for Web of Science ID 000461640000162
The Impact of Real Time Continuous Glucose Monitoring in the Classroom/School Environment Aye, T., Block, J. M., Buckingham, B. A., Wilson, D. M. AMER DIABETES ASSOC. 2011: A248
View details for Web of Science ID 000461640001046
Outcome measures for outpatient hypoglycemia prevention studies. Journal of diabetes science and technology Beck, R. W., Kollman, C., Xing, D., Buckingham, B. A., Chase, H. P. 2011; 5 (4): 999-1004
Abstract

Systems are being developed that utilize algorithms to predict impending hypoglycemia using commercially available continuous glucose monitoring (CGM) devices and to discontinue insulin delivery if hypoglycemia is predicted. In outpatient studies designed to test such systems, CGM-measured glycemic indices will not only be important outcome measures of efficacy but, in certain cases, will be the only good outcome. This is especially true in short-term studies designed to reduce hypoglycemia since the event rate for severe hypoglycemic events is too low for it to be a good outcome, and milder hypoglycemia often will be variably detected. Continuous glucose monitoring inaccuracy can be accounted for in the study design by increasing sample size and/or study duration.

View details for PubMedID 21880243
Factors Predictive of Severe Hypoglycemia in Type 1 Diabetes Analysis from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized control trial dataset DIABETES CARE Fiallo-Scharer, R., Cheng, J., Beck, R. W., Buckingham, B. A., Chase, H. P., Kollman, C., Laffel, L., Lawrence, J. M., Mauras, N., Tamborlane, W. V., Wilson, D. M., Wolpert, H., Bode, B., Ruedy, K. J., Weinzimer, S., Xing, D. 2011; 34 (3): 586-590
Abstract

Identify factors predictive of severe hypoglycemia (SH) and assess the clinical utility of continuous glucose monitoring (CGM) to warn of impending SH.In a multicenter randomized clinical trial, 436 children and adults with type 1 diabetes were randomized to a treatment group that used CGM (N = 224), or a control group that used standard home blood glucose monitoring (N = 212) and completed 12 months of follow-up. After 6 months, the original control group initiated CGM while the treatment group continued use of CGM for 6 months. Baseline risk factors for SH were evaluated over 12 months of follow-up using proportional hazards regression. CGM-derived indices of hypoglycemia were used to predict episodes of SH over a 24-h time horizon.The SH rate was 17.9 per 100 person-years, and a higher rate was associated with the occurrence of SH in the prior 6 months and female sex. SH frequency increased eightfold when 30% of CGM values were ? 70 mg/dL on the prior day (4.5 vs. 0.5%; P < 0.001), but the positive predictive value (PPV) was low (<5%). Results were similar for hypoglycemic area under the curve and the low blood glucose index calculated by CGM.SH in the 6 months prior to the study was the strongest predictor of SH during the study. CGM-measured hypoglycemia over a 24-h span is highly associated with SH the following day (P < 0.001), but the PPV is low.

View details for DOI 10.2337/dc10-1111

View details for Web of Science ID 000288145400010

View details for PubMedID 21266651

View details for PubMedCentralID PMC3041185
Hemoglobin A(1c) and Mean Glucose in Patients With Type 1 Diabetes Analysis of data from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial DIABETES CARE Wilson, D. M., Xing, D., Beck, R. W., Block, J., Bode, B., Fox, L. A., Hirsch, I., Kollman, C., Laffel, L., Ruedy, K. J., Steffes, M., Tamborlane, W. V. 2011; 34 (3): 540-544
Abstract

To determine the relationship between mean sensor glucose concentrations and hemoglobin A(1c) (HbA(1c)) values measured in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications laboratory at the University of Minnesota in a cohort of subjects with type 1 diabetes from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial.Near-continuous glucose sensor data (? 4 days/week) were collected for 3 months before a central laboratory-measured HbA(1c) was performed for 252 subjects aged 8-74 years, the majority of whom had stable HbA(1c) values (77% within � 0.4% of the patient mean).The slope (95% CI) for mean sensor glucose concentration (area under the curve) versus a centrally measured HbA(1c) was 24.4 mg/dL (22.0-26.7) for each 1% change in HbA(1c), with an intercept of -16.2 mg/dL (-32.9 to 0.6). Although the slope did not vary with age or sex, there was substantial individual variability, with mean sensor glucose concentrations ranging from 128 to 187 mg/dL for an HbA(1c) of 6.9-7.1%. The root mean square of the errors between the actual mean sensor glucose concentration versus the value calculated using the regression equation was 14.3 mg/dL, whereas the median absolute difference was 10.1 mg/dL.There is substantial individual variability between the measured versus calculated mean glucose concentrations. Consequently, estimated average glucose concentrations calculated from measured HbA(1c) values should be used with caution.

View details for DOI 10.2337/dc10-1054

View details for Web of Science ID 000288145400002

View details for PubMedID 21266647

View details for PubMedCentralID PMC3041177
A closed-loop artificial pancreas based on risk management. Journal of diabetes science and technology Cameron, F., Bequette, B. W., Wilson, D. M., Buckingham, B. A., Lee, H., Niemeyer, G. 2011; 5 (2): 368-379
Abstract

Control algorithms that regulate blood glucose (BG) levels in individuals with type 1 diabetes mellitus face several fundamental challenges. Two of these are the asymmetric risk of clinical complications associated with low and high glucose levels and the irreversibility of insulin action when using only insulin. Both of these nonlinearities force a controller to be more conservative when uncertainties are high. We developed a novel extended model predictive controller (EMPC) that explicitly addresses these two challenges.Our extensions to model predictive control (MPC) operate in three ways. First, they explicitly minimize the combined risk of hypoglycemia and hyperglycemia. Second, they integrate the effect of prediction uncertainties into the risk. Third, they understand that future control actions will vary if measurements fall above or below predictions. Using the University of Virginia/Padova Simulator, we compared our novel controller (EMPC) against optimized versions of a proportional-integral-derivative (PID) controller, a traditional MPC, and a basal/bolus (BB) controller, as well as against published results of an independent MPC (IMPC). The BB controller was optimized retrospectively to serve as a bound on the possible performance.We tuned each controller, where possible, to minimize a published blood glucose risk index (BGRI). The simulated controllers (PID/MPC/EMPC/BB) provided BGRI values of 2.99/3.05/2.51/1.27 as compared to the published IMPC BGRI value of 4.10. These correspond to 73/79/84/92% of BG values lying in the euglycemic range (70-180 mg/dl), respectively, with mean BG levels of 151/156/147/140 mg/dl.The EMPC strategy extends MPC to explicitly address the issues of asymmetric glycemic risk and irreversible insulin action using estimated prediction uncertainties and an explicit risk function. This controller reduces the avoidable BGRI by 56% (p < .05) relative to a published MPC algorithm studied on a similar population.

View details for PubMedID 21527108
Optimal Sampling Intervals to Assess Long-Term Glycemic Control Using Continuous Glucose Monitoring DIABETES TECHNOLOGY & THERAPEUTICS Xing, D., Kollman, C., Beck, R. W., Tamborlane, W. V., Laffel, L., Buckingham, B. A., Wilson, D. M., Weinzimer, S., Fiallo-Scharer, R., Ruedy, K. J. 2011; 13 (3): 351-358
Abstract

AIMS AND HYPOTHESIS: The optimal duration and frequency of short-term continuous glucose monitoring (CGM) to reflect long-term glycemia have not been determined. The Juvenile Diabetes Research Foundation CGM randomized trials provided a large dataset of longitudinal CGM data for this type of analysis.The analysis included 185 subjects who had 334 3-month intervals of CGM data meeting specific criteria. For various glucose indices, correlations (r�) were computed for the entire 3-month interval versus selected sampling periods ranging from 3 to 15 days. Other computed agreement measures included median relative absolute difference, values within � 10% and � 20% of full value, and median absolute difference.As would be expected, the more days of glucose data that were sampled, the higher the correlation with the full 3 months of data. For 3 days of sampling, the r� value ranged from 0.32 to 0.47, evaluating mean glucose, percentage of values 71-180 mg/dL, percentage of values > 180 mg/dL, percentage of values ? 70 mg/dL, and coefficient of variation; in contrast, for 15 days of sampling, the r� values ranged from 0.66 to 0.75. The results were similar when the analysis intervals were stratified by age group (8-14, 15-24, and ? 25 years), by baseline hemoglobin A1c level (< 7.0% and ? 7.0%), and by CGM device type.Our data suggest that a 12-15-day period of monitoring every 3 months may be needed to optimally assess overall glucose control. Shorter periods of sampling can be useful, but the correlation with 3-month measures of glycemic control is lower.

View details for DOI 10.1089/dia.2010.0156

View details for Web of Science ID 000287798200009

View details for PubMedID 21299401
Diabetes technology and the human factor INTERNATIONAL JOURNAL OF CLINICAL PRACTICE Liberman, A., Buckingham, B., Phillip, M. 2011; 65: 83-90
Abstract

When developing new technologies for human use the developer should take into consideration not only the efficacy and safety of the technology but also the desire and capabilities of the potential user. Any chronic disease is a challenge for both the patient and his/her caregivers. This statement is especially true in the case of patients with type 1 diabetes mellitus (T1DM) where adherence to therapy is crucial 24 hours a day 365 days a year. No vacation days are possible for the T1DM patient. It is therefore obvious why any new technology which is developed for helping patients cope with the disease should take into consideration the 'human factor' before, during and after the production process starts. There is no doubt that technology has changed the life of patients with T1DM in the last few decades, but despite the availability of new meters, new syringes, new sophisticated insulin pumps and continuous glucose sensors and communication tools, these technologies have not been well utilised by many patients. It is therefore important to understand why the technology is not always utilised and to find new ways to maximise use and benefits from the technology to as many patients as possible. The present chapter will review papers published in the last year where the patient's ability or willingness was an important factor in the success of the technology. We will try to understand why insulin pumps, glucose sensors and self-monitoring of blood glucose (SMBG) are not used enough or appropriately, whether there is a specific group that finds it more difficult than others to adopt new technologies and what can be done to overcome that issue. For this chapter we chose articles from a Public Medicine review of the literature related to human factors affecting the outcome of studies and of user acceptance of continuous glucose monitoring, insulin infusion pump therapy. We also searched the literature in the field of psychology in order to accurately define the problems that the users of technology are facing (such as adherence, quality of life, motivations, executive functioning etc.) Those articles that had the most important contributions to understanding human factors as well as those highlighting the interface between technology and psychology, were chosen for this review, with emphasis on articles that provide insight into future studies and acceptance of emerging technologies for glycemic control.

View details for DOI 10.1111/j.1742-1241.2010.02583.x

View details for Web of Science ID 000287401500013

View details for PubMedID 21323817
Toward Closing the Loop: An Update on Insulin Pumps and Continuous Glucose Monitoring Systems ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA Aye, T., Block, J., Buckingham, B. 2010; 39 (3): 609-?
Abstract

This article reviews current pump and continuous glucose monitoring therapy and what will be required to integrate these systems into closed-loop control. Issues with sensor accuracy, lag time, and calibration are discussed as well as issues with insulin pharmacodynamics, which result in a delayed onset of insulin action in a closed-loop system. A stepwise approach to closed-loop therapy is anticipated, where the first systems will suspend insulin delivery based on actual or predicted hypoglycemia. Subsequent systems may control to range, limiting the time spent in hyperglycemia by mitigating the effects of a missed food bolus or underestimate of consumed carbohydrates, while minimizing the risk of hypoglycemia.

View details for DOI 10.1016/j.ecl.2010.05.005

View details for Web of Science ID 000282146100011

View details for PubMedID 20723823

View details for PubMedCentralID PMC2938733
The Pediatric Diabetes Consortium: Improving Care of Children with Type 1 Diabetes Through Collaborative Research DIABETES TECHNOLOGY & THERAPEUTICS Beck, R., Klingensmith, G., Haymond, M., Wood, J., Buckingham, B., Schatz, D., Silverstein, J., Lee, J., Cengiz, E., Tamborlane, W. 2010; 12 (9): 685-688
View details for DOI 10.1089/dia.2010.0065

View details for Web of Science ID 000280883100002
Validation of Measures of Satisfaction with and Impact of Continuous and Conventional Glucose Monitoring DIABETES TECHNOLOGY & THERAPEUTICS Hirsch, I. B., Gilliam, L. K., Fitzpatrick, K., Khakpour, D., Weinzimer, S. A., Tamborlane, W. V., Ives, B., Bosson-Heenan, J., Wolpert, H., Shetty, G., Atakov-Castillo, A., Giusti, J., O'Donnell, S., Ghiloni, S., Bode, B. W., O'Neil, K., Tolbert, L., Wysocki, T., Fox, L. A., Mauras, N., Englert, K., Permuy, J., Buckingham, B., Wilson, D. M., Block, J., Benassi, K., Tsalikian, E., Tansey, M., Kucera, D., Coffey, J., Cabbage, J., Laffel, L., Milaszewski, K., Pratt, K., Bismuth, E., Keady, J., Lawlor, M., Chase, H. P., Fiallo-Scharer, R., Wadwa, P., Messer, L., Gage, V., Burdick, P., Lawrence, J. M., Clemons, R., Maeva, M., Sattler, B., Beck, R. W., Ruedy, K. J., Kollman, C., Xing, D., Sibayan, J., Steffes, M., Bucksa, J. M., Nowicki, M. L., Van Hale, C., Makky, V., O'Grady, M., Huang, E., Basu, A., Meltzer, D. O., Zhao, L., Lee, J., Kowalski, A. J., Laffel, L., Tamborlane, W. V., Beck, R. W., Kowalski, A. J., Ruedy, K. J., Weinstock, R. S., Anderson, B. J., Kruger, D., Lavange, L., Rodriguez, H., Cheng, J. 2010; 12 (9): 679-684
Abstract

The evaluation of patient-reported outcomes (e.g. impact, satisfaction) is important in trials of continuous glucose monitoring (CGM). We evaluated psychometric properties of the CGM Satisfaction Scale (CGM-SAT) and the Glucose Monitoring Survey (GMS).CGM-SAT is a 44-item scale on which patients (n=224) or parents (n=102) rated their experience with CGM over the prior 6 months. GMS is a 22-item scale on which patients (n=447) or parents (n=221) rated the blood glucose monitoring system they were using (home glucose meter with or without CGM) at baseline and 6 months.The alpha coefficient for the CGM-SAT was > or = 0.94 for all respondents and for the GMS was > or = 0.84 for all respondents at baseline and 6 months. Parent-youth agreement was 0.52 for the CGM-SAT at 6 months and 0.24 and 0.20 for the GMS at baseline and 6 months for the Standard Care Group, respectively. Test-retest reliability of the GMS at 6 months for controls was r=0.76 for adult patients, 0.63 for pediatric patients, and 0.43 for parents. Factor analysis isolated measurement factors for the CGM-SAT labeled Benefits of CGM and Hassles of CGM, accounting for 33% and 9% of score variance, respectively. For the GMS, two factors emerged: Glucose Control and Social Complications, accounting for 28% and 9% of variance, respectively. Significant correlations of CGM-SAT with frequency of CGM use between 6 months and baseline and GMS with frequency of conventional daily self-monitoring of blood glucose at baseline support their convergent validity.The CGM-SAT and GMS are reliable and valid measures of patient-reported CGM outcomes.

View details for DOI 10.1089/dia.2010.0015

View details for Web of Science ID 000280883100001

View details for PubMedID 20799388

View details for PubMedCentralID PMC3045572
Insulin Pumps in Young Children DIABETES TECHNOLOGY & THERAPEUTICS Fuld, K., Conrad, B., Buckingham, B., Wilson, D. M. 2010; 12: S67-S71
Abstract

Insulin infusion pump therapy has dramatically improved over the past 20 years and can now address some of the specific challenges related to toddlers with diabetes. We discuss both the non-randomized and randomized controlled trials comparing continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) in this age group. There are advantages and disadvantages related to both CSII and MDI treatments, and ultimately the decision to use CSII should be individualized for each patient and family with the guidance of their diabetes team.

View details for DOI 10.1089/dia.2009.0182

View details for PubMedID 20515310
Real-Time Hypoglycemia Prediction Suite Using Continuous Glucose Monitoring A safety net for the artificial pancreas DIABETES CARE Dassau, E., Cameron, F., Lee, H., Bequette, B. W., Zisser, H., Jovanovic, L., Chase, H. P., Wilson, D. M., Buckingham, B. A., Doyle, F. J. 2010; 33 (6): 1249-1254
Abstract

The purpose of this study was to develop an advanced algorithm that detects pending hypoglycemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycemia, a major concern of patients with diabetes.This real-time hypoglycemia prediction algorithm (HPA) combines five individual algorithms, all based on continuous glucose monitoring 1-min data. A predictive alarm is issued by a voting algorithm when a hypoglycemic event is predicted to occur in the next 35 min. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. We confirmed the function of the HPA using a separate dataset from 22 admissions of type 1 diabetic subjects. During these admissions, hypoglycemia was induced by gradual increases in the basal insulin infusion rate up to 180% from the subject's own baseline infusion rate. RESULTS Using a prediction horizon of 35 min, a glucose threshold of 80 mg/dl, and a voting threshold of three of five algorithms to predict hypoglycemia (defined as a FreeStyle plasma glucose readings <60 mg/dl), the HPA predicted 91% of the hypoglycemic events. When four of five algorithms were required to be positive, then 82% of the events were predicted.The HPA will enable automated insulin-pump suspension in response to a pending event that has been detected prior to severe immediate complications.

View details for DOI 10.2337/dc09-1487

View details for Web of Science ID 000279304300020

View details for PubMedID 20508231

View details for PubMedCentralID PMC2875433
Prevention of Nocturnal Hypoglycemia Using Predictive Alarm Algorithms and Insulin Pump Suspension DIABETES CARE Buckingham, B., Chase, H. P., Dassau, E., Cobry, E., Clinton, P., Gage, V., Caswell, K., Wilkinson, J., Cameron, F., Lee, H., Bequette, B. W., Doyle, F. J. 2010; 33 (5): 1013-1017
Abstract

The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes.Forty subjects with type 1 diabetes (age range 12-39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care).The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events.Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur.

