Deficiency of a -arrestin-2 signal complex contributes to insulin resistance

Insulin resistance, a hallmark of type 2 diabetes,is a defect of insulin in stimulating insulin receptor signalling 1,2,which has become one of the most serous pubkic health threats.Upon stimulation by insulin,insulin receptor recruits and phosphorylates insulin receptor substrate proteins 3,leading to activation of the phosphatedylinositol-3-OH kinase (PI(3)K)-Akt pathway.Activated Akt phosphorylates downstream kinases and transcription factors,thus mediating most of the metavolic actions of insulin 4,5,6.B-arrestins mediate biological funcions of G-protein-coupled receptors by linking activated receptors with distinct sets of accessoty and effecter proteins,thereby determining the specificity,efficiency and capacity of signals 7,8,9,10,11.Here we show that in diabetic mouse models,B-arrestin-2 is severely downregulated.Knockdown of B-arrestin-2 exacebates insulin resistance,whereas administration of b-arrestin-2 restores insulin sensitivity in mice.Further investigation reveals that insulin stimulates the formation of a new B-arrestin-2 signal complex,in which b-arrestin-2 scaffolds Akt and Src to insulin receptor.Loss or dysfunction of B-arrestin-2 results in deficiency of this signal complex and disturbance of insulin signalling in vivo,thereby contributing to the development of insulin resistance and progression of type 2 diabetes.Our findings provide new insight into the molecular pathogenesis of insulin resistance, and implicate new preventive and therapeutic strategies against insulin resistance and type 2 diabetes.