Lu Zhu, Joana Almaça, Prasanna K. Dadi, Hao Hong, Wataru Sakamoto, Mario Rossi, Regina J. Lee, Nicholas C. Vierra, Huiyan Lu, Yinghong Cui, Sara M. McMillin, Nicole A. Perry, Vsevolod V. Gurevich, Amy Lee, Bryan Kuo, Richard D. Leapman, Franz M. Matschinsky, Nicolai M. Doliba, Nikhil M. Urs, Marc G. Caron, David A. Jacobson, Alejandro Caicedo, Jürgen Wess

β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.