38-OR: Beta-Arrestin-1 Regulates Pancreatic Beta-Cell Function and Plays a Key Role in Maintaining Whole Body Glucose Homeostasis

Beta-arrestin-1 and -2 (barr1 and barr2, respectively) are major GPCR-associated signaling molecules that are widely expressed throughout the body. Studies with whole body barr1 and barr2 KO mice have shown that beta-arrestins play important roles in key metabolic functions. In this study, we inactivated the barr1 gene in a conditional fashion specifically in beta-cells of adult mice (beta-barr1-KO mice). In vivo studies showed that beta-barr1-KO mice exhibited a pronounced impairment in glucose tolerance and glucose-stimulated insulin secretion (GSIS), when mice were maintained on high-fat diet (HFD). Studies with isolated perifused pancreatic islets prepared from HFD beta-barr1-KO mice confirmed that barr1 deletion in beta-cells led to a significant decrease in GSIS. Interestingly, HFD beta-barr1-KO mice displayed pronounced reductions in beta-cell mass and the rate of beta-cell proliferation, suggesting that barr1 is required for the expansion of beta-cell mass that occurs during HFD feeding. To test whether enhanced barr1 signaling in beta-cells might ameliorate the metabolic deficits associated with the consumption of a HFD, we also generated transgenic mice over-expressing barr1 in beta-cells (RIPII-barr1 mice). These transgenic mice displayed metabolic phenotypes that were opposite to those observed with the beta-barr1-KO mice, including improved glucose tolerance and GSIS in vivo as well as increased beta-cell mass. This is the first study demonstrating that barr1 is critical for the proper function of pancreatic beta-cells and for maintaining whole body glucose homeostasis. Identification of the cellular mechanisms through which barr1 signaling promotes beta-cell function and proliferation may lead to the development of novel drugs useful for the treatment of type 2 diabetes.