What question did this study set out to answer?

The study aims to model the epigenetic changes induced by glucose exposure in fetal-like pancreatic islets derived from Indigenous American iPSCs.

June 7, 2026

2669-P: Glucose-Exposure–Induced DNA Methylation Modeling in Fetal-Like Pancreatic Islets Derived from Indigenous American iPSCs

Key Points

The study aims to model the epigenetic changes induced by glucose exposure in fetal-like pancreatic islets derived from Indigenous American iPSCs.
Differentiated pancreatic progenitors from two IA iPSC lines under glucose concentrations of 5 mM and 25 mM.
Conducted Reduced Representation Bisulfite Sequencing (RRBS) to identify differentially methylated regions in the islets.
Identified 64 hypermethylated and 50 hypomethylated regions in iPSC1; 65 hypermethylated and 70 hypomethylated regions in iPSC2 after glucose exposure.
Notable hypermethylation observed in PRDM16, with one significant region (12 CpGs, FDR < 0.05) and two near-significant regions (18 and 5 CpGs, FDR < 0.1).
Overlap observed with ATAC-seq data indicated reduced chromatin accessibility in one identified hypermethylated region.

Abstract

Introduction and Objective: Type 2 diabetes onset often occurs in early adulthood in Indigenous Americans (IA) and exposure to maternal diabetes during fetal development has been shown to increase future diabetes risk in the offspring through epigenetic mechanisms. This study models the effect of in-vitro glucose exposure on epigenetic changes in fetal-like pancreatic islets derived from IA iPSC lines. Methods: Pancreatic progenitors derived from two IA iPSC lines were differentiated under 5 mM or 25 mM glucose to generate immature islets (similar to fetal islets) to mimic intrauterine glucose exposure. DNA from these were used for Reduced Representation Bisulfite Sequencing (RRBS) to identify differentially methylated regions. Results: Methylome profiling of immature pancreatic islets identified 64 hypermethylated and 50 hypomethylated regions (FDR ≤ 0.05, minimum 5 CpGs/ region) in iPSC1 and 65 hypermethylated and 70 hypomethylated regions in iPSC2 following glucose exposure. Most of the significant regions showed directionally concordant methylation changes in each cell line and many were in genes involved in islet function, including insulin secretion. Three hypermethylated regions were identified in PRDM16, a gene consistently associated with epigenetic changes in offspring of diabetic pregnancies, including one significant region (12 CpGs, FDR 0.05) and two near-significant regions (18 and 5 CpGs, FDR 0.1). Interestingly, ad-hoc analysis of previously obtained ATAC-seq data from the same experiment identified an overlap with an enhancer showing reduced chromatin accessibility in the ATAC-seq data with the 18 CpG region, supporting the observed hypermethylation. Conclusion: This study modeled the epigenomic changes (CpG methylation) in a diabetes relevant tissue type (iPSC-derived fetal-like pancreatic islets) due to excess glucose exposure during development and identified candidate genes potentially involved in metabolic/epigenomic reprogramming in offspring of diabetic pregnancies. Disclosure K. Cheranda: None. A.K. Nair: None. D. Anup: None. J.R. Sutherland: None. L. Baier: None.

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