View details for DOI 10.2337/dc09-2303

View details for PubMedID 20200307
Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes DIABETES CARE Tsalikian, E., Tamborlane, W., Xing, D., Becker, D. M., Mauras, N., Fiallo-Scharer, R., Buckingham, B., Weinzimer, S., Steffes, M., Singh, R., Beck, R., Ruedy, K., Kollman, C. 2009; 32 (11): 1954-1959
Abstract

Hypoglycemia in young children with type 1 diabetes is an acute complication of intensive insulin therapy and is commonly observed in the absence of signs or symptoms. The effect of intensive treatment and patient age on sympathoadrenal responses has not been established in youth with type 1 diabetes because of difficulties in testing procedures.We developed a standardized inpatient continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose concentrations in insulin pump-treated patients. Plasma glucose and counterregulatory hormone concentrations were measured in 14 young children (3 to <8 years, A1C 7.7 +/- 0.6%) vs. 14 adolescents (12 to <18 years, A1C 7.6 +/- 0.8%).Plasma glucose decreased to similar nadir concentrations in the two groups. Four young children and four adolescents never had an epinephrine response. In the four young children and five adolescents who had a modest epinephrine response, this only occurred when plasma glucose fell to <60 mg/dl. In evaluating symptom scores, 29% of parents of young children felt that their child looked hypoglycemic, even at the lowest plasma glucose concentrations. Adolescents were better able to detect symptoms of hypoglycemia. In comparison with our data, epinephrine response to hypoglycemia in 14 nondiabetic adolescents studied at the Children's Hospital of Pittsburgh was higher.These data suggest that even young children and adolescents with type 1 diabetes are prone to develop hypoglycemia-associated autonomic failure regardless of duration. Whether these abnormalities can be reversed using continuous glucose monitoring and closed-loop insulin delivery systems awaits further study.

View details for DOI 10.2337/dc08-2298

View details for Web of Science ID 000271682800002

View details for PubMedID 19675205
Factors Predictive of Use and of Benefit From Continuous Glucose Monitoring in Type 1 Diabetes DIABETES CARE Beck, R. W., Buckingham, B., Miller, K., Wolpert, H., Xing, D., Block, J. M., Chase, H. P., Hirsch, I., Kollman, C., Laffel, L., Lawrence, J. M., Milaszewski, K., Ruedy, K. J., Tamborlane, W. V. 2009; 32 (11): 1947-1953
Abstract

To evaluate factors associated with successful use of continuous glucose monitoring (CGM) among participants with intensively treated type 1 diabetes in the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Clinical Trial.The 232 participants randomly assigned to the CGM group (165 with baseline A1C >or=7.0% and 67 with A1C <7.0%) were asked to use CGM on a daily basis. The associations of baseline factors and early CGM use with CGM use >or=6 days/week in the 6th month and with change in A1C from baseline to 6 months were evaluated in regression models.The only baseline factors found to be associated with greater CGM use in month 6 were age >or=25 years (P < 0.001) and more frequent self-reported prestudy blood glucose meter measurements per day (P < 0.001). CGM use and the percentage of CGM glucose values between 71 and 180 mg/dl during the 1st month were predictive of CGM use in month 6 (P < 0.001 and P = 0.002, respectively). More frequent CGM use was associated with a greater reduction in A1C from baseline to 6 months (P < 0.001), a finding present in all age-groups.After 6 months, near-daily CGM use is more frequent in intensively treated adults with type 1 diabetes than in children and adolescents, although in all age-groups near-daily CGM use is associated with a similar reduction in A1C. Frequency of blood glucose meter monitoring and initial CGM use may help predict the likelihood of long-term CGM benefit in intensively treated patients with type 1 diabetes of all ages.

View details for DOI 10.2337/dc09-0889

View details for Web of Science ID 000271682800001

View details for PubMedID 19675206
Probabilistic evolving meal detection and estimation of meal total glucose appearance. Journal of diabetes science and technology Cameron, F., Niemeyer, G., Buckingham, B. A. 2009; 3 (5): 1022-1030
Abstract

Automatic compensation of meals for type 1 diabetes patients will require meal detection from continuous glucose monitor (CGM) readings. This is challenged by the uncertainty and variability inherent to the digestion process and glucose dynamics as well as the lag and noise associated with CGM sensors. Thus any estimation of meal start time, size, and shape is fundamentally uncertain. This uncertainty can be reduced, but not eliminated, by estimating total glucose appearance and using new readings as they become available.In this article, we propose a probabilistic, evolving method to detect the presence and estimate the shape and total glucose appearance of a meal. The method is unique in continually evolving its estimates and simultaneously providing uncertainty measures to monitor their convergence. The algorithm operates in three phases. First, it compares the CGM signal to no-meal predictions made by a simple insulin-glucose model. Second, it fits the residuals to potential, assumed meal shapes. Finally, it compares and combines these fits to detect any meals and estimate the meal total glucose appearance, shape, and total glucose appearance uncertainty.We validate the performance of this meal detection and total glucose appearance estimation algorithm both separately and in cooperation with a controller on the Food and Drug Administration-approved University of Virginia/Padova Type I Diabetes Simulator. In cooperation with a controller, the algorithm reduced the mean blood glucose from 137 to 132 mg/dl over 1.5 days of control without any increased hypoglycemia.This novel, extensible meal detection and total glucose appearance estimation method shows the feasibility, relevance, and performance of evolving estimates with explicit uncertainty measures for use in closed-loop control of type 1 diabetes.

View details for PubMedID 20144415
A closed-loop artificial pancreas using model predictive control and a sliding meal size estimator. Journal of diabetes science and technology Lee, H., Buckingham, B. A., Wilson, D. M., Bequette, B. W. 2009; 3 (5): 1082-1090
Abstract

The objective of this article is to present a comprehensive strategy for a closed-loop artificial pancreas. A meal detection and meal size estimation algorithm is developed for situations in which the subject forgets to provide a meal insulin bolus. A pharmacodynamic model of insulin action is used to provide insulin-on-board constraints to explicitly include the future effect of past and currently delivered insulin boluses. In addition, a supervisory pump shut-off feature is presented to avoid hypoglycemia. All of these components are used in conjunction with a feedback control algorithm using model predictive control (MPC). A model for MPC is developed based on a study of 20 subjects and is tested in a hypothetical clinical trial of 100 adolescent and 100 adult subjects using a Food and Drug Administration-approved diabetic subject simulator. In addition, a performance comparison of previously and newly proposed meal size estimation algorithms using 200 in silico subjects is presented. Using the new meal size estimation algorithm, the integrated artificial pancreas system yielded a daily mean glucose of 138 and 132 mg/dl for adolescents and adults, respectively, which is a substantial improvement over the MPC-only case, which yielded 159 and 145 mg/dl.

View details for PubMedID 20144421
The effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes care Beck, R. W., Hirsch, I. B., Laffel, L., Tamborlane, W. V., Bode, B. W., Buckingham, B., Chase, P., Clemons, R., Fiallo-Scharer, R., Fox, L. A., Gilliam, L. K., Huang, E. S., Kollman, C., Kowalski, A. J., Lawrence, J. M., Lee, J., Mauras, N., O'Grady, M., Ruedy, K. J., Tansey, M., Tsalikian, E., Weinzimer, S. A., Wilson, D. M., Wolpert, H., Wysocki, T., Xing, D. 2009; 32 (8): 1378-1383
Abstract

OBJECTIVE The potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined. RESEARCH DESIGN AND METHODS A total of 129 adults and children with intensively treated type 1 diabetes (age range 8-69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level < or =70 mg/dl, A1C level, and severe hypoglycemic events. RESULTS At 26 weeks, biochemical hypoglycemia (< or =70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant (P = 0.16). Median time with a glucose level < or =60 mg/dl was 18 versus 35 min/day, respectively (P = 0.05). Time out of range (< or =70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline (P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively (P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group (P < 0.001, 0.007, 0.005, and 0.003). CONCLUSIONS Most outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%.

View details for DOI 10.2337/dc09-0108

View details for PubMedID 19429875
In Silico Evaluation Platform for Artificial Pancreatic beta-Cell Development-A Dynamic Simulator for Closed-Loop Control with Hardware-in-the-Loop DIABETES TECHNOLOGY & THERAPEUTICS Dassau, E., Palerm, C. C., Zisser, H., Buckingham, B. A., Jovanovic, L., Doyle, F. J. 2009; 11 (3): 187-194
Abstract

A critical step in algorithm development for an artificial beta-cell is extensive in silico testing. Computer simulations usually involve only the controller software, leaving untested the hardware elements, including the critical communication interface between the controller and the glucose sensor and insulin pump.An in silico simulation platform has been developed that uses all of the components of the clinical system. At the core is a comprehensive in silico population model that covers the variability of principal metabolic parameters observed in vivo, to replace the human subject, with the ability to use historical clinical data. A continuous glucose monitor, in this case either the Abbott Diabetes Care (Alameda, CA) FreeStyle Navigator or the DexCom (San Diego, CA) STS7, is supplied with a glucose signal provided by the simulator. The Insulet (Bedford, MA) OmniPod insulin pump is also interfaced with the simulator to provide insulin delivery data. These hardware elements are an integral part of the system under testing, which also includes the algorithm components.The system is unique in that it uses the same hardware components for simulations as are required in clinical trials, allowing for full-system level verification and validation. With a detailed mathematical model, a suite of patients can be simulated to reflect various conditions. Because all hardware is used, their related limitations are automatically included.A complete artificial beta-cell evaluation platform was realized with the flexibility to interface various algorithms and patient models, allowing for the systematic analysis of monitoring and control algorithms. The system facilitates a variety of tests and challenges to the software and the component devices, streamlining preclinical validation trials.

View details for DOI 10.1089/dia.2008.0055

View details for Web of Science ID 000264197200008

View details for PubMedID 19191486
In silico preclinical trials: methodology and engineering guide to closed-loop control in type 1 diabetes mellitus. Journal of diabetes science and technology Patek, S. D., Bequette, B. W., Breton, M., Buckingham, B. A., Dassau, E., Doyle, F. J., Lum, J., Magni, L., Zisser, H. 2009; 3 (2): 269-282
Abstract

This article sets forth guidelines for in silico (simulation-based) proof-of-concept testing of artificial pancreas control algorithms. The goal was to design a test procedure that can facilitate regulatory approval [e.g., Food and Drug Administration Investigational Device Exemption] for General Clinical Research Center experiments without preliminary testing on animals. The methodology is designed around a software package, based on a recent meal simulation model of the glucose-insulin system. Putting a premium on generality, this document starts by specifying a generic, rather abstract, meta-algorithm for control. The meta-algorithm has two main components: (1) patient assessment and tuning of control parameters, i.e., algorithmic processes for collection and processing patient data prior to closed-loop operation, and (2) controller warm-up and run-time operation, i.e., algorithmic processes for initializing controller states and managing blood glucose. The simulation-based testing methodology is designed to reveal the conceptual/mathematical operation of both main components, as applied to a large population of in silico patients with type 1 diabetes mellitus.

View details for PubMedID 20144358
Preventing Hypoglycemia Using Predictive Alarm Algorithms and Insulin Pump Suspension DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B., Cobry, E., Clinton, P., Gage, V., Caswell, K., Kunselman, E., Cameron, F., Chase, H. P. 2009; 11 (2): 93-97
Abstract

Nocturnal hypoglycemia is a significant problem. From 50% to 75% of hypoglycemia seizures occur at night. Despite the development of real-time glucose sensors (real-time continuous glucose monitor [CGM]) with hypoglycemic alarms, many patients sleep through these alarms. The goal of this pilot study was to assess the feasibility using a real-time CGM to discontinue insulin pump therapy when hypoglycemia was predicted.Twenty-two subjects with type 1 diabetes had two daytime admissions to a clinical research center. On the first admission their basal insulin was increased until their blood glucose level was <60 mg/dL. On the second admission hypoglycemic prediction algorithms were tested to determine if hypoglycemia was prevented by a 90-min pump shutoff and to determine if the pump shutoff resulted in rebound hyperglycemia.Using a statistical prediction algorithm with an 80 mg/dL threshold and a 30-min projection horizon, hypoglycemia was prevented 60% of the time. Using a linear prediction algorithm with an 80 mg/dL threshold and a 45-min prediction horizon, hypoglycemia was prevented 80% of the time. There was no rebound hyperglycemia following pump suspension.Further development of algorithms is needed to prevent all episodes of hypoglycemia from occurring.

View details for DOI 10.1089/dia.2008.0032

View details for Web of Science ID 000262811200006

View details for PubMedID 19848575

View details for PubMedCentralID PMC2979338
Use of continuous glucose monitoring with a proportional- integral-derivative algorithm to achieve tight glucose control in the pediatric intensive care unit Fuld, K. B., Pageler, N., Cortez, B., Cache, S., Buckingham, B. KARGER. 2009: 31?31
View details for Web of Science ID 000270489900102
Intensive Care Unit Insulin Delivery Algorithms: Why So Many? How to Choose? Journal of diabetes science and technology Steil, G. M., Deiss, D., Shih, J., Buckingham, B., Weinzimer, S., Agus, M. S. 2009; 3 (1): 125-140
Abstract

OBJECTIVE: Studies showing improved outcomes with tight glycemic control in the intensive care unit (ICU) have resulted in a substantial number of new insulin delivery algorithms being proposed. The present study highlights mechanisms used in the better-known approaches, examines what might be critical differences among them, and uses systems theory to characterize the conditions under which each can be expected to perform best. METHODS: Algorithm dose (DeltaI/DeltaG) and step (response to a persistent elevation in glucose) response curves were calculated for written instruction algorithms, developed at the Providence Heart and Vascular Institute (Portland [P] protocol), the University of Washington (UW), and Yale University (Y), together with similar curves for the Glucommander (GM) and proportional integral derivative (PID) computer algorithms. From the simulated curves, different mechanisms used to adjust insulin delivery were identified. RESULTS: All algorithms increased insulin delivery in response to persistent hyperglycemia, but the mechanism used altered the algorithm's sensitivity to glucose, or gain, in the GM, UW, and Y protocols, while leaving it unchanged for the P protocol and PID algorithm. CONCLUSIONS: The increase in insulin delivery in response to persistent hyperglycemia observed with all the algorithms can be expected to bring subjects who respond to insulin to targeted glucose ranges. However, because the PID and P protocols did not alter the insulin delivery response curves, these algorithms can be expected to take longer to achieve target glucose levels in individuals who are insulin resistant and/or are exposed to increased carbohydrate loads (e.g., glucose infusions). By contrast, the GM, UW, and Y algorithms can be expected to adapt to the insulin resistance such that the time to achieve target levels is unchanged if the time for insulin to act does not change. If the insulin resistance is accompanied by a longer time for insulin to act, the UW, Y, and GM algorithms may increase the risk of hypoglycemia. Under these conditions, the longer time required for the PID and P protocols to achieve a target glucose level may be a reasonable trade-off for no increase in the risk of hypoglycemia.

View details for PubMedID 19865614
Duration of Nocturnal Hypoglycemia Before Seizures DIABETES CARE Buckingham, B., Wilson, D. M., Lecher, T., Hanas, R., Kaiserman, K., Cameron, F. 2008; 31 (11): 2110-2112
Abstract

Despite a high incidence of nocturnal hypoglycemia documented by the use of continuous glucose monitoring (CGM), there are no reports in the literature of nocturnal hypoglycemic seizures while a patient is wearing a CGM device.In this article, we describe four such cases and assess the duration of nocturnal hypoglycemia before the seizure.In the cases where patients had a nocturnal hypoglycemic seizure while wearing a CGM device, sensor hypoglycemia (<60 mg/dl) was documented on the CGM record for 2.25-4 h before seizure activity.Even with a subcutaneous glucose lag of 18 min when compared with blood glucose measurements, glucose sensors have time to provide clinically meaningful alarms. Current nocturnal hypoglycemic alarms need to be improved, however, since patients can sleep through the current alarm systems.

View details for DOI 10.2337/dc08-0863

View details for Web of Science ID 000260565000007

View details for PubMedID 18694975

View details for PubMedCentralID PMC2571056
Continuous glucose monitoring and intensive treatment of type 1 diabetes NEW ENGLAND JOURNAL OF MEDICINE Tamborlane, W. V., Beck, R. W., Bode, B. W., Buckingham, B., Chase, H. P., Clemons, R., Fiallo-Scharer, R., Fox, L. A., Gilliam, L. K., Hirsch, I. B., Huang, E. S., Kollman, C., Kowalski, A. J., Laffel, L., Lawrence, J. M., Lee, J., Mauras, N., O'Grady, M., Ruedy, K. J., Tansey, M., Tsalikian, E., Weinzimer, S., Wilson, D. M., Wolpert, H., Wysocki, T., Xing, D. 2008; 359 (14): 1464-U65
Abstract

The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined.In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks.The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference.Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

View details for Web of Science ID 000259631700007

View details for PubMedID 18779236
Sensor-augmented insulin pump therapy: Results of the first randomized treat-to-target study DIABETES TECHNOLOGY & THERAPEUTICS Hirsch, I. B., Abelseth, J., Bode, B. W., Fischer, J. S., Kaufman, F. R., Mastrototaro, J., Parkin, C. G., Wolpert, H. A., Buckingham, B. A. 2008; 10 (5): 377-383
Abstract

The objective of the study was to evaluate the clinical effectiveness and safety of a device that combines an insulin pump with real-time continuous glucose monitoring (CGM), compared to using an insulin pump with standard blood glucose monitoring systems.This 6-month, randomized, multicenter, treat-to-target study enrolled 146 subjects treated with continuous subcutaneous insulin infusion between the ages of 12 and 72 years with type 1 diabetes and initial A1C levels of >or=7.5%. Subjects were randomized to pump therapy with real-time CGM (sensor group [SG]) or to pump therapy and self-monitoring of blood glucose only (control group [CG]). Clinical effectiveness and safety were evaluated.A1C levels decreased (P<0.001) from baseline (8.44+/-0.70%) in both groups (SG, -0.71+/-0.71%; CG, -0.56+/-0.072%); however, between-group differences did not achieve significance. SG subjects showed no change in mean hypoglycemia area under the curve (AUC), whereas CG subjects showed an increase (P=0.001) in hypoglycemia AUC during the blinded periods of the study. The between-group difference in hypoglycemia AUC was significant (P<0.0002). Greater than 60% sensor utilization was associated with A1C reduction (P=0.0456). Fourteen severe hypoglycemic events occurred (11 in the SG group and three in the CG group, P=0.04).A1C reduction was no different between the two groups. Subjects in the CG group had increased hypoglycemia AUC and number of events during blinded CGM use; however, there was no increase in hypoglycemia AUC or number of events in the SG group. Subjects with greater sensor utilization showed a greater improvement in A1C levels.

