Control of pancreatic islet function and glucose homeostasis by a novel microexon program misregulated in type 2 diabetes

Abstract

AbstractPancreatic islets control glucose homeostasis by the balanced secretion of insulin and other hormones, and their abnormal function causes diabetes or hypoglycemia. Here, we uncover a conserved program of alternative microexons included in mRNAs of islet cells, particularly in genes involved in vesicle transport and exocytosis. Islet microexons (IsletMICs) are regulated by the RNA binding proteinSRRM3and represent a subset of the larger neural program that are particularly sensitive to the levels of this regulator. BothSRRM3and IsletMICs are induced by elevated glucose levels, and depletion ofSRRM3in beta cell lines and mouse islets, or repression of particular IsletMICs using antisense oligonucleotides, leads to inappropriate insulin secretion. Consistently,SRRM3mutant mice display defects in islet cell identity and function, leading to hyperinsulinemic hypoglycemia. Importantly, human genetic variants that influenceSRRM3expression and IsletMIC inclusion in islets are associated with fasting glucose variation and type 2 diabetes risk.