biostudies-literatureHu XAmerican Diabetes AssociationJDRF1825-1838https://www.ebi.ac.uk/biostudies/studies/S-EPMC12451085biostudies-literatureUnknown74(10)Metabolic stress elicits functional changes in pancreatic islets, contributing to the pathogenesis of type 2 diabetes. However, the molecular mechanisms underlying overnutrition stress in islet cells is not well understood. In our study, we subjected human islets to overnutrition with 25 mmol/L glucose and 0.5 mmol/L palmitic acid (glucolipotoxicity) or to a control culture condition with 5.1 mmol/L glucose. We used single-cell RNA sequencing to comprehensively characterize the gene expression changes between these two conditions in a cell type-specific manner. We found that among all islet endocrine cell types, α-cells were the most resilient to glucolipotoxicity, while β-cells were the most susceptible. We also observed a reduction in cell-cell interactions within islet endocrine cells uDiabetesMolecular Mechanisms of Human Pancreatic Islet Dysfunction Under Overnutrition Metabolic Stress.PMC124510851-INO-2022-1129-A-N11-22-JDFPM-03Pilar Toledo MIrianto JNaji AGuo LXie GHu XLiu CRoper MGSandoval Sanchez PWang YJfalseMolecular Mechanisms of Human Pancreatic Islet Dysfunction Under Overnutrition Metabolic Stress.Metabolic stress elicits functional changes in pancreatic islets, contributing to the pathogenesis of type 2 diabetes. However, the molecular mechanisms underlying overnutrition stress in islet cells is not well understood. In our study, we subjected human islets to overnutrition with 25 mmol/L glucose and 0.5 mmol/L palmitic acid (glucolipotoxicity) or to a control culture condition with 5.1 mmol/L glucose. We used single-cell RNA sequencing to comprehensively characterize the gene expression changes between these two conditions in a cell type-specific manner. We found that among all islet endocrine cell types, α-cells were the most resilient to glucolipotoxicity, while β-cells were the most susceptible. We also observed a reduction in cell-cell interactions within islet endocrine cells u2025-01-01T00:00:00Z2025 Oct2026-06-03T03:09:48.362Z2026-06-03T03:07:30.484ZS-EPMC124510854077337510.2337/db24-1038