Dataset Information

Understanding islet dysfunction in type 2 diabetes through multidimensional pancreatic phenotyping: The Human Pancreas Analysis Program.

ABSTRACT: In this perspective, we provide an overview of a recently established National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) initiative, the Human Pancreas Analysis Program for Type 2 Diabetes (HPAP-T2D). This program is designed to define the molecular pathogenesis of islet dysfunction by studying human pancreatic tissue samples from organ donors with T2D. HPAP-T2D generates detailed datasets of physiological, histological, transcriptomic, epigenomic, and genomic information. Importantly, all data collected, generated, and analyzed by HPAP-T2D are made immediately and freely available through a centralized database, PANC-DB, thus providing a comprehensive data resource for the diabetes research community.

SUBMITTER: Shapira SN

PROVIDER: S-EPMC9742126 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Understanding islet dysfunction in type 2 diabetes through multidimensional pancreatic phenotyping: The Human Pancreas Analysis Program.

Shapira Suzanne N SN Naji Ali A Atkinson Mark A MA Powers Alvin C AC Kaestner Klaus H KH

Cell metabolism 20221006 12

In this perspective, we provide an overview of a recently established National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) initiative, the Human Pancreas Analysis Program for Type 2 Diabetes (HPAP-T2D). This program is designed to define the molecular pathogenesis of islet dysfunction by studying human pancreatic tissue samples from organ donors with T2D. HPAP-T2D generates detailed datasets of physiological, histological, transcriptomic, epigenomic, and genomic information. ...[more]

PMID: 36206763

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Project description:Aims/hypothesisIslet prohormone-processing enzymes convert peptide hormone precursors to mature hormones. Defective beta cell prohormone processing and the release of incompletely processed peptide hormones are observed prior to the onset of diabetes, yet molecular mechanisms underlying impaired prohormone processing during the development of diabetes remains largely unknown. Previous studies have shown that prohormone convertase 1/3 (PC1/3) protein and mRNA expression levels are reduced in whole islets from donors with type 1 diabetes, although whether PC1/3-mediated prohormone processing in alpha and beta cells is disrupted in type 1 diabetes remained to be explored. Herein, we aimed to analyse the expression of PC1/3 in islets from non-diabetic donors, autoantibody-positive donors and donors diagnosed with type 1 diabetes or type 2 diabetes.MethodsImmunostaining and high-dimensional image analysis were performed on pancreatic sections from a cross-sectional cohort of 54 donors obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD) repository, to evaluate PC1/3 expression patterns in islet alpha, beta and delta cells at different stages of diabetes.ResultsAlpha and beta cell morphology were altered in donors with type 1 diabetes, including decreased alpha and beta cell size. As expected, the insulin-positive and PC1/3-positive areas in the islets were both reduced, and this was accompanied by a reduced percentage of PC1/3-positive and insulin-positive/PC1/3-positive cells in islets. PC1/3 and insulin co-localisation was also reduced. The glucagon-positive area, as well as the percentage of glucagon-positive and glucagon-positive/PC1/3-positive cells in islets, was increased. PC1/3 and glucagon co-localisation was also increased in donors with type 1 diabetes. The somatostatin-positive cell area and somatostatin staining intensity were elevated in islets from donors with recent-onset type 1 diabetes.Conclusions/interpretationOur high-resolution histomorphological analysis of human pancreatic islets from donors with and without diabetes has uncovered details of the cellular origin of islet prohormone peptide processing defects. Reduced beta cell PC1/3 and increased alpha cell PC1/3 in islets from donors with type 1 diabetes pinpointed the functional deterioration of beta cells and the concomitant potential increase in PC1/3 usage for prohormone processing in alpha cells during the pathogenesis of type 1 diabetes. Our finding of PC1/3 loss in beta cells may inform the discovery of new prohormone biomarkers as indicators of beta cell dysfunction, and the finding of elevated PC1/3 expression in alpha cells may encourage the design of therapeutic targets via leveraging alpha cell adaptation in diabetes.

Dataset Information

Understanding islet dysfunction in type 2 diabetes through multidimensional pancreatic phenotyping: The Human Pancreas Analysis Program.

Publications

Understanding islet dysfunction in type 2 diabetes through multidimensional pancreatic phenotyping: The Human Pancreas Analysis Program.

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