View details for DOI 10.1089/dia.2008.0068

View details for Web of Science ID 000259177600007

View details for PubMedID 18715214
Clinical application of emerging sensor technologies in diabetes management: Consensus guidelines for continuous glucose monitoring (CGM) DIABETES TECHNOLOGY & THERAPEUTICS Hirsch, I. B., Armstrong, D., Bergenstal, R. M., Buckingham, B., Childs, B. P., Clarke, W. L., Peters, A., Wolpert, H. 2008; 10 (4)
Abstract

Continuous glucose monitoring (CGM) is an evolving technology poised to redefine current concepts of glycemic control and optimal diabetes management. To date, there are few randomized studies examining how to most effectively use this new tool. Therefore, a group of eight diabetes specialists heard presentations on continuous glucose sensor technology and then discussed their experience with CGM in order to identify fundamental considerations, objectives, and methods for applying this technology in clinical practice. The group concluded that routine use of CGM, with real-time data showing the rate and direction of glucose change, could revolutionize current approaches to evaluating and managing glycemia. The need for such progress is indicated by the growing prevalence of inadequately treated hyperglycemia. Coordinating financial and educational resources and developing clear protocols for using glucose sensor technology are urgent priorities in promoting wide adoption of CGM by patients and health care providers. Finally, researchers, manufacturers, payers, and advocacy groups must join forces on the policy level to create an environment conducive to managing continuous data, measuring outcomes, and formalizing best practices.

View details for DOI 10.1089/dia.2008.0016

View details for Web of Science ID 000258900000001

View details for PubMedID 18699743
Statistical hypoglycemia prediction. Journal of diabetes science and technology Cameron, F., Niemeyer, G., Gundy-Burlet, K., Buckingham, B. 2008; 2 (4): 612-621
Abstract

Hypoglycemia presents a significant risk for patients with insulin-dependent diabetes mellitus. We propose a predictive hypoglycemia detection algorithm that uses continuous glucose monitor (CGM) data with explicit certainty measures to enable early corrective action.The algorithm uses multiple statistical linear predictions with regression windows between 5 and 75 minutes and prediction horizons of 0 to 20 minutes. The regressions provide standard deviations, which are mapped to predictive error distributions using their averaged statistical correlation. These error distributions give confidence levels that the CGM reading will drop below a hypoglycemic threshold. An alarm is generated if the resultant probability of hypoglycemia from our predictions rises above an appropriate, user-settable value. This level trades off the positive predictive value against lead time and missed events.The algorithm was evaluated using data from 26 inpatient admissions of Navigator(R) 1-minute readings obtained as part of a DirecNet study. CGM readings were postprocessed to remove dropouts and calibrate against finger stick measurements. With a confidence threshold set to provide alarms that correspond to hypoglycemic events 60% of the time, our results were (1) a 23-minute mean lead time, (2) false positives averaging a lowest blood glucose value of 97 mg/dl, and (3) no missed hypoglycemic events, as defined by CGM readings. Using linearly interpolated FreeStyle capillary glucose readings to define hypoglycemic events provided (1) the lead time was 17 minutes, (2) the lowest mean glucose with false alarms was 100 mg/dl, and (3) no hypoglycemic events were missed.Statistical linear prediction gives significant lead time before hypoglycemic events with an explicit, tunable trade-off between longer lead times and fewer missed events versus fewer false alarms.

View details for PubMedID 19885237
Use of the DirecNet Applied Treatment Algorithm (DATA) for diabetes management with a real-time continuous glucose monitor (the FreeStyle Navigator) PEDIATRIC DIABETES Buckingham, B., Xing, D., Weinzimer, S., Fiallo-Scharer, R., Kollman, C., Mauras, N., Tsalikian, E., Tamborlane, W., Wysocki, T., Ruedy, K., Beck, R. 2008; 9 (2): 142-147
Abstract

There are no published guidelines for use of real-time continuous glucose monitoring data by a patient; we therefore developed the DirecNet Applied Treatment Algorithm (DATA). The DATA provides algorithms for making diabetes management decisions using glucose values: (i) in real time which include the direction and rate of change of glucose levels, and (ii) retrospectively based on downloaded sensor data.To evaluate the use and effectiveness of the DATA in children with diabetes using a real-time continuous glucose sensor (the FreeStyle Navigator).Thirty children and adolescents (mean +/- standard deviation age = 11.2 +/- 4.1 yr) receiving insulin pump therapy.Subjects were instructed on use of the DATA and were asked to download their Navigator weekly to review glucose patterns. An Algorithm Satisfaction Questionnaire was completed at 3, 7, and 13 wk.At 13 wk, all of the subjects and all but one parent thought that the DATA gave good, clear directions for insulin dosing, and thought the guidelines improved their postprandial glucose levels. In responding to alarms, 86% of patients used the DATA at least 50% of the time at 3 wk, and 59% reported doing so at 13 wk. Similar results were seen in using the DATA to adjust premeal bolus doses of insulin.These results show the feasibility of implementing the DATA when real-time continuous glucose monitoring is initiated and support its use in future clinical trials of real-time continuous glucose monitoring.

View details for DOI 10.1111/j.1399-5448.2007.00301.x

View details for Web of Science ID 000255130400011

View details for PubMedID 18221427

View details for PubMedCentralID PMC2390770
Clinical overview of continuous glucose monitoring. Journal of diabetes science and technology Buckingham, B. 2008; 2 (2): 300-306
Abstract

Continuous glucose monitoring (CGM) is now available from several companies in the United States for purchase or research studies. This article provides an overview of these devices and reviews the use of sensors for managing diabetes in "real time," as well as the use of retrospective analysis of CGM results.

View details for PubMedID 19885360
Detection of a Meal Using Continuous Glucose Monitoring implications for an artificial beta-cell DIABETES CARE Dassau, E., Bequette, B. W., Buckingham, B. A., Doyle, F. J. 2008; 31 (2): 295-300
Abstract

The purpose of this study was to introduce a novel meal detection algorithm (MDA) to be used as part of an artificial beta-cell that uses a continuous glucose monitor (CGM).We developed our MDA on a dataset of 26 meal events using records from 19 children aged 1-6 years who used the MiniMed CGMS Gold. We then applied this algorithm to CGM records from a DirecNet pilot study of the FreeStyle Navigator continuous glucose sensor. During a research center admission, breakfast insulin was withheld for 1 h, and discrete glucose levels were obtained every 10 min after the meal.Based on the Navigator readings, the MDA detected a meal at a mean time of 30 min from the onset of eating, at which time the mean serum glucose was 21 mg/dl above baseline (range 2-36 mg/dl), and >90% of meals were detected before the glucose had risen 40 mg/dl from baseline.The MDA will enable automated insulin dosing in response to meals, facilitating the development of an artificial pancreas.

View details for DOI 10.2337/dc07-1293

View details for Web of Science ID 000266563300023

View details for PubMedID 17977934
Continuous glucose monitoring in children with type 1 diabetes JOURNAL OF PEDIATRICS Anonymous 2007; 151 (4): 388-393
Abstract

To examine the feasibility of daily use of a continuous glucose monitor, the FreeStyle Navigator Continuous Glucose Monitoring System ("Navigator"), in children with type 1 diabetes (T1D).After a masked Navigator was used for 4 to 7 days to establish a baseline level of glycemic control, 30 insulin pump users with T1D (average age 11.2 years) were asked to use the Navigator daily for 13 weeks.Subjects averaged 149 h/wk of Navigator use during the first 4 weeks, which decreased slightly to 134 h/wk during weeks 9 to 13 (P = .006). Mean hemoglobin A1c improved from 7.1% at baseline to 6.8% at 13 weeks (P = .02), and the percentage of glucose values between 71 and 180 mg/dL increased from 52% to 60% (P = .01). Subjects and parents reported high satisfaction with the Navigator on the Continuous Glucose Monitor Satisfaction Scale. Two subjects had severe skin reactions related to sensor mount adhesive.This study indicates that incorporating real-time continuous glucose monitoring into the daily treatment of children with T1D is feasible. The results provide a compelling rationale for conducting a randomized trial of daily use of a continuous glucose monitor in children with T1D.

View details for DOI 10.1016/j.jpeds.2007.03.047

View details for Web of Science ID 000249966800017

View details for PubMedID 17889075
The medtronic MiniMed gold continuous glucose monitoring system: An effective means to discover hypo- and Hyperglycemia in children under 7 years of age DIABETES TECHNOLOGY & THERAPEUTICS Gandrud, L. M., Xing, D., Kollman, C., Block, J. M., Kunselman, B., Wilson, D. M., Buckingham, B. A. 2007; 9 (4): 307-316
Abstract

The glycemic patterns of children less than 7 years with type 1 diabetes have not been well studied using continuous glucose monitoring. Our goal was to assess the incidence of hypoglycemia as well as postprandial glycemic patterns in this age group utilizing continuous glucose monitoring.Nineteen children used the Medtronic MiniMed (Northridge, CA) CGMS System Gold on three to seven occasions over approximately 6 months.Nineteen children (nine girls and 10 boys; mean age 4.8 +/- 1.4 years, range 1.6-6.8 years) used the CGMS 102 times, providing 434 days of data; 79% of days were optimal based on CGMS Solutions software version 3.0. Mild hypoglycemia (glucose or=2 mg/dL/min following 50% of breakfasts. Children with hemoglobin A1c levels >or=8% had higher postprandial glucose concentrations. There was no significant advantage of continuous subcutaneous insulin infusion therapy over multiple daily injection therapy in decreasing postprandial hyperglycemia.CGMS tracings from young children with diabetes demonstrate frequent mild nocturnal hypoglycemia and significant postprandial hyperglycemia, with a rapid rise in glucose following the meal. The most rapid rate of rise and the most severe postprandial hyperglycemia occurred after breakfast.

View details for DOI 10.1089/dia.2007.0026

View details for PubMedID 17705686
Real-time continuous glucose monitoring. Current opinion in endocrinology, diabetes, and obesity Buckingham, B., Caswell, K., Wilson, D. M. 2007; 14 (4): 288-295
Abstract

To summarize the current literature on real-time continuous glucose monitors, focusing on devices that have been approved or are pending approval.Real-time continuous glucose sensors are new tools to assist in diabetes management. Several devices are currently being sold and additional monitors are expected to be available shortly. These sensors measure interstitial glucose - a distinct physiologic space when compared with the blood glucose. The ability to recognize trends in blood glucose levels provides a new paradigm for making insulin dose decisions and treating hypo- and hyperglycemia.Real-time continuous glucose monitoring systems are currently less accurate than home glucose meters, but provide information every 1-5 min throughout the day and night with alarms for hyper- and hypoglycemia, providing information on glucose trends and nocturnal glycemic excursions. Current real-time sensors are behavior modification tools. Thus, improvements in diabetes control depend on the willingness of patients to modify their diabetes management based on information provided by these devices.

View details for PubMedID 17940454
Glucose control in pediatric intensive care unit patients using an insulin-glucose algorithm DIABETES TECHNOLOGY & THERAPEUTICS Wintergerst, K. A., Deiss, D., Buckingham, B., Cantwell, M., Kache, S., Agarwal, S., Wilson, D. M., Steil, G. 2007; 9 (3): 211-222
Abstract

Control of hyperglycemia in adult medical and surgical intensive care units (ICUs) has been shown to dramatically decrease morbidity and mortality. Algorithms to achieve glycemic control in the ICU setting are evolving. We have evaluated the use of a discrete proportional-integral-derivative (PID) algorithm to control hyperglycemia in pediatric ICU (PICU) patients both with and without diabetes.Six PICU patients [four with diabetic ketoacidosis (DKA) and two with glucocorticoid-induced hyperglycemia] with glucose values >150 mg/dL were enrolled. Their hyperglycemia was managed with a PID algorithm that provided recommendations for both changes in the intravenous insulin infusion rate and the time to obtain the next discrete glucose value. Glucose targets were adjusted based on clinical circumstances.Patients (mean age 9.2 years; range 1.8-14 years) utilized the algorithm for a total of 454.4 h. Mean time to the initial glucose target was 8.7 h (range 1.3-15.1 h) in five patients. One subject with hyperosmolar DKA did not achieve target before discharge from the PICU, and another was at target when the algorithm was initiated. After the glucose target was achieved, the mean SD was 23.5 mg/dL, and glucose values were >40 mg/dL above target 13% of the time and <40 mg/dL below target 1% of the time. There were no glucose values <55 mg/dL.The PID algorithm safely and effectively controlled hyperglycemia in a PICU, despite multiple changes in intravenous fluids, steroid doses (including high-dose pulses), and hemodialysis.

View details for DOI 10.1089/dia.2006.0031

View details for Web of Science ID 000247337800002

View details for PubMedID 17561791
Relative accuracy of the BD Logic (R) and FreeStyle (R) blood glucose meters DIABETES TECHNOLOGY & THERAPEUTICS Fox, L. A., Beck, R., Steffes, M., Chase, P., Coffey, J., Wysocki, T., Buckingham, B., Weinzimer, S., Tamborlane, W., Kollman, C., Ruedy, K. 2007; 9 (2): 165-168
View details for DOI 10.1089/dia.2006.0005

View details for Web of Science ID 000245818600005
Increasing the accuracy of oral glucose tolerance testing and extending its application to individuals with normal glucose tolerance for the prediction of type 1 diabetes - The Diabetes Prevention Trial-Type 1 DIABETES CARE Sosenko, J. M., Palmer, J. P., Greenbaum, C. J., Mahon, J., Cowie, C., Krischer, J. P., Chase, H. P., White, N. H., Buckingham, B., Herold, K. C., Cuthbertson, D., Skyler, J. S. 2007; 30 (1): 38-42
Abstract

We assessed the extent to which both standard and alternative indexes from 2-h oral glucose tolerance testing predict type 1 diabetes and whether oral glucose tolerance tests (OGTTs) predict type 1 diabetes in individuals with normal glucose tolerance.The prediction of type 1 diabetes from baseline OGTTs was studied in 704 Diabetes Prevention Trial-Type 1 participants (islet-cell autoantibody [ICA]-positive relatives of type 1 diabetic patients). The maximum follow-up was 7.4 years. Analyses utilized receiver-operator curves (ROCs), proportional hazards models, and survival curves.ROC areas under the curve (ROCAUCs) for both the AUC glucose (0.73 +/- 0.02) and an OGTT prediction index (0.78 +/- 0.02) were higher (P < 0.001) than those for the fasting (0.53 +/- 0.02) and 2-h glucose (0.66 +/- 0.02). ROCAUCs for the 60- and 90-min glucose (0.71 +/- 0.02 and 0.72 +/- 0.02, respectively) were also higher (P < 0.01) than those for the fasting and 2-h glucose. Among individuals with normal glucose tolerance, OGTTs were highly predictive, with 4th versus 1st quartile hazard ratios for the 2-h glucose, AUC glucose, and OGTT prediction index ranging from 3.77 to 5.30 (P < 0.001 for all).Certain alternative OGTT indexes appear to better predict type 1 diabetes than standard OGTT indexes in ICA-positive relatives of type 1 diabetic patients. Moreover, even among those with normal glucose tolerance, OGTTs are strongly predictive. This suggests that subtle metabolic abnormalities are present several years before the diagnosis of type 1 diabetes.

View details for DOI 10.2337/dc06-1615

View details for Web of Science ID 000243469800007

View details for PubMedID 17192330
Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit PEDIATRICS Wintergerst, K. A., Buckingham, B., Gandrud, L., Wong, B. J., Kache, S., Wilson, D. M. 2006; 118 (1): 173-179
Abstract

We evaluated retrospectively plasma glucose levels and the degree of hypoglycemia, hyperglycemia, and glucose variability in a PICU and then assessed their association with hospital length of stay and mortality rates.Electronic medical records at the Packard Children's Hospital at Stanford University were reviewed retrospectively for all PICU admissions between March 1, 2003, and March 31, 2004. Patients with a known diagnosis of diabetes mellitus were excluded. The prevalence of hyperglycemia was defined with cutoff values of 110, 150, and 200 mg/dL. Hypoglycemia was defined as < or = 65 mg/dL. Glucose variability was assessed with a calculated glucose variability index.In 13 months, 1094 eligible admissions generated 18865 glucose values (median: 107 mg/dL; range: 13-1839 mg/dL). Patients in the highest maximal glucose quintile had a significantly longer median PICU length of stay, compared with those in the lowest quintile (7.5 days vs 1 day). Mortality rates increased as patients' maximal glucose levels increased, reaching 15.2% among patients with the greatest degree of hyperglycemia. Hypoglycemia was also prevalent, with 18.6% of patients (182 of 980 patients) having minimal glucose levels of < or = 65 mg/dL. There was an increased median PICU length of stay (9.5 days vs 1 day) associated with glucose values in the lowest minimal quintile, compared with those in the highest quintile. Hypoglycemia was correlated with mortality rates; 16.5% of patients with glucose levels of < or = 65 mg/dL died. Glucose variability also was associated with increased length of stay and mortality rates. In multivariate logistic regression analyses, glucose variability, taken with hyperglycemia and hypoglycemia, showed the strongest association with mortality rates.Hyperglycemia and hypoglycemia were prevalent in the PICU. Hypoglycemia, hyperglycemia, and, in particular, increased glucose variability were associated with increased morbidity (length of stay) and mortality rates.

