{"doi":"10.2337/db24-1038","title":"Molecular Mechanisms of Human Pancreatic Islet Dysfunction Under Overnutrition Metabolic Stress","abstract":"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.","journal":"Diabetes","year":2025,"id":524100,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9609,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":625995,"name":"Guo Li","orcid":"0000-0003-2539-9970","position":1,"is_corresponding":false},{"id":867551,"name":"Maria Pilar Toledo","orcid":"0000-0001-5553-6417","position":2,"is_corresponding":false},{"id":1397598,"name":"Pamela Sandoval Sanchez","orcid":null,"position":3,"is_corresponding":false},{"id":270349,"name":"Gengqiang Xie","orcid":"0000-0002-2064-4757","position":4,"is_corresponding":false},{"id":275497,"name":"Chengyang Liu","orcid":"0000-0001-9812-1676","position":5,"is_corresponding":false},{"id":109221,"name":"Ali Naji","orcid":"0000-0002-6926-3306","position":6,"is_corresponding":false},{"id":506157,"name":"Jerome Irianto","orcid":"0000-0002-4804-7225","position":7,"is_corresponding":false},{"id":317830,"name":"Michael G. Roper","orcid":"0000-0002-0184-1333","position":8,"is_corresponding":false},{"id":688224,"name":"Yue J. Wang","orcid":"0000-0003-2641-6904","position":9,"is_corresponding":false},{"id":1396971,"name":"Xue Hu","orcid":"0000-0002-4974-6730","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:50:07.396155Z","pmid":"40773375","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}