Dataset Information

Single-cell RNA Sequencing Uncovers 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 mM glucose and 0.5 mM palmitic acid 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. Additionally, we observed a reduction in cell-cell interactions within islet endocrine cells under glucolipotoxic conditions, 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 cellular response to overnutrition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282230 | GEO | 2024/11/20

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Pancreatic islet (dys)function is central to glucose homeostasis and type 2 diabetes (patho)physiology. Human islets consist of multiple endocrine (alpha, beta, delta, gamma), endothelial, and resident/inflitrating immune cells whose coordinated functions modulate glucose mobilization or disposal. Single cell transcriptome profiling (scRNA-seq) studies have been applied to dissect human islet cellular heterogeneity, identify islet cell (sub)populations, and define their molecular repertoire. However, precise understanding of cell type-specific alterations in type 2 diabetic vs. non-diabetic individuals is lacking, due in part to the limited number of individuals or single cell transcriptomes per individual profiled for comparison. Here, we create a comprehensive single cell transcriptome atlas of 245,878 human islet cells from 48 individuals spanning non-diabetic (ND), pre-diabetic (PD), and type 2 diabetic (T2D) states and matched for sex, age, and ancestry and define marker gene sets that are robustly expressed across disease states for each of the 14 cell types identified. We observe significant decreases in the number of beta cells sampled from T2D vs. ND or PD donors. Two of eight putative beta cell subpopulations, with ‘high functioning’ and ‘senescent’ cell gene signatures, increase and decrease in T2D donor islets, respectively. Importantly, we identify 511 differentially expressed genes in beta cells from T2D vs. ND donors. This includes monogenic and type 2 diabetes effector genes, such as HNF1A, DGKB, ST6GAL1, and FXYD2, for which genetic and environmental effects on their expression is concordant. Human beta cell and islet knockdown of selected newly-identified down-regulated genes impairs beta cell viability or function. Together, this study provides new and robust, cell type-resolved insights on the cellular and molecular changes in healthy vs. diabetic human islets and represents a valuable resource to the islet biology and type 2 diabetes communities.

Dataset Information

Single-cell RNA Sequencing Uncovers Molecular Mechanisms of Human Pancreatic Islet Dysfunction Under Overnutrition Metabolic Stress

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets