2129-P: Glucagon Secretion from Pancreatic Islets Is Regulated by Beta-Arrestin-1

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Glucagon, a hormone released from alpha cells of pancreatic islets, plays a key role in maintaining proper glucose homeostasis. Substantial evidence suggests that inappropriately elevated plasma glucagon levels contribute to the pathophysiology of type 1 and 2 diabetes. Therefore, it is of great importance to understand the signaling pathways that regulate glucagon release from alpha cells. As is the case with virtually all cell types, the function of pancreatic alpha cells is modulated by the activity of cell surface receptors known as G protein-coupled receptors (GPCRs). GPCR signaling is regulated by two intracellular proteins, β-arrestin-1 and -2 (barr1 and barr2, respectively), which can terminate GPCR signaling. Interestingly, barr1 and barr2 can also act as signaling molecules in their own right. Studies with whole body knockout mice have shown the two β-arrestins regulate many important physiological functions. The potential roles of barr1 and barr2 in modulating alpha cell function in vivo remain unknown at present. To address this issue, we used Cre-lox technology to delete barr1 in a conditional fashion in pancreatic alpha cells of adult mice (alpha-barr1 KO mice). Alpha-barr1 KO mice showed significantly decreased plasma glucagon levels and impaired glucose-stimulated insulin secretion. Studies with hamster alpha cells demonstrated that the ability of forskolin and arginine vasopressin to stimulate glucagon secretion was significantly decreased after knockdown of barr1 expression. We also found that the islets prepared from alpha-barr1 KO mice showed a significant reduction in glucagon content and mRNA expression, while insulin content and mRNA expression remained unaltered. In future studies, we will explore the molecular/cellular mechanisms through which barr1 regulates alpha cell function and glucagon content. This work may identify novel signaling pathways modulating glucagon secretion that can be targeted for therapeutic purposes. Disclosure D. Dattaroy: None. L.F. Barella: None. S. Pydi: None. Y. Cui: None. K.H. Kaestner: None. J. Wess: None.