Molecular 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 under glucolipotoxicity, alongside alterations in gene regulatory networks linked to type 2 diabetes genetic risk. Finally, targeted drug screening underscored the critical role of histone H3K9 methyltransferases G9a (EHMT2) and GLP (EHMT1) in modulating the β-cell cellular response to overnutrition. ARTICLE HIGHLIGHTS: Glucolipotoxicity disrupts insulin secretion in human islets, yet its cell type-specific impacts and the molecular mechanisms driving these effects remain poorly understood. Single-cell RNA sequencing reveals β-cells as the most sensitive to glucolipotoxicity, with pronounced shifts in the gene regulatory network linked to cellular stress and lineage-specific transcription factors, while α-cells exhibit greater resilience. Cell-cell communications among islet endocrine cells are reduced under glucolipotoxicity. H3K9 methyltransferases G9a and GLP mediate glucolipotoxicity in β-cells. Our study provides a road map of how metabolic stress causally contributes to cellular dysfunction and diabetes pathogenesis.