View details for DOI 10.1542/peds.2005-1819

View details for PubMedID 16818563
Evaluation of factors affecting CGMS calibration DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B. A., Kollman, C., Beck, R. W., Kalajian, A., Fiallo-Scharer, R., Tansey, M. J., Fox, L. A., Wilson, D. M., Weinzimer, S. A., Ruedy, K. J., Tamborlane, W. V. 2006; 8 (3): 318-325
Abstract

The optimal number/timing of calibrations entered into the CGMS (Medtronic MiniMed, Northridge, CA) continuous glucose monitoring system have not been previously described.Fifty subjects with Type 1 diabetes mellitus (10-18 years old) were hospitalized in a clinical research center for approximately 24 h on two separate days. CGMS and OneTouch Ultra meter (LifeScan, Milpitas, CA) data were obtained. The CGMS was retrospectively recalibrated using the Ultra data varying the number and timing of calibrations. Resulting CGMS values were compared against laboratory reference values.There was a modest improvement in accuracy with increasing number of calibrations. The median relative absolute deviation (RAD) was 14%, 15%, 13%, and 13% when using three, four, five, and seven calibration values, respectively (P < 0.001). Corresponding percentages of CGMS-reference pairs meeting the International Organisation for Standardisation criteria were 66%, 67%, 71%, and 72% (P < 0.001). Nighttime accuracy improved when daytime calibrations (pre-lunch and pre-dinner) were removed leaving only two calibrations at 9 p.m. and 6 a.m. (median difference, -2 vs. -9 mg/dL, P < 0.001; median RAD, 12% vs. 15%, P = 0.001). Accuracy was better on visits where the average absolute rate of glucose change at the times of calibration was lower. On visits with average absolute rates <0.5, 0.5 to <1.0, 1.0 to <1.5, and >or=1.5 mg/dL/min, median RAD values were 13% versus 14% versus 17% versus 19%, respectively (P = 0.05).Although accuracy is slightly improved with more calibrations, the timing of the calibrations appears more important. Modifying the algorithm to put less weight on daytime calibrations for nighttime values and calibrating during times of relative glucose stability may have greater impact on accuracy.

View details for Web of Science ID 000242531200007

View details for PubMedID 16800753
Family assessment of the utility of the DirecNet applied treatment algorithm (DATA) for insulin adjustments in real-tilme and retrospective analyses of continuous glucose monitoring (CGM) Buckingham, B., Ruedy, K., Kollman, C., Beck, R., Tamborlane, W., Mauras, N., Weinzimer, S., Chase, P., Tsalikian, E., Diabetes Res Children Network AMER DIABETES ASSOC. 2006: A453
View details for Web of Science ID 000238055802587
Extended use of a new continuous glucose monitoring system with wireless data transmission in children with type 1 diabetes mellitus DIABETES TECHNOLOGY & THERAPEUTICS Wong, L. J., Buckingham, B. A., Kunselman, B., Istoc, E., Leach, J., Purvis, R. 2006; 8 (2): 139-145
Abstract

A new continuous glucose monitoring system (CGMS Datalogger, Medtronic MiniMed, Northridge, CA) potentiates extended sensor use by eliminating the cable connection to a monitor and by being waterproof. We evaluated the performance, safety, and patient tolerance of using the CGMS for 7 continuous days in children with type 1 diabetes mellitus who were encouraged to participate fully in their usual sports and activities in their home environment.Twenty pediatric subjects (12.2 +/- 4.6 years old [mean +/- SD] and glycosylated hemoglobin of 8.06 +/- 1.22%) wore two CGMS devices simultaneously for 7 days. Sensor function was assessed by paired sensor-meter values obtained from the CGMS and their Paradigm Link (Medtronic Minimed) home glucose meter and a daily patient log of sensor and Datalogger sites.Subjects were wearing 90% of the sensors at the end of 7 days. The devices were well tolerated except for pruritus at the adhesive sites in 29% of subjects, and one sensor site (3%) became infected. Once a correction was made to the connection between the cable and Datalogger, 89% of the 18 sensors that initialized were functional at the end of 5 days [r = 0.91; percent mean absolute relative difference (%MARD) = 12.4%], and 78% were functioning at the end of 7 days (r = 0.91; %MARD s 15.4%). Patient comfort while wearing the device decreased after 5 days of sensor wear.This study demonstrates that the life of the glucose sensor can be extended well beyond the current labeling of 72 h. Once the cable connection was corrected, there was no statistically significant change in sensor performance over 7 days. Patients preferred to wear the device for a maximum of 5-6 days.

View details for Web of Science ID 000242405400002

View details for PubMedID 16734544
Vitamin D deficiency in the San Francisco bay area JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM McAllister, J. C., Lane, A. T., Buckingham, B. A. 2006; 19 (3): 205-208
View details for Web of Science ID 000236479400003

View details for PubMedID 16607919
Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1 DIABETES CARE Sosenko, J. M., Palmer, J. P., Greenbaum, C. J., Mahon, J., Cowie, C., Krischer, J. P., Chase, H. P., White, N. H., Buckingham, B., Herold, K. C., Cuthbertson, D., Skyler, J. S. 2006; 29 (3): 643-649
Abstract

There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial-Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis.Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points.Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P < 0.001 for all indexes). Area under the curve (AUC) C-peptide (P < 0.05) and AUC C-peptide-to-AUC glucose ratio (P < 0.001) values decreased in the oral group; peak C-peptide-to-2-h glucose ratio values decreased in both groups (P < 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P < 0.05) and peak C-peptide (oral group, P < 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide-to-glucose ratio values decreased in both groups (P < 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P < 0.01). Fasting C-peptide-to-fasting glucose ratio values remained constant throughout the 30-month follow-up.These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.

View details for Web of Science ID 000235764100027

View details for PubMedID 16505520
The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes 65th Annual Meeting of the American-Diabetes-Association Tansey, M. J. AMER DIABETES ASSOC. 2006: 20?25
Abstract

To examine the acute glucose-lowering effects of aerobic exercise in children and adolescents with type 1 diabetes.Fifty children and adolescents with type 1 diabetes (ages 10 to <18 years) were studied during exercise. The 75-min exercise session consisted of four 15-min periods of walking on a treadmill to a target heart rate of 140 bpm and three 5-min rest periods. Blood glucose and plasma glucagon, cortisol, growth hormone, and norepinephrine concentrations were measured before, during, and after exercise.In most subjects (83%), plasma glucose concentration dropped at least 25% from baseline, and 15 (30%) subjects became hypoglycemic (< or = 60 mg/dl) or were treated for low glucose either during or immediately following the exercise session. The incidence of hypoglycemia and/or treatment for low glucose varied significantly by baseline glucose, occurring in 86 vs. 13 vs. 6% of subjects with baseline values <120, 120-180, and >180 mg/dl, respectively (P < 0.001). Exercise-induced increases in growth hormone and norepinephrine concentrations were marginally higher in subjects whose glucose dropped < or = 70 mg/dl. Treatment of hypoglycemia with 15 g of oral glucose resulted in only about a 20-mg/dl rise in glucose concentrations.In youth with type 1 diabetes, prolonged moderate aerobic exercise results in a consistent reduction in plasma glucose and the frequent occurrence of hypoglycemia when preexercise glucose concentrations are <120 mg/dl. Moreover, treatment with 15 g of oral glucose is often insufficient to reliably treat hypoglycemia during exercise in these youngsters.

View details for Web of Science ID 000234349300004

View details for PubMedID 16373890
Hypoglycemia detection, and better yet, prevention, in pediatric patients. Diabetes technology & therapeutics Buckingham, B. 2005; 7 (5): 792-796
View details for PubMedID 16241885
Accuracy of newer-generation home blood glucose meters in a Diabetes Research in Children Network (DirecNet) inpatient exercise study. Diabetes technology & therapeutics Weinzimer, S. A., Beck, R. W., Chase, H. P., Fox, L. A., Buckingham, B. A., Tamborlane, W. V., Kollman, C., Coffey, J., Xing, D., Ruedy, K. J. 2005; 7 (5): 675-680
Abstract

The objective of this study was to assess how the accuracy of the FreeStyle Flash (Abbott Diabetes Care, Alameda, CA) meter compares with that of the One Touch Ultra (Lifescan, Milpitas, CA) home glucose meter (HGM).Fifty children with type 1 diabetes (T1D), 10-17 years old, were admitted for two separate 24-h periods to assess the effect of exercise on subsequent nocturnal hypoglycemia. Resulting data were used in a preplanned analysis of the accuracy of the Ultra and FreeStyle HGMs. Glucose levels were measured throughout the day and night and every 15-20 min during a standardized exercise protocol. Reference samples were assayed in a central laboratory using a hexokinase enzymatic method. These reference glucose measurements were paired with HGM values from venous blood obtained within +/- 5 min.The median relative absolute difference was 5% for both the Ultra and FreeStyle HGMs, and the percentages of pairs meeting the International Organisation for Standardization criteria were 99% and 98%, respectively. The FreeStyle tended to read slightly higher than the reference method (median difference = +3 mg/dL; P < 0.001), and there was trend in this direction for the Ultra (median difference = +2 mg/dL, P = 0.15). Sensitivities for detection of hypoglycemia (reference < or = 60 and HGM < or = 70 mg/dL) were 96% and 100% for the Ultra and FreeStyle, respectively, and corresponding false-positive rates were both 5%.In a controlled clinical setting using venous blood samples, both the Ultra and FreeStyle meters demonstrated a high degree of accuracy compared with the laboratory reference over a broad range of glucose concentrations in children with T1D.

View details for PubMedID 16241867
Impact of exercise on overnight glycemic control in - Children with type 1 diabetes mellitus JOURNAL OF PEDIATRICS Tsalikian, E., Mauras, N., Beck, R. W., Tamborlane, W. V., Janz, K. F., Chase, H. P., Wysocki, T., Weinzimer, S. A., Buckingham, B. A., KOLLMAN, C., Xing, D. Y., Ruedy, K. J., Fiallo-Scharer, R., Fisher, J. H., Tallant, B., Tsalikian, E., Tansey, M. J., Larson, L. F., Coffey, J., Wysocki, T., Mauras, N., Fox, L. A., Bird, K., Lofton, K. L., Buckingham, B. A., Wilson, D. M., Block, J. M., Clinton, P., Doyle, E. A., Sikes, K., Kalajian, A., Stockdale, C. R., Steffes, M. W., Bucksa, J. M., Nowicki, M. L., Van Hale, C. A., Makky, V., Grave, G. D., Linder, B., Winer, K. K., Becker, D. M., Cox, C., Ryan, C. M., White, N. H., White, P. C. 2005; 147 (4): 528-534
Abstract

To examine the effect of exercise on overnight hypoglycemia in children with type 1 diabetes mellitus (T1DM).At 5 clinical sites, 50 subjects with T1DM (age 11 to 17 years) were studied in a clinical research center on 2 separate days. One day included an afternoon exercise session on a treadmill. On both days, frequently sampled blood glucose levels were measured at the DirecNet central laboratory. Insulin doses were similar on both days.During exercise, plasma glucose levels fell in almost all subjects; 11 (22%) developed hypoglycemia. Mean glucose level from 10 pm to 6 am was lower on the exercise day than on the sedentary day (131 vs 154 mg/dL; P=.003). Hypoglycemia developed overnight more often on the exercise nights than on the sedentary nights (P=.009), occurring on the exercise night only in 13 (26%), on the sedentary night only in 3 (6%), on both nights in 11 (22%), and on neither night in 23 (46%). Hypoglycemia was unusual on the sedentary night if the pre-bedtime snack glucose level was>130 mg/dL.These findings indicate that overnight hypoglycemia after exercise is common in children with T1DM and support the importance of modifying diabetes management after afternoon exercise to reduce the risk of hypoglycemia.

View details for DOI 10.1016/j.jpeds.2005.04.065

View details for Web of Science ID 000232865300024

View details for PubMedID 16227041
Youth and parent satisfaction with clinical use of the GlucoWatch G2 Biographer in the management of pediatric type 1 diabetes DIABETES CARE Wysocki, T., Beck, R. W., Tamborlane, W. V., Fiallo-Scharer, R., Tansey, M. J., Weinzimer, S. A., KOLLMAN, C., Ruedy, K. J., Xing, D. Y., Davis, B., Chase, H. P., Fiallo-Scharer, R., Fisher, J. H., Tallant, B., Tsalikian, E., Tansey, M. J., Larson, L. F., Coffey, J., Wysocki, T., Mauras, N., Fox, L. A., Bird, K., Lofton, K. L., Buckingham, B. A., Wilson, D. M., Block, J. M., Clinton, P., Weinzimer, S. A., Tamborlane, W. V., Doyle, E. A., Sikes, K., Beck, R. W., Ruedy, K. J., KOLLMAN, C., Xing, D. Y., Kalajian, A., Stockdale, C. R., Grave, G. D., Linder, B., Winer, K. K., Steffes, M. W., Bucksa, J. M., Nowicki, M. L., Van Hale, C. A., Becker, D. M., Cox, C., Ryan, C. M., White, N. H., White, P. C. 2005; 28 (8): 1929-1935
Abstract

A continuous glucose monitor satisfaction scale (CGM-SAT) was evaluated during a 6-month randomized controlled trial of the GlucoWatch G2 Biographer (GW2B) in youths with type 1 diabetes.At the end of the 6-month trial, 97 parents and 66 older children who had been randomized to the GW2B group completed the CGM-SAT, which assesses satisfaction on 37 items using a five-point Likert scale. Descriptive analysis, calculation of several reliability estimates, and assessment of concurrent validity were performed.The CGM-SAT demonstrated high internal reliability (Cronbach's alpha = 0.95 for parents and 0.94 for youths aged > or = 11 years), split-half reliability (rho = 0.91 for parents and 0.93 for youths), and parent-adolescent agreement (rho = 0.68, P < 0.001). Convergent validity was supported by marginally significant associations with treatment adherence and frequency of GW2B use. CGM-SAT scores did not correlate significantly with changes in treatment adherence, quality of life, or diabetes-related anxiety from baseline to 6 months. Mean scores on CGM-SAT items indicated that 81% of parental responses and 73% of youths' responses were less favorable than "neutral." Descriptive analysis indicated the GW2B requires substantial improvement before it can achieve widespread clinical utility and acceptance.The results supported the psychometric properties of the CGM-SAT. The CGM-SAT warrants further research use and cross-validation with other continuous glucose monitors. This study provides a benchmark for comparison with new glucose sensors.

View details for Web of Science ID 000230869700013

View details for PubMedID 16043734
Response to nocturnal alarms using a real-time glucose sensor. Diabetes technology & therapeutics Buckingham, B., Block, J., Burdick, J., Kalajian, A., Kollman, C., Choy, M., Wilson, D. M., Chase, P. 2005; 7 (3): 440-447
Abstract

The objective of this study was to determine how subjects responded to alarms for hypo- and hyperglycemia while they were sleeping.Twenty subjects with type 1 diabetes (4-17 years old) were admitted to a clinical research center for approximately 24 h. Each subject wore two GlucoWatch G2 Biographers (GW2B) (Cygnus, Inc., Redwood City, CA) and was videotaped using an infrared camera from 9 p.m. to 7 a.m. The videotapes were reviewed to determine if the GW2B alarms were audible on the tape and to document the subject's response to the alarms. Because many alarms can occur surrounding a change in blood glucose, GW2B alarm "events" are defined as a one or more alarms separated from previous alarms by more than 30 min.Downloaded data from the biographers identified 240 individual alarms, 75% of which occurred while the subject was sleeping. Of the 240 alarms 68% were audible on the videotape. Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects 4-6 years old responded to 17% of alarms, 7-11 year olds responded to 20% of alarms, adolescents responded to 53% of alarms, and parents responded to 37% of alarms. Subjects awoke to 40% of the first alarm during the night, but to only 28% of subsequent alarms. There were 11 events when the glucose was confirmed to be < or = 70 mg/dL, and in each case the subject was awoken. Fifty-five percent of alarm events occurred when there was no hypo- or hyperglycemia confirmed by a reference glucose value.Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects awoke during all alarm events when hypoglycemia was confirmed, but there was a high incidence of false alarms.

View details for PubMedID 15929675
Eight-point glucose testing versus the continuous glucose monitoring system in evaluation of glycemic control in type 1 diabetes JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Fiallo-Scharer, R., Xing, D. Y., Weinzimer, S., Buckingham, B., Mauras, N., Tansey, M., Chase, P., Beck, R., Ruedy, K., KOLLMAN, C., Tamborlane, W., Chase, H. P., Fiallo-Scharer, R., Fisher, J. H., Tallant, B., Tsalikian, E., Tansey, M. J., Larson, L. F., Coffey, J., Wysocki, T., Mauras, N., Fox, L. A., Bird, K., Lofton, K. L., Buckingham, B. A., Wilson, D. M., Block, J. M., Clinton, P., Weinzimer, S. A., Tamborlane, W. V., Doyle, E. A., Sikes, K., Beck, R. W., Ruedy, K. J., KOLLMAN, C., Xing, D. Y., Kalajian, A., Silvester, C. R., Steffes, M. W., Bucksa, J. M., Nowicki, M. L., Van Hale, C. A., Grave, G. D., Linder, B., Winer, K. K., Becker, D. M., Cox, C., Ryan, C. M., White, N. H., White, P. C. 2005; 90 (6): 3387-3391
Abstract

Advantages/disadvantages of continuous vs. discrete glucose monitoring are not well documented.Compare glucose profiles from home meters vs. continuous sensors.Randomized clinical trial conducted by the Diabetes Research in Children Network (DirecNet) to assess the utility of the GlucoWatch G2 Biographer.Home glucose measurements.Two hundred children (age, 7 to < 18 yr) with type 1 diabetes.At baseline, subjects were asked to wear the continuous glucose monitoring system (CGMS) sensor and perform meter tests at eight prespecified times of the day (eight-point testing) each for 3 d (2 d using both, 1 d eight-point testing only, 1 d CGMS only). Hemoglobin A1c was measured in a central laboratory.Six-month hemoglobin A1c. This analysis looked at baseline glucose profiles/hemoglobin A1c.Only 10% of subjects completed full eight-point testing for 3 d, but median CGMS use was 70 h. Mean glucose was lower when measured by the CGMS compared with eight-point testing (183 +/- 37 vs. 188 +/- 41 mg/dl; 10.2 +/- 2.1 vs.10.4 +/- 2.3 mmol/liter; P = 0.009), especially overnight (2400-0400 h; 174 vs. 199 mg/dl; 9.7 vs. 11.1 mmol/liter; P < 0.001). Associations of hemoglobin A1c with mean glucose were similar for eight-point testing [slope 23 mg/dl per 1% (1.3 mmol/liter); correlation 0.40; P < 0.001] and CGMS [slope 19 mg/dl per 1% (1.1 mmol/liter); correlation 0.39; P < 0.001]. Postprandial excursions were lower for eight-point testing vs. CGMS, especially after dinner (mean excursion -17 vs. 63 mg/dl; -1.0 vs. 3.5 mmol/liter; P < 0.001).Both methods gave similar mean glucose profiles and associations with hemoglobin A1c. Advantages of the CGMS were higher density of data and better detection of postprandial peaks. However, the CGMS may overestimate the frequency of low glucose levels, especially overnight.

View details for DOI 10.1210/jc.2004-2510

View details for Web of Science ID 000229351000036

View details for PubMedID 15784705
A randomized multicenter trial comparing the GlucoWatch Biographer with standard glucose monitoring in children with type 1 diabetes. Diabetes care Chase, H. P., Beck, R., Tamborlane, W., Buckingham, B., Mauras, N., Tsalikian, E., Wysocki, T., Weinzimer, S., Kollman, C., Ruedy, K., Xing, D. 2005; 28 (5): 1101-1106
Abstract

This study assesses whether use of the GlucoWatch G2 Biographer (GW2B) in addition to standard glucose monitoring lowers HbA(1c) and reduces hypoglycemia compared with standard glucose monitoring alone.In all, 200 subjects aged 7 to <18 years with type 1 diabetes were randomly assigned at five centers to standard glucose monitoring (usual care) or standard glucose monitoring plus GW2B use for 6 months. Study outcomes included HbA(1c) values obtained at 6 months and occurrence of severe hypoglycemia.The mean HbA(1c) at baseline was 8.0% in both groups; at 6 months, HbA(1c) was 7.9% in the usual care group and 8.1% in the GW2B group (95% CI for mean reduction in the GW2B group compared with the usual care group -0.4 to 0.1%; P = 0.15). A decrease in HbA(1c) of > or =0.5% was achieved in 21% of the usual care group and 28% of the GW2B group (P = 0.29). Severe hypoglycemia events occurred in 7% of the GW2B group and in 2% of the usual care group (P = 0.10). In the GW2B group, sensor use declined throughout the study from a mean value of 2.1 times/week in the 1st month to 1.5 times/week in the 6th month. Reasons given for declining use included skin irritation (76%), frequent skips (56%), excessive alarms (47%), and inaccurate readings (33%).Use of the GW2B in addition to standard glucose monitoring did not improve glycemic control or reduce the frequency of severe hypoglycemia. Skin reactions and other problems led to decreasing sensor use over time.

View details for PubMedID 15855573
The extended Kalman filter for continuous glucose monitoring. Diabetes technology & therapeutics Knobbe, E. J., Buckingham, B. 2005; 7 (1): 15-27
Abstract

Glucose monitoring is a problem with evolving solutions using sensors and data processing techniques that are continually improving. This paper presents the development and application of the extended Kalman filter to the problem of real-time estimation of blood glucose levels and is consistent with sensors based on optical, electrical, or chemical processes. The structure of the extended Kalman filter provides the capability to systematically accommodate new information as it develops. This flexibility and the potential for performance improvement are demonstrated by processing patient data files generated using the Medtronic (Northridge, CA) MiniMed continuous glucose monitoring system (CGMS).

View details for PubMedID 15738701
Accuracy of the modified Continuous Glucose Monitoring System (CGMS) sensor in an outpatient setting: results from a diabetes research in children network (DirecNet) study. Diabetes technology & therapeutics Tansey, M. J., Beck, R. W., Buckingham, B. A., Mauras, N., Fiallo-Scharer, R., Xing, D., Killman, C., Tamborlane, W. V., Ruedy, K. J. 2005; 7 (1): 109-114
Abstract

We previously reported the results of an inpatient accuracy study in children with type 1 diabetes using the Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA). During the course of that study, a new process was implemented for manufacturing the CGMS sensor. Accuracy from the resulting modified sensor used by only 14 children was significantly better than the original version [median relative absolute difference (RAD), 11% vs. 19%; P < 0.001]. Baseline data from a subsequent outpatient study provide an opportunity to further assess the accuracy of the modified sensor in a much larger sample of children with type 1 diabetes.As part of a randomized trial to assess the utility of the GlucoWatch G2 Biographer (Cygnus, Inc., Redwood City, CA), 200 children with type 1 diabetes were instructed to wear a CGMS for 48-72 h in an outpatient setting at baseline. Glucose measurements from a OneTouch UltraSmart (Lifescan, Inc., Milpitas, CA) home glucose meter were downloaded and used as reference values to calculate accuracy measures.The overall median RAD was 12%. Accuracy was better during hyperglycemia than during hypoglycemia (median RAD, 10% vs. 20%; P < 0.001) and on optimal versus non-optimal days but did not vary significantly by the number of calibrations entered.These data confirm the improved accuracy previously reported for the modified version of the CGMS sensor.

View details for PubMedID 15738708
Insulin infusion set survival comparing Novolog with Humalog 41st Annual Meeting of the European-Association-for-the-Study-of-Diabetes Buckingham, B., Block, J., Clinton, P., Kunselman, E., Wilson, D. SPRINGER. 2005: A299?A299
View details for Web of Science ID 000231743202023
A two-center randomized controlled feasibility trial of insulin pump therapy in young children with diabetes 63rd Annual Meeting of the American-Diabetes-Association Wilson, D. M., Buckingham, B. A., Kunselman, E. L., Sullivan, M. M., Paguntalan, H. U., Gitelman, S. E. AMER DIABETES ASSOC. 2005: 15?19
Abstract

Our goals were to determine if continuous subcutaneous insulin infusion (CSII), compared with those continuing multiple daily injections (MDIs), can be safely used in young children, if those on CSII will have superior glycemic control, if subjects using CSII will have less hypoglycemia for their level of control, and if families using CSII will report an improved quality of life.We conducted a randomized 1-year feasibility trial comparing CSII with continuing MDIs in preschool children with a history of type 1 diabetes for at least 6 months' duration. Prospective outcomes included measures of overall glycemic control (HbA1c and continuous glucose monitoring system), the incidence of severe hypoglycemia and diabetic ketoacidosis, the percent of glucose values below 3.9 mmol/l, and the parents' report of quality of life.The 19 subjects' ages ranged from 1.7 to 6.1 (mean 3.6) years, duration of diabetes ranged from 0.6 to 2.6 (mean 1.4) years, and baseline HbA1c ranged from 6.7 to 9.6% (mean 7.9%). Seven subjects were male. Nine subjects were randomized to start CSII and 10 to continue on MDI. All baseline characteristics were well balanced. Overall metabolic control, diabetes quality of life, and the incidence of hypoglycemia were similar in the two groups. No subject had diabetic ketoacidosis, while one subject in each group had an episode of severe hypoglycemia. No CSII subject discontinued using the pump during or after the study.CSII can be a safe and effective method to deliver insulin in young children.

View details for PubMedID 15616227
GlucoWatch G2 Biographer alarm reliability during hypoglycemia in children. Diabetes technology & therapeutics Tsalikian, E., Kollman, C., Mauras, N., Weinzimer, S., Buckingham, B., Xing, D., Beck, R., Ruedy, K., Tamborlane, W., Fiallo-Scharer, R. 2004; 6 (5): 559-566
Abstract

The GlucoWatch G2 Biographer (GW2B) (Cygnus, Inc., Redwood City, CA) provides near-continuous monitoring of glucose values in near real time. This device is equipped with two types of alarms to detect hypoglycemia. The hypoglycemia alarm is triggered when the current glucose measurement falls below the level set by the user. The "down alert" alarm is triggered when extrapolation of the current glucose trend anticipates hypoglycemia to occur within the next 20 min.We used data from an inpatient accuracy study to assess the performance of these alarms. During a 24-h clinical research center stay, 89 children and adolescents with Type 1 diabetes mellitus (3.5-17.7 years old) wore 174 GW2B devices and had frequent serum glucose determinations during the day and night.Sensitivity to detect hypoglycemia (reference glucose < or = 60 mg/dL) during an insulin-induced hypoglycemia test was 24% with the hypoglycemia alarm alone and 88% when combined with the down alert alarm. Overnight sensitivity from 11 p.m. to 6 a.m. was 23% with the hypoglycemia alarm alone and 77% when combined with the down alert alarm. For 16% of hypoglycemia alarms, the reference glucose was above 70 mg/dL for 30 min before and after the time of the alarm. For the two alarm types combined, the corresponding false-positive rate increased to 62%.The down alert alarm substantially improves the sensitivity of the GW2B to detect hypoglycemia at the price of a large increase in the false alarm rate. The utility of these alarms in the day-to-day management of children with diabetes remains to be determined.

View details for PubMedID 15628809
Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously administered pamidronate PEDIATRICS Cagle, A. P., Waguespack, S. G., Buckingham, B. A., Shankar, R. R., DiMeglio, L. A. 2004; 114 (4): 1091-1095
Abstract

Infantile hypercalcemia occurs in approximately 15% of children with Williams syndrome (WS) and is typically not clinically severe. We report on 3 children with WS (confirmed with fluorescent in situ hybridization probes) who presented with severe symptomatic hypercalcemia. The first patient's severe hypercalcemia resolved with traditional therapies, whereas the subsequent 2 patients were treated with intravenously administered pamidronate after traditional measures proved only partially successful. Besides asymptomatic mild hypocalcemia, there were no complications resulting from pamidronate administration. We conclude that WS-associated hypercalcemia can be quite severe and symptomatic and that it can be successfully and safely treated with intravenously administered bisphosphonate in some cases.

View details for DOI 10.1542/peds.2003-1146-L

View details for Web of Science ID 000224242200052

View details for PubMedID 15466114
Lack of accuracy of continuous glucose sensors in healthy, nondiabetic children: Results of the Diabetes Research in Children Network (DirecNet) Accuracy study JOURNAL OF PEDIATRICS Mauras, N., Beck, R. W., Ruedy, K. J., KOLLMAN, C., Tamborlane, W. V., Chase, P., Buckingham, B. A., Tsalikian, E., Weinzimer, S. A., Booth, A. D., Xing, D. Y. 2004; 144 (6): 770-775
Abstract

The workup of hypoglycemia requires frequent glucose sampling. We designed these studies to determine if the Continuous Glucose Monitoring System (CGMS) and the GlucoWatch G2 Biographer (GW2B) are sufficiently accurate to use in nondiabetic children. Study design Fifteen healthy children (aged 9-17 years, 11 boys) wore a GW2B and a CGMS during a 24-hour period, and reference serum glucose was measured hourly during the day and half-hourly overnight.Compared with the reference glucose, the median absolute difference in concentrations measured by the GW2B (487 pairs) was 13 mg/dL, and the difference measured by the CGMS was 17 mg/dL (668 pairs), with 30% and 42% of values using the GW2B and CGMS, respectively, deviating >20 mg/dL from the reference value. The GW2B reported values <60 mg/dL in 73% of subjects, the CGMS in 60% of subjects. In none of these episodes was serum glucose truly low. Spurious high glucose concentrations also were observed with the sensors. The mean reference glucose was lowest at 5 am (89 mg/dL) and highest at 11:30 pm (106 mg/dL) during the 24-hour period.Neither the CGMS nor the GW2B is accurate enough to establish population standards of the glycemic profile of healthy children and cannot be recommended in the workup of hypoglycemia in nondiabetic youth.

View details for DOI 10.1016/j.jpeds.2004.03.042

View details for Web of Science ID 000222047900017

View details for PubMedID 15192625
Initiation of insulin glargine in children and adolescents with type I diabetes PEDIATRIC DIABETES Tan, C. Y., Wilson, D. M., Buckingham, B. 2004; 5 (2): 80-86
Abstract

Glargine (Lantus) is a recently approved, long-acting insulin analog that is increasingly being used in children with diabetes. The aim of this retrospective chart review was to summarize our experience in starting glargine in children and adolescents with diabetes. SUBJECTS AND STUDY METHODS: We reviewed the medical records of 71 children with type 1 diabetes (29 boys and 42 girls) who initiated glargine therapy to improve glycemic control between 1 June 2001 and 30 June 2002. Data were collected for 6 months before and 6 months after adding glargine.Subjects' mean age [+/-standard deviation (SD)] at diagnosis of diabetes was 7.5 +/- 4.1 yr. Mean age at initiation of glargine therapy was 11.5 +/- 4.9 yr. The total daily long-acting insulin dose decreased by about 20% after initiating glargine therapy. There were no significant differences in hemoglobin A1c (HbA1c) and blood glucose control prior to and after initiating glargine therapy (HbA1c at baseline 8.9 +/- 1.6% and HbA1c after 6 months of glargine therapy was 8.9 +/- 1.5%). Overall, blood glucose concentrations did not differ significantly throughout the study. Patients who switched to glargine because of nocturnal hypoglycemia had a 65% decrease in nocturnal blood glucose reading less than 50 mg/dL. There were three seizures in the first week after initiating glargine therapy.This retrospective study suggests that glargine is at least as effective as other long-acting insulins but that care must be taken during the conversion process to avoid hypoglycemia.

View details for Web of Science ID 000223649200004

View details for PubMedID 15189493
Accuracy of the GlucoWatch G2 Biographer and the continuous glucose monitoring system during hypoglycemia - Experience of the Diabetes Research in Children Network DIABETES CARE Tsalikian, E., Beck, R. W., Tamborlane, W. V., Chase, P., Buckingham, B. A., Weinzimer, S. A., Mauras, N., Ruedy, K. J., KOLLMAN, C., Xing, D. Y., Fiallo-Scharer, R., Fisher, J. H., Tsalikian, E., Tansey, M. J., Larson, L. F., Wysocki, T., Gagnon, K. M., Todd, P., Wilson, D. M., Block, J. M., Kunselman, E. L., Tamborlane, W. V., Doyle, E. A., Moke, P. S., Labastie, L. M., Becker, D. M., Cox, C., Ryan, C. M., White, N. H., White, P. C., Steffes, M. W., Bucksa, J. M., Nowicki, M. L., Grave, G. D., Linder, B., Winer, K. K. 2004; 27 (3): 722-726
Abstract

The goal of this study was to assess the accuracy of the GlucoWatch G2 Biographer (GW2B) and the continuous glucose monitoring system (CGMS) during hypoglycemia in children and adolescents with type 1 diabetes.During a 24-h clinical research center stay, 91 children and adolescents with type 1 diabetes (aged 3.5-17.7 years) wore one or two CGMSs, and 89 of these subjects wore one or two GW2Bs. Frequent serum glucose determinations were made during the day, overnight, and during insulin-induced hypoglycemia resulting in 192 GW2B reference pairs and 401 CGMS reference pairs during hypoglycemia (reference glucose < or =60 mg/dl).During hypoglycemia, the median absolute difference between the 192 GW2B reference glucose pairs was 26 mg/dl and between the 401 CGMS reference glucose pairs was 19 mg/dl with 31 and 42%, respectively, of the sensor values within 15 mg/dl of the reference glucose. Sensitivity to detect hypoglycemia when the GW2B alarm level was set to 60 mg/dl was 23% with a false-alarm rate of 51%. Analyses suggested that modified CGMS sensors that became available in November 2002 might be more accurate than the original CGMS sensors (median absolute difference 15 vs. 20 mg/dl).These data show that the GW2B and the CGMS do not reliably detect hypoglycemia. Both of these devices perform better at higher glucose levels, suggesting they may be more useful in reducing HbA1c levels than in detecting hypoglycemia.

View details for Web of Science ID 000189307400014

View details for PubMedID 14988292
Use of the Cygnus GlucoWatch biographer at a diabetes camp PEDIATRICS Gandrud, L. M., Paguntalan, H. U., Van Wyhe, M. M., Kunselman, B. L., Leptien, A. D., Wilson, D. M., Eastman, R. C., Buckingham, B. A. 2004; 113 (1): 108-111
Abstract

Detection and prevention of nocturnal hypoglycemia is a major medical concern at diabetes camps.We conducted an open-label trial of the Cygnus GlucoWatch biographer to detect nocturnal hypoglycemia in a diabetes camp, a nonclinical environment with multiple activities.Forty-five campers (7-17 years old) wore a biographer. The biographer was placed on the arm at 6:00 PM, with the low alarm set to 85 mg/dL (4.7 mmol/L). Overnight glucose monitoring occurred per usual camp protocol. Counselors were to check and record blood glucose values if the biographer alarmed.Biographers were worn for 154 nights by 45 campers. After a 3-hour warm-up period, 67% of biographers were calibrated, of which 28% were worn the entire night (12 hours). Thirty-four percent of readings were skipped because of: "data errors" (65%), sweat (20%), and temperature change (16%). Reported biographer values correlated with meter glucose values measured 11 to 20 minutes later (r = 0.90). Of 20 low-glucose alarms with corresponding meter values measured within 20 minutes, there were 10 true-positive alarms, 10 false-positive alarms, and no false-negative alarms. Campers reported sleep disruption 32% of the nights, and 74% found the biographer helpful. Campers reported they would wear the biographer 4 to 5 nights each week.Half of the biographer low-glucose alarms that had corresponding blood meter values were true-positive alarms, and the remaining were false-positive alarms. There was close correlation between the biographer and meter glucose values. The majority of campers found the biographer helpful and would use it at home.

