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Pancreatic Microexons Found to be Involved in Glucose Homeostasis

A newly discovered subset of microexons in pancreatic islets that regulate glucose homeostasis is reported in Nature Metabolism this week. Pancreatic islets contain beta cells responsible for insulin production and transcriptomic, epigenomic, and genetic data have shown that dysregulation of islet-specific gene function is a common mechanism underlying both type 2 diabetes and monogenic forms of diabetes. The role of alternative splicing in pancreatic islet function, however, is poorly understood. In the study, researchers from the Barcelona Institute of Science and Technology describe the identification of islet microexons — dubbed IsletMICs — that respond to physiological changes in glucose levels and are regulated by the RNA binding protein SRRM3, which is essential to nervous system development. They show that both the depletion of SRRM3 in human and rat beta cell lines and mouse islets, as well as the repression of particular IsletMICs using antisense oligonucleotides, lead to dysfunctional insulin secretion. Importantly, human genetic variants that influence SRRM3 expression and IsletMIC inclusion in islets were shown to be associated with fasting glucose variation and type 2 diabetes risk. "Future research on the molecular function of IsletMICs and other islet-enriched exons and their role in islet dysfunction might provide valuable knowledge not only for islet biology but also for the development of novel therapies for [type 2 diabetes] based on splicing modulation," the study's authors write.