Pancreatic islets play a crucial role in maintaining blood glucose levels through the balanced secretion of insulin and other hormones. Dysfunction of islet cells leads to metabolic disorders such diabetes and rare forms of congenital hypoglycemia. While genomic organization and transcriptional regulation has been extensively studied in islet cells, little is known about the impact of alternative splicing, the process that allows single genes to produce multiple protein isoforms.
Here, we compared RNA catalogs from multiple tissues and cell types to identify alternative exons preferentially included in islet cells. We found that the alternative splicing landscape of islets is dominated by an evolutionarily conserved program of microexons, extremely short exons (3-27 nucleotides) previously found largely only in neural cells. Islet microexons (which we termed IsletMICs) respond to changes in glucose concentrations, and are frequently included in genes related to hormone secretion and risk of type 2 diabetes (T2D). Moreover, we found they are regulated in islets by a protein called SRRM3.
To understand the function of IsletMICs in glucose homeostasis, we combined assays in cell cultures and mice. We observed that mis-regulation of IsletMICs causes morphological and functional defects in islets, leading to impaired insulin secretion and glucose homeostasis, which causes pathologically low glucose levels (hypoglycemia) in mice. Moreover, we found that human genetic variants that influence SRRM3 expression are associated with increased fasting glucose and T2D risk.
Together, our data provide multiple lines of evidence that IsletMICs have important roles in modulating islet function, particularly affecting processes involved in the regulation of insulin secretion. Our findings also suggest that changes in the activity of SRRM3 and its microexon targets in islets affect glucose homeostasis in humans, potentially contributing to T2D predisposition.