View details for PubMedID 14702457
Infantile hypercalcemia associated with Williams Syndrome treated successfully with bisphosphonate. 25th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research Cagle, A. P., Waguespack, S. G., Buckingham, B. A., Shankar, R., DiMeglio, L. A. WILEY-BLACKWELL. 2003: S412?S412
View details for Web of Science ID 000186080501674
A two center randomized controlled trial of insulin pump therapy in young children with diabetes Wilson, D., Buckingham, B., Kunselman, E., Sullivan, M., Paguntalan, H., Gitelman, S. AMER DIABETES ASSOC. 2003: A402
View details for Web of Science ID 000183173801733
Diabetes research in children network (DirecNet) accuracy study of the continuous glucose monitoring system (CGMS) and Gluco Watch (R) G2 (TM) biographer (GWB) in children with type 1 diabetes - A CRC-based study Buckingham, B., Beck, R., Tamborlane, W., Ruedy, K., Boland, E., Chase, P., Wysocki, T., Tsalikian, E., Wilson, D., Mauras, N., Weinzimer, S., Tansey, M., Fiallo-Scharer, R., Booth, A., Kollman, C., DirecNet Study Grp AMER DIABETES ASSOC. 2003: A36
View details for Web of Science ID 000183173800156
A 5-center CRC-Based study of the accuracy of the GlucoWatch((R)) G2((TM)) biographer in children and adolescents with type 1 diabetes Wilson, D., Buckingham, B., Beck, R., Ruedy, K., Kollman, C., Tsalikian, E., Wysocki, T., Weinzimer, S., Chase, P., Diabet Res Children Network AMER DIABETES ASSOC. 2003: A101
View details for Web of Science ID 000183173800430
How should we interpret "real life" conditions. Pediatric diabetes Eastman, R. C., Chase, H. P., Buckingham, B., Hathout, E., Tamada, J., Ginsberg, B. 2003; 4 (1): 59-?
View details for PubMedID 14655525
Analysis: dawn of real-time continuous glucose sensing. Diabetes technology & therapeutics Buckingham, B. 2003; 5 (3): 381-383
View details for PubMedID 12828821
Use of the GlucoWatch biographer in children and adolescents with diabetes. Pediatric diabetes Eastman, R. C., Chase, H. P., Buckingham, B., Hathout, E. H., Fuller-Byk, L., Leptien, A., Van Wyhe, M. M., Davis, T. L., Fermi, S. J., Pechler, H., Sahyun, G., Lopatin, M., Wang, B. Y., Wei, C., Bartkowiak, M., Ginsberg, B. H., Tamada, J. A., Pitzer, K. R. 2002; 3 (3): 127-134
Abstract

This study was done to evaluate the accuracy and safety of measuring glucose with the GlucoWatch biographer in children and adolescents with diabetes.Accuracy was assessed by comparing biographer glucose measurements with hourly blood glucose measurements using the HemoCue (Aktiebolaget Leo, Helsingborg, Sweden) Photometer for up to 12 h of monitoring. Safety was evaluated by examining the biographer application sites immediately upon removal of the devices, and then at regular intervals.Sixty-six subjects each wore three biographers at sites including the forearm, upper arm, leg, and torso. For forearm biographers, the mean absolute relative difference between biographer readings and blood glucose was 21%. Ninety-five per cent of biographer readings fell into the A or B regions of the Clarke error grid, and 97.3% into the A or B regions of the consensus error grid. Data from biographers worn at the alternative sites were similar to data from the forearm biographers. Two strong reactions to the adhesive pad of the biographer AutoSensor were observed. Most skin reactions were mild.The GlucoWatch biographer is well tolerated by children and adolescents with diabetes. Performance is similar when the device is worn at different anatomical sites, and is similar to the performance on the forearm, previously reported in adults.

View details for PubMedID 15016152
Cognitive and behavioral characteristics of turner syndrome: exploring a role for ovarian hormones in female sexual differentiation. Hormones and behavior Collaer, M. L., Geffner, M. E., Kaufman, F. R., Buckingham, B., Hines, M. 2002; 41 (2): 139-155
Abstract

To better understand factors contributing to behavioral development, we studied patients with Turner syndrome (TS), a disorder typically marked by prenatal onset of ovarian dysfunction. We compared girls and women (ages 12 and up) with TS (n = 21) to matched controls (n = 21) in cognitive and motor skills, as well as sex-typed personality characteristics and activity preferences. Measures were categorized (based on prior studies) as showing an average male advantage (male-superior measures), female advantage (female-superior measures), or no sex difference (sex-neutral measures). It was hypothesized that, if gonadal function contributes to behavioral development, effects of this deficiency would be more prominent on sexually differentiated than sex-neutral measures and thus that patient-control differences would be most marked for measures that show sex differences. Our findings indicated that TS patients and controls differed more on cognitive and motor domains that show sex differences than on sex-neutral domains. Patients also had more "undifferentiated" personalities and showed reduced sex-typed interests and activities. Differing experiences, as indexed by interests and activities, did not explain the observed cognitive and motor differences. These results are consistent with a role for ovarian hormones acting on the brain to influence cognitive and behavioral development, although they do not rule out other possible interpretations.

View details for PubMedID 11855899
Cognitive and behavioral characteristics of Turner syndrome: Exploring hormones in female sexual a role for ovarian differentiation HORMONES AND BEHAVIOR Collaer, M. L., Geffner, M. E., Kaufman, F. R., Buckingham, B., Hines, M. 2002; 41 (2): 139-155
View details for DOI 10.1006/hbeh.2001.1751

View details for Web of Science ID 000174171400003
Type 1 diabetes mellitus and epilepsia partialis continua in a 6-year-old boy with elevated anti-GAD65 antibodies PEDIATRICS Olson, J. A., Olson, D. M., Sandborg, C., Alexander, S., Buckingham, B. 2002; 109 (3)
Abstract

A 6-year-old boy presented with epilepsia partialis continua 6 months after diagnosis of type 1 diabetes. Anti-glutamic acid decarboxylase 65 antibodies were found in his serum and cerebrospinal fluid. Anti-epileptic agents did not improve his seizures. High-dose steroids, plasmapheresis, and intravenous immunoglobulin resulted in decreased anti-glutamic acid decarboxylase 65 antibody levels and resolution of his seizures.

View details for Web of Science ID 000174202800012

View details for PubMedID 11875178
Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB JOURNAL OF CLINICAL INVESTIGATION Ding, C. L., Buckingham, B., Levine, M. A. 2001; 108 (8): 1215-1220
Abstract

Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and absent or markedly reduced circulating concentrations of parathyroid hormone. The transcription factor GCMB is predominantly, if not exclusively, expressed in parathyroid cells and is critical for development of the parathyroid glands in mice. Thus, in the present study we examined the GCMB gene, mapped to 6p23-24, as a candidate for isolated hypoparathyroidism. We defined the boundaries of the five exons of the human GCMB gene and then identified a large intragenic mutation in the GCMB genes of the proband of an extensive kindred with isolated hypoparathyroidism. Her parents and several other unaffected relatives were heterozygous for the mutation. Despite an absence of any history of consanguinity, microsatellite analysis showed shared genotypes that flanked the GCMB gene over a span of 5 cM, suggesting that both of the proband's GCMB alleles had been derived from a single common ancestor. Analysis of additional, unrelated cases did not disclose the same mutation. We conclude that homozygous loss of function of the GCMB gene impairs normal parathyroid gland embryology and is responsible for isolated hypoparathyroidism in a subset of patients with this disease.

View details for Web of Science ID 000171614500016

View details for PubMedID 11602629

View details for PubMedCentralID PMC209530
Intensive diabetes management in pediatric patients. Current diabetes reports Buckingham, B., Bluck, B., Wilson, D. M. 2001; 1 (1): 11-18
Abstract

Intensive diabetes management requires frequent home glucose monitoring, multiple daily insulin injections or chronic subcutaneous insulin infusion, and adjustments of insulin doses in response to changes in blood glucose levels, food intake, and exercise. It also requires a periodic review of previous glucose results to recognize patterns of hyper- or hypoglycemia. The goals of intensive management are age dependent. In young children, avoidance of severe hypoglycemia is the major goal. In older children and adolescents, lowering hemoglobin A(1c) becomes an increasingly important goal. In children of all ages, the ability to have a flexible lifestyle and meal plan is often a priority. This article provides a brief overview of the rationale for implementing intensive diabetes management in pediatric patients, and practical guidelines for implementation.

View details for PubMedID 12762952
Continuous subcutaneous insulin infusion (CSD) in children under five years of age Buckingham, B. A., Paguntalan, H., Fassl, B., Wilson, D. M. AMER DIABETES ASSOC. 2001: A107
View details for Web of Science ID 000168964300432
Data entry errors in using the minimed continuous glucose sensor (CGS) Buckingham, B. A., Paguntalan, H., Wilson, D. M. AMER DIABETES ASSOC. 2001: A431
View details for Web of Science ID 000168964301786
Prevention of type 1a diabetes mellitus*. Pediatric diabetes Wilson, D. M., Buckingham, B. 2001; 2 (1): 17-24
Abstract

Type 1 diabetes begins with the progressive autoimmune mediated destruction of the insulin-producing beta cells. When sufficient beta cell function is lost, the endocrine phase, characterized by insulin deficiency and hyperglycemia, supervenes. While a genetic predisposition to diabetes is an important precondition, most believe an environmental factor or factors serve as the trigger for initiating this process. In this paper we review trials designed to prevent or delay the clinical onset of diabetes. In these studies, high-risk individuals are identified by their genetic predisposition to diabetes, and/or by the presence of immune markers indicating activation of the autoimmune process directed against islet cells. The Deutsche Nicotinamide Intervention Study (DENIS) randomized 55 high-risk subjects to either nicotinamide or placebo and found no significant benefit. The European Nicotinamide Diabetes Intervention Trial (ENDIT) completed enrollment in May 1998. ENDIT screened over 40 000 relatives, randomizing 552 to either nicotinamide or placebo. Results are expected in May of 2003. Designed to test if avoidance of cow's milk in infancy will decrease the incidence of diabetes, the Trial to Reduce Type I Diabetes in the Genetically at Risk (TRIGR). High-risk infants are randomly assigned to different supplemental formulas in the first 6 months of life. Initial results suggest that removing cow's milk has a protective effect. The ongoing, NIH funded, multicenter Diabetes Prevention Trial-Type 1 (DPT-1) is testing two antigen-based (insulin) interventions in relatives at high risk for diabetes. Now in its sixth year, the DPT-1 study group has screened over 84,000 individuals. As of November 2000, 339 subjects have been randomized in the parenteral insulin study, completing the enrollment phase. Enrollment continues in the oral insulin study. Results of this trial are not yet available. Different epitopes of insulin and its analogs, monoclonal antibodies, and cytokine-based therapy, among others, have all been proposed as potential new interventional agents. While a great deal of effort will be required to test these approaches, the potential benefits of prevention justify these research efforts.

View details for PubMedID 15016206
A randomized trial of methotrexate in newly diagnosed patients with type 1 diabetes mellitus CLINICAL IMMUNOLOGY Buckingham, B. A., Sandborg, C. I. 2000; 96 (2): 86-90
Abstract

The aim of this study was to determine whether low-dose, oral methotrexate therapy would prolong the remission phase at the onset of Type 1 diabetes. Ten newly diagnosed, nonacidotic, ICA-positive, Type 1 diabetics were randomly assigned to receive either methotrexate (5 mg/m(2)/week) or no immunosuppressive treatment. The study was not blinded and no placebo was given. Endogenous insulin production was assessed every 3 months by fasting and Sustacal-stimulated C-peptide levels. Methotrexate therapy was not beneficial in prolonging islet survival as assessed by fasting and stimulated C-peptide levels. Insulin requirements were generally lower in the control group, and islet failure, determined by an insulin requirement of >0.7 u/kg/day, occurred earlier for those receiving MTX (P < 0.02). Side effects of methotrexate treatment were minimal. There was no benefit from methotrexate therapy, and methotrexate therapy was associated with an earlier increase in insulin requirements.

View details for DOI 10.1006/clim.2000.4882

View details for Web of Science ID 000088615500003

View details for PubMedID 10900154
Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus JOURNAL OF IMMUNOLOGY Berman, M. A., Sandborg, C. I., Wang, Z. S., Imfeld, K. L., Zaldivar, F., Dadufalza, V., Buckingham, B. A. 1996; 157 (10): 4690-4696
Abstract

IL-4 has been shown to protect against diabetes development in rodent models of insulin-dependent (type I) diabetes mellitus (IDDM). To study IL-4 production in human IDDM, PBMC from IDDM patients and controls were stimulated in vitro with PHA, anti-CD3 mAb, or PMA and ionophore. IL-4 production by PBMC or T cells was strongly impaired in IDDM patients at diabetes onset (p < 0.0001). The mean IL-4 response of patients in the honeymoon stage was higher than the mean of the new onset patients, but significantly lower than the control group (p = 0.01). Patients with IDDM of longer duration (>2 yr) showed a wide range of IL-4 responses and their mean IL-4 response was lower than the controls; however, the difference was not statistically significant. IL-4 mRNA levels were measured using competitive reverse transcription PCR. The results showed greatly reduced mRNA levels in new onset IDDM. In contrast, IL-1 production (measured by ELISA) and IFN-gamma mRNA (measured by reverse transcription PCR) were not significantly different in IDDM. The results suggest an imbalance of inflammatory vs anti-inflammatory cytokine production at the onset of IDDM. Deficient IL-4 production as seen at the onset of IDDM may play a role in the development of diabetes by allowing the inflammatory/autoimmune process in pancreatic islets to progress.

View details for Web of Science ID A1996VR79300053

View details for PubMedID 8906850
Self-care behaviors in insulin-dependent diabetes: Evaluative tools and their associations with glycemic control JOURNAL OF PEDIATRIC PSYCHOLOGY Hanson, C. L., DEGUIRE, M. J., SCHINKEL, A. M., Kolterman, O. G., Goodman, J. P., Buckingham, B. A. 1996; 21 (4): 467-482
Abstract

Clarified the relationships between self-care behaviors and illness-specific outcomes in approximately 270 youths with IDDM. Youths were assessed at three points in time using a semistructured interview measure and multiple indices of dietary intake and physical activity with two different methodologies (i.e., recalls, logs). Glycemic control was most strongly related to the semistructured Self-Care Adherence Interview (SCAI); and second to the overall quality of the youth's dietary intake. The SCAI also predicted glycemic control over time. Physical activity levels and specific nutritional components from the logs and recalls were generally unrelated to glycemic control.

View details for Web of Science ID A1996UZ76000001

View details for PubMedID 8863457
T-]A TRANSVERSION 11 BP FROM A SPLICE ACCEPTOR SITE IN THE HUMAN GENE FOR STEROIDOGENIC ACUTE REGULATORY PROTEIN CAUSES CONGENITAL LIPOID ADRENAL-HYPERPLASIA HUMAN MOLECULAR GENETICS Tee, M. K., LIN, D., Sugawara, T., HOLT, J. A., Guiguen, Y., Buckingham, B., Strauss, J. F., Miller, W. L. 1995; 4 (12): 2299-2305
Abstract

Congenial lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH. Affected individuals can make no adrenal or gonadal steroids. All affected individuals are phenotypic females irrespective of gonadal sex, and frequently die in infancy if mineralocorticoid and glucocorticoid replacements are not instituted. Recent data implicate the steroidogenic acute regulatory (StAR) protein in this disorder. We now describe a 46,XY patient of Vietnamese ancestry with lipoid CAH who had a somewhat milder form of the disease. Diagnosis was at 10 weeks of age, and low levels of plasma progesterone, corticosterone, 180H-corticosterone and androstenedione were detectable. Testicular RNA for StAR was reverse transcribed, amplified, cloned and sequenced, revealing a 185 bp deletion corresponding to all of exon 5. The corresponding mRNA did not encode active protein in transfected cells. Cloned genomic DNA from the patient revealed only a T-->A transversion in intron 4,11 bp from the splice acceptor site of exon 5. This transversion destroys an NcoI site; digestion of PCR-amplified genomic DNA from the patient and both parents confirmed that the patient was homozygous and the parents were heterozygous. Expression vectors for StAR minigenes were constructed containing all StAR exons plus introns 4, 5 and 6 either with or without the T-->A mutation in intron 4. RNase protection assays showed that expression of the vector with normal intron 4 yielded correctly spliced StAR mRNA in transfected COS-1 cells, while most, but not all StAR mRNA from the vector with the T-->A transversion in intron 4 was abnormally spliced. RNase protection of the patient's testicular RNA confirmed that most, but not all StAR mRNA was similarly spliced abnormally. Splicing errors appear to be a rare cause of genetic diseases, but subtle intronic mutations may be missed when genomic DNA is the only material available for study. The low level of normal StAR mRNA produced may account for the later clinical presentation and low levels of steroid hormones detected in this patient.

