Beta-arrestin-1 is required for the proper function of pancreatic beta-cells and whole body glucose homeostasis

Authors

• LF Barella
• M Rossi
• L Zhu
• J Wess

Abstract

Beta-arrestin-1 and -2 (barr1 and barr2, respectively) are major signaling molecules widely expressed throughout the body that regulate many physiological functions. Studies with whole body barr1 and barr2 KO mice have shown that beta-arrestins play important roles in key metabolic functions, including euglycemia maintenance and peripheral insulin sensitivity. However, the potential role of beta-arrestins to modulate pancreatic beta-cell function and euglycemia in vivo remains unclear. In this study, we inactivated the barr1 gene in a conditional fashion in beta-cells of adult mice (beta-barr1-KO mice). When beta-barr1-KO mice were fed a high-fat diet (HFD), they exhibited a pronounced impairment in glucose tolerance and glucose-stimulated insulin secretion (GSIS) in vivo. This deficit in GSIS was also observed with perifused pancreatic islets isolated from HFD beta-barr1-KO mice. Additionally, injecting bethanechol (a muscarinic receptor agonist) or exendin-4 (a GLP1 receptor agonist) led to reduced insulin responses in beta-barr1-KO mice, as compared to control mice. To test whether enhanced barr1 signaling in beta-cells ameliorates the HFD metabolic deficits, we also generated transgenic mice that over-expressed barr1 in beta-cells (RIPII-barr1 mice). These transgenic mice displayed metabolic phenotypes opposite to those displayed by beta-barr1-KO mice, including improved glucose tolerance and GSIS in vivo. This study is the first to demonstrate that barr1 is critical for the proper function of pancreatic beta-cells and for maintaining whole body glucose homeostasis. Strategies aimed at promoting barr1 signaling in beta-cells may prove useful for the development of novel antidiabetic drugs.

Scientific Focus Area: Molecular Biology and Biochemistry

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