Publications

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

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

Abstract

Regulation of glucose metabolism after a meal is the major task of hepatic glucokinase (GCK). Inhibition and nuclear retention of glucokinase during fasting is achieved by glucokinase regulatory protein (GKRP). Compounds disrupting the GCK-GKRP interaction alter glucose but not triglyceride levels, whilst GKRP coding alleles lower glucose but elevate triglycerides. The aim of this study was to identify yet unknown functions of GKRP by examining human variants both rare (p.Q234P, p.H438Y) and common (p.P446L).Fluorescently labelled human GKRP variant and GCK proteins were expressed in hepatoma cells or primary mouse hepatocytes to investigate the subcellular localization of both proteins, cellular glucose uptake, and triglyceride levels. Mutational effects on GKRP protein structure were analyzed with PyMOL. Nuclear-to-cytoplasmic distribution of the GCK-GKRP complex was modeled in MATLAB.Nuclear localization of the GKRP variants was decreased compared to wild-type. Only H438Y-GKRP still evoked WT-like GCK nuclear accumulation. Nuclear localization of Q234P-GKRP was most impaired and depended on the presence of GCK, which, supported by structural analyses, could stabilize its conformation. Nonetheless, inhibition of glucose uptake was least impaired with Q234P-GKRP. Triglyceride contents related to the glucose uptake of hepatoma cells were disproportionately high for cells expressing wild-type or H438Y-GKRP, the two variants that induced higher nuclear sequestration of GCK.Our results, supported by a modeling approach, suggest that GKRP-mediated nuclear localization of GCK has a function in liver metabolism beyond GCK inhibition and sequestration. This needs further elucidation given that GKRP disruptors have been proposed for antihyperglycemic therapy.

View details for DOI 10.1016/j.metabol.2025.156150

View details for PubMedID 39894388

View details for DOI 10.1101/2025.04.01.25324926