View details for Web of Science ID A1995TK36300016

View details for PubMedID 8634702
IL-4 EXPRESSION IN HUMAN T-CELLS IS SELECTIVELY INHIBITED BY IL-1-ALPHA AND IL-1-BETA JOURNAL OF IMMUNOLOGY Sandborg, C. I., Imfeld, K. L., Zaldivar, F., Wang, Z. S., Buckingham, B. A., Berman, M. A. 1995; 155 (11): 5206-5212
Abstract

Imbalances in anti-inflammatory and proinflammatory cytokines may be responsible for initiation or progression of diverse pathologic states including autoimmune and infectious diseases. IL-4 production of proinflammatory cytokines and IL-12 promotes differentiation and activation of IFN-gamma-producing T cells, but does a counter-regulatory effect of proinflammatory cytokines on IL-4 production exist? This study evaluates the effect of proinflammatory cytokines (IL-1 alpha, IL-1 beta, IL-6, IL-12, and TNF-alpha) on IL-4 production in primary human T cell cultures. PBMCs from healthy individuals were tested for IL-4 production in response to PHA and various cytokines. IL-4 was measured by proliferation of the IL-4-sensitive T cell line (CT.h4S) or ELISA. IL-1 alpha and IL-1 beta inhibited IL-4 production by 20 to 80% in > 92% of healthy individuals (p = 0.0001, paired t-test). IL-12 had an inhibitory effect on PBMC IL-4 production as previously described, but neither IL-6 nor TNF-alpha inhibited IL-4 production. IL-1 had no effect on PHA-induced PBMC or purified T cell proliferation or IL-2 production. IL-4 production by purified T cells stimulated by PHA or the combination of PMA with calcium ionophore (A23187) was inhibited by IL-1, and reconstitution with peripheral blood-derived adherent macrophages had no effect. IL-12 did not inhibit IL-4 production in stimulated purified T cells. Steady state IL-4 mRNA levels were determined by semiquantitative competitive reverse transcribed PCR (RT-PCR). Marked inhibition of IL-4 mRNA levels were seen at 5 h after exposure to IL-1. This interaction between IL-1 and IL-4 may be an important physiologic regulator of the balance between proinflammatory cytokines from activated macrophages and anti-inflammatory cytokines from T cells.

View details for Web of Science ID A1995TF68600016

View details for PubMedID 7594531
BIOCHEMICAL-ABNORMALITIES IN VITREOUS OF HUMANS WITH PROLIFERATIVE DIABETIC-RETINOPATHY ARCHIVES OF OPHTHALMOLOGY SEBAG, J., Buckingham, B., Charles, M. A. 1992; 110 (10): 1472-1476
Abstract

Vitreous changes in diabetes can exacerbate proliferative diabetic retinopathy. These changes may be due to the effects of diabetes on vitreous collagen. Vitreous samples from 19 patients with proliferative diabetic retinopathy and 23 patients without diabetes were analyzed for collagen crosslinks, as well as for the early glycation products, glucitolyllysine and glucitolylhydroxylysine. Fluorometry was performed to measure advanced glycation end products. Vitreous collagen derived from diabetic patients was found to have significantly higher levels of the crosslink dihydroxylysinonorleucine (3.15 vs 1.24 mol/mol collagen, P<.01) than that of control subjects. Early glycation products were elevated in diabetic vitreous (1.65 vs 0.54 mol/mol collagen, P<.05). Levels of advanced glycation end products were 20 times higher in diabetic vitreous compared with the vitreous of controls. These diabetes-induced alterations of human vitreous may be of particular importance given the role of vitreous in proliferative diabetic retinopathy and vision loss.

View details for Web of Science ID A1992JT34900029

View details for PubMedID 1417549
A NATURALLY-OCCURRING 6-9-KILODALTON INTERLEUKIN-1 (IL-1) INHIBITOR PREVENTS IL-1-MEDIATED ISLET CYTOTOXICITY BUT NOT IL-1-MEDIATED SUPPRESSION OF INSULIN-SECRETION JOURNAL OF IMMUNOTHERAPY KAWAHARA, D. J., Everts, M., Buckingham, B., Sandborg, C., Berman, M. 1991; 10 (3): 182-188
Abstract

Earlier studies have shown direct effects of interleukin-1 (IL-1) on isolated pancreatic islets. Coculture of isolated rat pancreatic islets with human rIL-1 beta for 6 days resulted in dose-dependent cytotoxicity (up to 100%) and suppression of insulin secretion (up to 88.5%). The cytotoxic effects of rIL-1 beta beta were blocked by the simultaneous presence of a naturally occurring 6-9-kilodalton (kDa) inhibitor of IL-1-induced T-cell proliferation. However, the ability of rIL-1 beta to suppress insulin secretion was not blocked by the 6-9-kDa inhibitor of IL-1 activity. This IL-1 inhibitor is produced by mononuclear cells and is resistant to pH 2, sensitive to heating at 56 degrees C for 30 min, has a pI of 4.5-5.6, and appears to be different from other recognized IL-1 inhibitors in both composition and mechanism of action. Unlike this IL-1 inhibitor, a monoclonal antibody specific for rIL-1 beta was able to neutralize both the islet cytotoxic and insulin modulatory effects of rIL-1 beta. These results demonstrate the use of an IL-1 inhibitor to prevent at least one mechanism of islet destruction, and suggest separate pathways for IL-1 mediated islet cytotoxicity and suppression of insulin secretion.

View details for Web of Science ID A1991FM89500004

View details for PubMedID 1868042
HETEROGENEITY IN THE SPECIFICITY OF THE ISLET CELL CYTOPLASMIC ANTIBODY-RESPONSE IN INSULIN-DEPENDENT DIABETES-MELLITUS PANCREAS KAWAHARA, D. J., Buckingham, B., Kershnar, A. 1990; 5 (6): 647-651
Abstract

We assessed the heterogeneity in the islet cell cytoplasmic antibody (ICA) response of insulin-dependent diabetes mellitus (IDDM) patients via indirect immunofluorescence on frozen sections of human, bovine, and porcine pancreas. The three substrates detected comparable frequencies of ICA positives among the IDDM sera tested, whereas control sera were ICA negative on all three substrates. However, individual IDDM serum samples showed heterogeneity in ICA binding on the three pancreata. Of 28 sera tested on all three substrates, 22 were ICA positive on human pancreas, three were ICA positive on bovine pancreas, and two were ICA positive on porcine pancreas. Sensitivity of ICA epitopes to neuraminidase treatment and periodate oxidation suggests that glycoconjugates are recognized by serum ICA. Cholera toxin blocked ICA binding. However, the functional cholera toxin receptor ganglioside Gm1 is resistant to neuraminidase treatment and periodate oxidation. Therefore, it is unlikely that Gm1 is the ICA determinant. These data suggest that not all ICA antigens are equivalently expressed on islets from different pancreata and/or that each individual responds to a hierarchy of islet antigens such that restricted patterns of specific ICA binding are found.

View details for Web of Science ID A1990EE50500003

View details for PubMedID 1704123
RELATIONSHIP BETWEEN THE CONTENT OF LYSYL OXIDASE DEPENDENT CROSS-LINKS IN SKIN COLLAGEN, NONENZYMATIC GLYCOSYLATION, AND LONG-TERM COMPLICATIONS IN TYPE-I DIABETES-MELLITUS JOURNAL OF CLINICAL INVESTIGATION Buckingham, B., Reiser, K. M. 1990; 86 (4): 1046-1054
Abstract

Many abnormalities in collagen have been reported in insulin-dependent diabetes mellitus, some or all of which have been attributed to increased cross-linking. Although recent work has focused on the role of glucose-derived collagen cross-links in the pathogenesis of diabetic complications, relatively few studies have investigated the role of lysyl oxidase-dependent (LOX) cross-links. In the present study, LOX cross-links and nonenzymatic glycosylation were quantified in skin collagen from diabetic subjects. There was an increase in the difunctional cross-link dihydroxylysinonorleucine (DHLNL) as well as in one of its trifunctional maturation products, hydroxypyridinium. All other LOX crosslinks were normal. Nonenzymatic glycosylation was increased in diabetic skin collagen, and this increase was correlated with increases in DHLNL (P less than 0.001). The biochemical results were examined for correlations with clinical data from the same subjects. Increases in DHLNL content were associated with duration of diabetes (P less than 0.003), glycohemoglobin levels (P less than 0.001), hand contractures (P less than 0.05), skin changes (P less than 0.005), and microalbuminuria (P less than 0.01). In nondiabetic subjects age was not correlated with collagen cross-link content with the exception that his-HLNL increased with age (r = 0.79, P less than 0.02). In diabetic subjects, PA levels decreased with age (r = 0.51, P less than 0.02). With increased duration of diabetes, DHLNL content was increased (r = 0.55, P less than 0.003) and OHP was increased (r = 0.59, P less than 0.01), whereas PA levels were decreased (r = -0.48, P less than 0.04). Nonenzymatic glycosylation of collagen was also increased with increased duration of diabetes (hex-lys, r = 0.47, P less than 0.02; hex-hyl, r = 0.39, P less than 0.05). We conclude that: (a) lysyl oxidase-dependent cross-linking is increased in skin collagen in diabetes and (b) that these changes in skin collagen are correlated with duration of diabetes, glycemic control, and long-term complications.

View details for Web of Science ID A1990EE19900005

View details for PubMedID 1976653
THE SURGICAL-MANAGEMENT OF HYPERINSULINISM IN INFANCY DUE TO NESIDIOBLASTOSIS JOURNAL OF PEDIATRIC SURGERY Warden, M. J., GERMAN, J. C., Buckingham, B. A. 1988; 23 (5): 462-465
Abstract

Severe neonatal hypoglycemia due to nesidioblastosis demands prompt diagnosis and treatment to prevent mental retardation. Early central venous catheter placement is essential for a constant glucose infusion. At surgery, near-total (95%) pancreatectomy is done, starting at the tail and preserving the spleen. Bipolar electrocoagulation is very useful for the tiny vessels. The uncinate process is removed leaving a small amount of pancreas adjacent to the preserved common bile duct. Three patients, diagnosed shortly after birth, had surgery at 34 days, 2 years, and 17 days of life. Two patients developed staphylococcal infections, one of whom exhibited the "scalded baby" syndrome and required reoperation for evisceration. Insulin was required for one to seven days in two and for three months in one. Diazoxide was needed for 18 months in the initial patient, who did not have uncinate resection. All patients are healthy and off medication with a postoperative follow-up period of 11, 12, and 65 months.

View details for Web of Science ID A1988N446800018

View details for PubMedID 2837563
INTERFERON RESPONSIVENESS OF NATURAL-KILLER CELLS IN TYPE-I HUMAN DIABETES DIABETES RESEARCH CLINICAL AND EXPERIMENTAL Negishi, K., Gupta, S., Chandy, K. G., Waldeck, N., Kershnar, A., Buckingham, B., Charles, M. A. 1988; 7 (1): 49-52
Abstract

Abnormally low circulating numbers and function of NK cells are associated with new onset type I diabetes. Since alpha interferon is a stimulator of NK function, enriched T and non-T lymphocytes were incubated with 0, 100 and 1,000 units/ml of recombinant alpha interferon (rIFN alpha) and natural killing against K562 and pancreatic islet cell targets was measured. The killing of K562 (1:20 target:effector ratio) cells by non-T cells incubated with 0, 100 and 1,000 units/ml of rIFN alpha in patients was decreased to 27% (p less than 0.014 vs control), 34% (p less than 0.001) and 39% (p less than 0.003) when compared to killing by normal control non-T cells (48%, 74% and 58% respectively). T cell mediated killing of K562 cells in patients was decreased to 3.9% (p less than 0.03), 5.3% and 6.6% (p less than 0.003) when compared to that of controls (8.7%, 10-8% and 22.6% respectively). Non-T cell mediated killing of islet cells (1:20 target:effector ratio) following treatment of effector cells with 0, 100 and 1,000 units/ml of rIFN alpha in patients was 19%, 27%, and 26% which was comparable to control subjects killing of 31%, 18% and 37% respectively. Similar data were obtained using T-cells as effectors. These data indicate that in new onset type I diabetes; (a) NK cell functional activity is diminished in both T and non-T lymphocyte subpopulations and (b) NK activity is suboptimally enhanced with rIFN alpha.

View details for Web of Science ID A1988N469200008

View details for PubMedID 3402165
NATURAL-KILLER-CELL AND ISLET KILLER-CELL ACTIVITIES IN HUMAN TYPE-1 DIABETES EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY Negishi, K., Waldeck, N., Chandy, G., Buckingham, B., Kershnar, A., Fisher, L., Gupta, S., Charles, A. M. 1987; 89 (3): 345-353
Abstract

Peripheral blood mononuclear cells from 14 type 1 diabetic patients were examined for natural killer cell activity using the K562 cell line as 51Cr labeled targets. Mean cytotoxicity of K562 cells by unseparated mononuclear cells derived from new onset type 1 patients (12 +/- 1.6%) was lower (P less than .01) than that observed in non diabetic controls, (25 +/- 4.2%). Mean natural killer cell cytotoxicity mediated by enriched non-T cells from patients (41 +/- 5.8%) was also lower (P less than 0.03) than in the control group (56 +/- 3.7%). Specificity of these findings was evaluated by also examining other diabetic patient subgroups. Mean non T cell mediated natural killer cell activity in type 2 diabetic patients and type 1 patients with long term disease was 65 +/- 5.4% and 62 +/- 4.8% respectively (p less than 0.001 vs new onset type 1 patients). Longitudinal studies of new onset type 1 patients during the remission (honeymoon) phase revealed no improvement of impaired natural killer cell activity. In 30 new onset and 11 remission diabetic patients, mean non-T cell-mediated cytotoxicity was also measured using dispersed 51Cr labeled pancreatic islet target cells. Mean islet cytotoxicity mediated by cells from new onset patients was 34 +/- 2.4%, whereas in nondiabetic control subjects mean cytotoxicity was 25 +/- 1.8% (p less than 0.005). During remission, islet cytotoxicity returned to normal values in over half of the patients. There was no correlation between K562 and islet cell cytotoxicity in either of the latter two patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1987K252900017

View details for PubMedID 3311777
JOINT AND PULMONARY CHANGES IN DIABETES - REPLY AMERICAN JOURNAL OF DISEASES OF CHILDREN Buckingham, B., Kershnar, A., Anas, N., Sandborg, C., UITTO, J. 1987; 141 (3): 245-245
View details for Web of Science ID A1987G226900014
NATURAL-KILLER-CELL AND ISLET KILLER-CELL ACTIVITIES IN TYPE-1 (INSULIN-DEPENDENT) DIABETES DIABETOLOGIA Negishi, K., Waldeck, N., Chandy, G., Buckingham, B., Kershnar, A., Fisher, L., Gupta, S., Charles, M. A. 1986; 29 (6): 352-357
Abstract

Peripheral blood mononuclear cells from 20 Type 1 (insulin-dependent) diabetic patients were examined for natural killer cell activity using the K562 cell line as 51Cr labeled targets. Mean natural killer cell cytotoxicity mediated by enriched non-T cells from patients (37 +/- 4.0%) was lower (p less than 0.03) than in controls (56 +/- 3.7%). Specificity was evaluated by examining other patient subgroups. Mean non-T cell mediated natural killer cell activity in Type 2 (non-insulin-dependent) diabetic patients and Type 1 patients with long term disease was 65 +/- 5.4% and 62 +/- 4.8% respectively (p less than 0.003 vs new onset Type 1 patients). Longitudinal studies of new onset Type 1 patients during the remission (honeymoon) phase revealed persistently impaired natural killer cell activity in 3 of 4 patients. In 30 new onset and 11 remission Type 1 diabetic patients, mean non-T cell-mediated cytotoxicity was also measured using dispersed 51Cr labeled islet target cells. Mean islet cytotoxicity mediated by cells from new onset patients was 34 +/- 2.4%, whereas in non-diabetic control subjects mean cytotoxicity was 25 +/- 1.8% (p less than 0.005). During remission, islet cytotoxicity remained at similar or elevated levels in most patients. In patients evaluated simultaneously for K562 and islet cell cytotoxicity, natural killer cell activity was decreased, whereas islet killing was increased. These results suggest a dichotomy in natural killer cell and islet killer cell activities in new onset Type 1 diabetes that could have an important role in the pathogenesis of Type diabetes.

View details for Web of Science ID A1986D148400002

View details for PubMedID 3527835
MULTIPARAMETER IMMUNOLOGICAL STUDIES IN PATIENTS WITH NEWLY DIAGNOSED TYPE-1 INSULIN-DEPENDENT DIABETES-MELLITUS DIABETES RESEARCH CLINICAL AND EXPERIMENTAL Gupta, S., Charles, M. A., Waldeck, N., Kershnar, A., Buckingham, B. 1986; 3 (5): 225-229
Abstract

Peripheral blood mononuclear cells from patients with Type 1 diabetes mellitus were examined for the proportion of monoclonal antibody-defined T-cell subsets, natural killer (NK) cells, and macrophages and the proliferative response to phytohemagglutinin (PHA), Concanavalin A (Con A), pokeweed mitogen (PWM) and in the autologous mixed lymphocyte reaction (AMLR) and allogeneic mixed lymphocyte reaction (MLR). The in vitro response of purified IL-2 on PHA- and PWM-induced proliferative response was also examined. Total T cells (Leu 1+), helper/inducer phenotype (Leu 3+) T cells, suppressor/cytotoxic phenotype (Leu 2+) T cells, surface Ig+ B lymphocytes and monoclonal antibody-defined monocytes (Mac +) in patient group were comparable to the control group. The Leu 7+ NK cells were, however significantly (p less than 0.05) decreased in the diabetic group. The NK function was also deficient in the diabetic group when compared to healthy non-diabetic controls. The proliferative responses to all 3 concentrations of PHA, PWM, and Con A, and in the MLR were similar in 2 groups. However, the proliferative response in the AMLR was significantly reduced (p less than 0.05) in the diabetic group. Exogenous purified IL-2 failed to induce any enhancement in the PHA- and PWM-induced proliferative response; this was in contrast to control group in which IL-2 enhanced proliferative response to both mitogens. This study demonstrates deficiency of the AMLR, Leu 7+ and of natural killer cell function and unresponsiveness of mitogen-activated T cells to purified IL-2. The significance of these findings is discussed.

