Publications

Anna L Gloyn
Professor of Pediatrics (Endocrinology) and of Genetics

Publications

  • Complete Loss of PAX4 causes Transient Neonatal Diabetes in Humans. Molecular metabolism Russ-Silsby, J., Lee, Y., Rajesh, V., Amoli, M., Mirhosseini, N. A., Godbole, T., Johnson, M. B., Ibarra, D. E., Sun, H., Krentz, N. A., Wakeling, M. N., Flanagan, S. E., Hattersley, A. T., Gloyn, A. L., De Franco, E. 2025: 102201

    Abstract

    Gene discovery studies in individuals with diabetes diagnosed within 6 months of life (neonatal diabetes, NDM) can provide unique insights into the development and function of human pancreatic beta-cells. We describe the identification of homozygous PAX4 loss-of-function variants in 2 unrelated individuals with NDM: a p.(Arg126*) stop-gain variant and a c.-352_104del deletion affecting the first 4 PAX4 exons. We confirmed the p.(Arg126*) variant causes nonsense mediated decay in CRISPR-edited human induced pluripotent stem cell (iPSC)-derived pancreatic endoderm cells. Integrated analysis of CUT&RUN and RNA-sequencing in PAX4-depleted islet cell models identified genes directly regulated by PAX4 involved in both pancreatic islet development and glucose-stimulated insulin secretion. Both probands had transient NDM which remitted in early infancy but relapsed at the ages of 2.4 and 6.7 years, demonstrating that in contrast to mouse models, PAX4 is not essential for the development of human pancreatic beta-cells.

    View details for DOI 10.1016/j.molmet.2025.102201

    View details for PubMedID 40614820

  • Diabetes mellitus polygenic risk scores: heterogeneity and clinical translation. Nature reviews. Endocrinology Ortega, H. I., Udler, M. S., Gloyn, A. L., Sharp, S. A. 2025

    Abstract

    Diabetes mellitus encompasses several disorders, each with differing clinical presentation, prognoses and pathophysiology. Distinct polygenic architectures underlie type 1 diabetes mellitus and type 2 diabetes mellitus, and govern numerous pathophysiological pathways that converge on dysglycaemia. Over the previous decade, polygenic risk scores (PRS) derived from large genome-wide association studies have become broadly recognized for their potential in precision medicine. PRS, and now partitioned polygenic scores generated by clustering of risk variants, can quantify individual genetic predisposition to diabetes mellitus and reveal molecular heterogeneity responsible for variation in clinical presentation and prognoses. In this Review, we examine and contrast progress in the development of type 1 diabetes mellitus PRS and type 2 diabetes mellitus PRS, and discuss paths to further methodological advances. We examine how studies in the past 10 years have harnessed PRS and novel partitioned polygenic scores to reveal insights into diabetes mellitus aetiology and characterize changes in cellular and tissue-specific disease-modifying molecular pathways. Additionally, we discuss advances and opportunities in areas of clinical translation, including improved classification of diabetes mellitus type, screening of those at risk and personalized interventions informed by PRS. Finally, we emphasize the urgent need to overcome ancestry-related challenges and highlight current progress and gaps in ensuring the equitable translation of PRS for diabetes mellitus precision medicine.

    View details for DOI 10.1038/s41574-025-01132-w

    View details for PubMedID 40467969

    View details for PubMedCentralID 8385600

  • Accelerating Medicines Partnership in Type 2 Diabetes and Common Metabolic Diseases: Collaborating to Maximize the Value of Genetic and Genomic Data. Diabetes Costanzo, M. C., Akolkar, B., Claussnitzer, M., Florez, J. C., Gloyn, A. L., Grant, S. F., Kaestner, K. H., Manning, A. K., Mohlke, K. L., Parker, S. C., Titchenell, P. M., Udler, M. S., Jones, M. A., Kamphaus, T. N., Fischer, R. A., McCarthy, M. I., Miller, M. R., Boehnke, M., Flannick, J., Burtt, N. P. 2025

    Abstract

    In the last two decades, significant progress has been made toward understanding the genetic basis of type 2 diabetes. An important supporter of this research has been the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), most recently through the Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD). These public-private partnerships of the National Institutes of Health, multiple biopharmaceutical and life sciences companies, and nonprofit organizations, facilitated and managed by the Foundation for the National Institutes of Health, were designed to improve understanding of therapeutically relevant biological pathways for type 2 diabetes. On the occasion of NIDDK's 75th anniversary, we review the history of NIDDK support for these partnerships, which saw the convergence of research directions prioritized by academic consortia, the pharmaceutical industry, and government funders. Although the NIDDK was not the sole originator or funder of these efforts, its support and leadership have been pivotal to the partnerships' success and have enabled their research to be broadly accessible through the AMP Common Metabolic Diseases Knowledge Portal (CMDKP) and the AMP Common Metabolic Diseases Genome Atlas (CMDGA). Findings from AMP CMD align with NIDDK's mission to conduct research and share results with the goal of improving health and quality of life.The Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD) were created to accelerate the translation of genetic and genomic data into knowledge about the biology of disease. Their goal was to gain a better understanding of the mechanisms underlying types 1 and 2 diabetes and prediabetes, obesity, cardiovascular disease, kidney disease, and nonalcoholic steatohepatitis. This work identified multiple genes and pathways underlying these diseases. The findings of AMP T2D and AMP CMD have implications for drug development and improved risk prediction, diagnosis, and treatment for common metabolic diseases.

    View details for DOI 10.2337/db25-0042

    View details for PubMedID 40272257

  • Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multiancestry Population Cohorts. Diabetes care Luckett, A. M., Oram, R. A., Deutsch, A. J., Ortega, H. I., Fraser, D. P., Ashok, K., Manning, A. K., Mercader, J. M., Rivas, M. A., Udler, M. S., Weedon, M. N., Gloyn, A. L., Sharp, S. A. 2025

    View details for DOI 10.2337/dc25-0142

    View details for PubMedID 40267362

  • Peptidylglycine alpha-amidating monooxygenase is important in mice for beta-cell cilia formation and insulin secretion but promotes diabetes risk through beta-cell independent mechanisms. Molecular metabolism Chen, Y., Back, N. E., Zhen, J., Xiong, L., Komba, M., Gloyn, A. L., MacDonald, P. E., Mains, R. E., Eipper, B. A., Verchere, C. B. 2025: 102123

    Abstract

    OBJECTIVE: Carriers of PAM (peptidylglycine alpha-amidating monooxygenase) coding variant alleles have reduced insulinogenic index, higher risk of developing type 2 diabetes (T2D), and islets from heterozygous carriers of the PAM p.Asp563Gly variant display reduced insulin secretion. Exactly how global PAM deficiency contributes to hyperglycemia remains unclear. PAM is the only enzyme capable of converting glycine-extended peptide hormones into amidated products. Like neuropeptide Y (NPY), alpha-melanocyte stimulating hormone (alphaMSH), and glucagon-like peptide 1 (GLP-1), islet amyloid polypeptide (IAPP), a beta cell peptide that forms islet amyloid in type 2 diabetes, is a PAM substrate. We hypothesized that Pam deficiency limited to beta cells would lead to reduced insulin secretion, prevent the production of amidated IAPP, and reveal the extent to which loss of Pam in beta-cells could accelerate the onset of hyperglycemia in mice.METHODS: PAM activity was assessed in human islets from donors based on their PAM genotype. We generated beta cell-specific Pam knockout (Ins1Cre/+, Pamfl/fl; betaPamKO) mice and performed islet culture, histological, and metabolic assays to evaluate the physiological roles of Pam in beta cells. We analyzed human IAPP (hIAPP) amyloid fibril forming kinetics using synthetic amidated and non-amidated hIAPP peptides, and generated hIAPP knock-in beta cell-specific Pam knockout (hIAPPw/w betaPamKO) mice to determine the impact of hIAPP amidation on islet amyloid burden, islet graft survival, and glucose tolerance.RESULTS: PAM enzyme activity was significantly reduced in islets from donors with the PAM p.Asp563Gly T2D-risk allele. Islets from betaPamKO mice had impaired second-phase glucose- and KCl- induced insulin secretion. Beta cells from betaPamKO mice had larger dense-core granules and fewer and shorter cilia. Interestingly, non-amidated hIAPP was less fibrillogenic in vitro, and high glucose-treated hIAPPw/w betaPamKO islets had reduced amyloid burden. Despite these changes in beta cell function, betaPamKO mice were not more susceptible to diet-induced hyperglycemia. In vitro beta cell death and in vivo islet graft survival remained comparable between hIAPPw/w betaPamKO and hIAPPw/w islets. Surprisingly, aged hIAPPw/w betaPamKO mice had improved insulin secretion and glucose tolerance.CONCLUSIONS: Eliminating Pam expression only in beta cells leads to morphological changes in insulin granules, reduced insulin secretion, reduced hIAPP amyloid burden and altered ciliogenesis. However, in mice beta-cell Pam deficiency has no impact on the development of diet- or hIAPP-induced hyperglycemia. Our data are consistent with current studies revealing ancient, highly conserved roles for peptidergic signaling in the coordination of the diverse signals needed to regulate fundamental processes such as glucose homeostasis.

    View details for DOI 10.1016/j.molmet.2025.102123

    View details for PubMedID 40120979

Mission Statement

Our mission is to improve understanding of pancreatic islet cell dysfunction in type 2 diabetes using human genetics as a tool to uncover causal disease mechanisms and shed light on potential targets for therapeutic development.

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Resources

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