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 mM glucose and 0.5 mM palmitic acid (glucolipotoxicity) or a control culture condition with 5.1 mM glucose. We utilized 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, alpha cells are the most resilient to glucolipotoxicity, while beta cells are 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. Lastly, targeted drug screening underscored the critical role of histone H3K9 methyltransferases G9a and GLP in modulating the beta cell cellular response to overnutrition.