View details for Web of Science ID A1986D364800001

View details for PubMedID 2943547
SKIN, JOINT, AND PULMONARY CHANGES IN TYPE-I DIABETES-MELLITUS AMERICAN JOURNAL OF DISEASES OF CHILDREN Buckingham, B., PEREJDA, A. J., Sandborg, C., KERSHNAR, A. K., UITTO, J. 1986; 140 (5): 420-423
Abstract

Three hundred seventy-five patients with diabetes mellitus were examined for the presence of sclerodermalike skin changes, limited joint mobility, and vital capacity changes. Nineteen percent of patients had vital capacities 2 SDs below the mean of predicted values. There was no significant relationship between decreased vital capacities and duration of diabetes, sclerodermalike skin changes, limited joint mobility, smoking history, proteinuria, or retinopathy. Cutaneous involvement consisting of thickening, tightening, and/or a waxy quality of the skin was noted in 190 patients (51%). The severity of skin involvement correlated positively with the patients' duration of diabetes, age, severity of joint contractures, and diabetic retinopathy. Thus, sclerodermalike skin changes appear to reflect generalized connective tissue alterations in diabetes and may indicate increased risk for diabetic microvascular complications.

View details for Web of Science ID A1986C085200017

View details for PubMedID 3962933
COMPLEMENT ACTIVATION IN TYPE-1 HUMAN DIABETES CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY Sundsmo, J. S., PAPIN, R. A., Wood, L., Hirani, S., Waldeck, N., Buckingham, B., Kershnar, A., Ascher, M., Charles, M. A. 1985; 35 (2): 211-225
Abstract

Complement activation was quantitated in serum and plasma of diabetic and normal subjects by sensitive competitive equilibrium radioimmunoassays (RIA) for C3a, C4a, C5a, Factor B, and a newly described C5 neoantigen (termed C5 activation antigen, and abbreviated C5-AA) in a stable 54-kDa fragment of C5. Plasma C3a levels were significantly elevated in 8 of 16 patients with newly diagnosed Type 1 diabetes (P less than 0.0005) with the mean C3a concentration for these patients being more than 10-times greater than the mean value of normal controls. C4a levels were also elevated in 2 of these patients (P less than 0.02), but C5a levels, although higher than normal, were not significantly increased. In contrast, the levels of C5-AA in the serum of all patients (11/11) with chronic Type 1 diabetes were significantly higher than in control Type 2 patients (noninsulin-dependent diabetes) (P less than 0.0005) and 4 of 7 patients with new onset insulin-dependent diabetes mellitus also had significantly higher levels of C5-AA than the Type 2 patients (P less than 0.01). The levels of Factor B in the serum of 5 of 9 patients with new onset diabetes were significantly higher than normal (P less than 0.0025). Five recent onset Type 1 diabetes patients were evaluated longitudinally for C3a, C4a, and C5a: in 3 the levels of C3a were elevated during new onset disease decreasing into the normal range during remission; in 2 of these patients C4a was also significantly elevated and the levels decreased during remission; and in 3 patients the levels of C5a were not significantly elevated but they decreased during remission. Purified human complement proteins and complement hemolytic assays were used to measure complement activation in serum during incubation with rat pancreatic islet cells. With diluted normal human serum, less than 20% of C3 or Factor B were consumed during 30 min at 37 degrees C, while with new onset Type 1 diabetic patient sera up to 90% of C3 and Factor B were consumed in 5/6 sera and 4/6 sera, respectively. These findings suggest (a) that complement activation fragments C3a, C4a, and C5a are generated in vivo in new onset Type 1 diabetes; (b) that both the classical and the alternative complement pathways may be activated; and (c) that this may result in a measurable activation of C5 generating biologically and immunologically active C5a and other C5 activation fragments.(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1985AFY6200008

View details for PubMedID 3907907
AUTOLOGOUS MIXED LYMPHOCYTE-REACTION IN MAN .15. CELLULAR AND MOLECULAR-BASIS OF DEFICIENT AUTOLOGOUS MIXED LYMPHOCYTE-RESPONSE IN INSULIN-DEPENDENT DIABETES-MELLITUS JOURNAL OF CLINICAL IMMUNOLOGY Chandy, K. G., Charles, A. M., Kershnar, A., Buckingham, B., Waldeck, N., Gupta, S. 1984; 4 (6): 424-428
Abstract

The autologous mixed lymphocyte response (AMLR) and the allogeneic mixed lymphocyte response were deficient in a subset of patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM). Using a single set of HLA-identical twins, the cellular and molecular basis of deficient AMLR was investigated and appears to be due to a defect in both responder T cells and stimulator non-T cells. Interleukin-2 production was diminished in the patient but not in the healthy twin. The in vitro addition of purified interleukin-2 enhanced the depressed AMLR in the diseased twin. This suggests that the deficient AMLR in IDDM may be in part due to a deficiency in the production of interleukin-2.

View details for Web of Science ID A1984TV30600002

View details for PubMedID 6239872
SCLERODERMA-LIKE CHANGES IN INSULIN-DEPENDENT DIABETES-MELLITUS - CLINICAL AND BIOCHEMICAL-STUDIES DIABETES CARE Buckingham, B. A., UITTO, J., Sandborg, C., Keens, T., Roe, T., Costin, G., KAUFMAN, F., Bernstein, B., Landing, B., Castellano, A. 1984; 7 (2): 163-169
Abstract

Children with insulin-dependent diabetes mellitus (IDDM) were examined for scleroderma-like changes of digital sclerosis and joint contractures. Of the 104 patients, 19 (18%) demonstrated these features; five patients had both multiple joint involvement and skin changes; three were studied in detail. All three had restrictive pulmonary disease. Histopathology of skin in these three patients demonstrated increased accumulation of collagen in the lower dermis. In two of the patients, the extractability of collagen in 0.5 N acetic acid was decreased by about 50% as compared with normal controls, which suggests increased cross-linkage of collagen. In addition, the mean nonenzymatic glycosylation of collagen in these three patients was 13 times that of controls. The results indicate that distinct histopathologic and biochemical changes can be detected in the skin of these patients. The results further support the hypothesis that nonenzymatic glycosylation may alter the turnover of collagen, thus contributing to the development of a scleroderma-like syndrome with skin, joint, and pulmonary findings in patients with IDDM.

View details for Web of Science ID A1984SN20800012

View details for PubMedID 6734383
IMMUNOLOGICAL EVENTS IN NEW ONSET DIABETES BIOMEDICA BIOCHIMICA ACTA CHARLES, M., Suzuki, M., SUNDSMO, J., Waldeck, N., Negishi, K., Slater, L., Ong, K., Buckingham, B., Kershnar, A. 1984; 43 (5): 615-619
Abstract

Data from our laboratory are reviewed showing that both cell-mediated cytotoxicity, complement-dependent antibody-mediated cytotoxicity, antibody-dependent cellular cytotoxicity, and complement-augmented antibody-dependent cellular cytotoxicity may provide mechanisms which kill pancreatic islets during pathogenesis of insulin-dependent (type I) diabetes. Xenogenic test systems employing dispersed rat islet target cells were employed. Most of the findings were reversible during clinical remission of diabetes.

View details for Web of Science ID A1984TA00700010

View details for PubMedID 6383365
DEFICIENCY OF MONOCLONAL-ANTIBODY (LEU 7) DEFINED NK-CELLS IN NEWLY DIAGNOSED INSULIN-DEPENDENT DIABETES-MELLITUS IMMUNOLOGY LETTERS Chandy, K. G., Charles, M. A., Buckingham, B., Waldeck, N., Kershnar, A., Gupta, S. 1984; 8 (2): 89-91
Abstract

Peripheral blood from 11 newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM) was studied for the proportion of monoclonal antibody (HNK 1, Leu 7) defined natural killer (NK) cells using a fluorescence-activated cell sorter analyzer. The proportion of Leu 7+ cells in patients with IDDM (7.0 +/- 4.0) was significantly (P less than 0.001) lower than in simultaneously studied healthy controls (16.8 +/- 7.0). A 2-yr-old boy with recent onset IDDM had a deficiency of Leu 7+ NK cells (6.1%), while his healthy identical twin had normal proportions of Leu 7+ cells (22.2%), when compared to a simultaneously studied healthy control. Two patients reexamined in remission and one other studied in remission alone, showed deficiency of Leu 7+ NK cells. This study demonstrates a quantitative deficiency of monoclonal antibody (Leu 7+) defined NK cells in newly diagnosed patients with IDDM that persists during remission of the disease and therefore appears to be independent of metabolic abnormality. The deficiency of NK cells may predispose genetically susceptible individuals to viral-induced islet cell injury, contributing to the pathogenesis of IDDM.

View details for Web of Science ID A1984TA79600007

View details for PubMedID 6746020
IMMUNE ISLET KILLING MECHANISMS ASSOCIATED WITH INSULIN-DEPENDENT DIABETES - INVITRO EXPRESSION OF CELLULAR AND ANTIBODY-MEDIATED ISLET CELL CYTO-TOXICITY IN HUMANS JOURNAL OF IMMUNOLOGY Charles, M. A., Suzuki, M., Waldeck, N., DODSON, L. E., Slater, L., Ong, K., Kershnar, A., Buckingham, B., Golden, M. 1983; 130 (3): 1189-1194
Abstract

Because immune mechanisms are associated with insulin-dependent diabetes, multiple organ specific and xenogeneic cytotoxicity assays were developed. Human cellular and antibody effector systems were incubated with 51Cr-labeled dispersed normal rat islet target cells. In eight of 11 diabetic patients, nonenriched mononuclear cells incubated with islet target cells were more cytotoxic than cells from age- and sex-matched controls (p less than 0.01). When non-T cell-enriched mononuclear cells were used at diabetes onset, seven of 11 patients' cells showed excessive islet cytotoxicity (p less than 0.05). In four patients showing elevated cytotoxicity at diabetes onset, cytotoxicity decreased to control levels during diabetes remission. Islet specificity was suggested in that mononuclear cells derived from diabetic subjects did not mediate cytotoxicity against rat spleen or macrophage target cells. Three cytotoxic antibody mechanisms were also evaluated. C-dependent antibody-mediated cytotoxicity with the use of patient serum-coated islet target cells was elevated above control levels in four of 14 patients. Antibody-dependent cellular cytotoxicity exceeded control values in only two of 16 patients, although four assay systems were evaluated. C-augmented antibody-dependent cellular cytotoxicity was elevated in three of 14 patients. No differences were observed for antibody-mediated mechanisms in four patients evaluated at both diabetes onset and remission. Cytotoxic antibody was present in only about one-half of the patients showing increased cellular cytotoxicity, whereas most patients expressing increased cytotoxic antibody had cellular cytotoxicity. Islet cell cytotoxicity assays with the use of effector systems from patients with recent onset insulin-dependent diabetes suggest that direct cellular cytotoxicity is more active than antibody-mediated cytotoxic mechanisms, and that cellular cytotoxicity can correlate with disease activity.

View details for Web of Science ID A1983QC72100033

View details for PubMedID 6337213
HYPERTHYRODISM IN CHILDREN - A RE-EVALUATION OF TREATMENT AMERICAN JOURNAL OF DISEASES OF CHILDREN Buckingham, B. A., Costin, G., Roe, T. F., Weitzman, J. J., KOGUT, M. D. 1981; 135 (2): 112-117
Abstract

The results of medical and surgical therapy were determined in 107 hyperthyroid children. After surgery, 85% of patients were rendered free of hyperthyroidism; however, 62% became hypothyroid. After medical treatment, 30% of patients were euthyroid and 2% became hypothyroid. The relapse rate, however, was higher after medical (22%) than after surgical (9%) therapy. Serious drug-related complications (arthritis-, hepatitis-, and collagen disease-like syndromes) occurred in 14% of patients. Complications occurred in 9% of surgically treated patients, but recurrent laryngeal nerve injury or permanent hypoparathyroidism did not occur. In medically treated patients, both a goiter size less than three times normal prior to treatment and a reduction in goiter size to less than two times normal at the completion of therapy correlated with a successful outcome.

View details for Web of Science ID A1981LC02800003

View details for PubMedID 7468542
STUDIES OF IMMUNE-COMPLEX GLOMERULONEPHRITIS MEDIATED BY HUMAN THYROGLOBULIN NEW ENGLAND JOURNAL OF MEDICINE Jordan, S. C., Buckingham, B., Sakai, R., Olson, D. 1981; 304 (20): 1212-1215
View details for Web of Science ID A1981LN88700006

View details for PubMedID 7012624
RHABDOMYOLYSIS IN DIABETIC-KETOACIDOSIS AMERICAN JOURNAL OF DISEASES OF CHILDREN Buckingham, B. A., Roe, T. F., Yoon, J. W. 1981; 135 (4): 352-354
Abstract

A 2-year-old boy became ill with diabetic ketoacidosis complicated by severe rhabdomyolysis. He completely recovered from the rhabdomyolysis, but has persistent insulin-dependent diabetes mellitus (IDDM). Serological studies showed that the patient's serum contained high titers of coxsackievirus B4 antibody, suggesting that the development of rhabdomyolysis and IDDM may have been related to this infection. A review of the records of 133 patients admitted with onset of IDDM disclosed one additional patient with marked myoglobinuria, and 11 patients with orthotolidine-positive urine in the absence of hematuria. These findings suggest that myoglobinuria may not be uncommon at the onset of IDDM.

View details for Web of Science ID A1981LL30700013

View details for PubMedID 6782859
THYROIDECTOMY FOR HYPERTHYRODISM IN CHILDREN JOURNAL OF PEDIATRIC SURGERY Andrassy, R. J., Buckingham, B. A., Weitzman, J. J. 1980; 15 (4): 501-504
Abstract

Between November 1964 and August 1978, 66 patients underwent subtotal thyroidectomy for hyperthyroidism. Fifty-seven of these patients have been followed for more than 2 yr postoperatively and form the basis for this report. The mean age of these patients was 11 7/12 yr. There wre no deaths in this series and no recurrent laryngeal nerve injuries. Hyperthyroidism recurred in 4 patients from 10 to 60 mo following surgery (mean of 30 mo). Patients with relapse had a significantly larger gland at operation, but no difference in estimated thyroid remnant. Those patients with larger glands at exploration need a relatively larger percentage of the gland removed to prevent recurrent hyperthyroidism.

View details for Web of Science ID A1980KD65400024

View details for PubMedID 7411364
SURGICAL TREATMENT OF HYPERTHYROIDISM IN CHILDREN SURGERY GYNECOLOGY & OBSTETRICS Wesley, J. R., Buckingham, B. A., GAHR, J. A., Isaacs, H., KOGUT, M. D., Weitzman, J. J. 1977; 145 (3): 343-346
Abstract

During the past ten years, subtotal thyroidectomy for hyperthyroidism was performed upon 43 children at Childrens Hospital of Los Angeles. There were no deaths, no recurrent laryngeal nerve injuries and no permanent hypoparathyroidism. During the one to ten year follow-up period, one patient had recurrent hyperthyroidism develop and was treated with 131I. Twenty-five patients are hypothyroid and require thyroid supplement; 14 are euthyroid and receiv no medication. Postoperative thyroid function did not correlate well with gland remnant size, degree of fibrosis or the extent of lymphoid follicle formation. Lymphocytic infiltration was more severe in patients who had hypothyroidism develop postoperatively. Transient hypocalcemia developed in 22 patients. The effectiveness and safety of the surgical treatment for hyperthyroidism in children is reaffirmed, and it is advocated for consideration over 131I or prolonged medical therapy.

View details for Web of Science ID A1977DT66200005

View details for PubMedID 888053
PATHOLOGIC AND IMMUNE FACTORS IN THYROID DISEASE JOURNAL OF PEDIATRICS Buckingham, B. A., Costin, G., KOGUT, M. D., Isaacs, H., Landing, B. H. 1977; 91 (5): 728-733
Abstract

Thyroid glands from 33 children with hyperthyroidism and nine with juvenile lymphocytic thyroiditis were examined histologically and for IgG, IgA, IgM, and C3 by immunofluorescent staining. There was no significant difference between glands with JLT and those with hyperthyroidism in the degree of lymphoid infiltration or lymphoid follicle formation. In thyroiditis there was no correlation between the degree of histologic abnormalities and the presence of immunofluorescent staining for IgG, IgM, or IgA. In hyperthyroidism there was a correlation between the degree of histologic abnormalities and the presence of IgG. In both groups of patients LI and LFF were distinctly more severe in glands positive for C3. Postsurgical hypothyroidism correlated with LI but not with LFF, IgG, or C3.

View details for Web of Science ID A1977DZ51600008

View details for PubMedID 333076
THYROID-FUNCTION IN CHILDREN WITH CHRONIC RENAL-FAILURE NEPHRON Wassner, S. J., Buckingham, B. A., KERSHNAR, A. J., MALEKZADEH, M. H., Pennisi, A. J., Fine, R. N. 1977; 19 (4): 236-241
Abstract

Thyroid function was evaluated in 24 children (aged 4-18 years) with chronic renal failure either before institution of hemodialysis or after more than 3 months of hemodialysis. 22 patients were clinically euthyroid and 2 were hypothyroid; in one case hypothyroidism was secondary to cystinosis and in the other it followed radiation therapy. The 2 hypothyroid patients had subnormal levels of T4, T3, FTI and FT4 as well as elevated serum TSH levels. Mean values for T4, T3, FTI and FT4 for the remaining 22 patients were within the normal range, but were significantly decreased, (all p values less than 0.01) when compared to controls. TSH and TBG levels were not significantly different from those of the normal population. Eleven of the euthyroid patients (50%) had either T3 or FT4, but not both, below the normal range without elevation of their TSH levels. These findings suggest that in the absence of other causes of hypothyroidism, children with chronic renal failure are able to maintain a clinically euthyroid state with either normal FT4 or T3 serum levels and can respond to primary gland failure with elevated TSH secretion.

View details for Web of Science ID A1977DW21800009

View details for PubMedID 917171

Bruce Buckingham

Professor of Pediatrics (Endocrinology) at the Lucile Salter Packard Children's Hospital, Emeritus

Pediatrics - Endocrinology and Diabetes

Bio

Clinical Focus

Academic Appointments

Professional Education

Contact

Links

Research & Scholarship

Current Research and Scholarly Interests

Clinical Trials

Teaching

2020-21 Courses

Stanford Advisees

Publications

All Publications

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract