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

The insulin resistance characteristic of type 2 diabetes and obesity is caused by the failure of insulin to stimulate receptor signalling. Defining the cellular mechanisms of this defect is critical to understanding these disorders. Experiments in type 2 diabetes clinical samples and mouse models now show that the scaffold protein β-arrestin-2 is necessary for efficient insulin signalling, linking the downstream kinases Akt and Src to the insulin receptor. β-arrestin-2 is downregulated both in diabetic mice and in patients. Without β-arrestin-2, insulin resistance develops, and reinstating its expression restores insulin sensitivity in mice. This suggests possible new therapeutic targets in insulin resistance and its related disorders. Beta-arrestin-2, an adaptor protein, is necessary for efficient insulin signalling by scaffolding downstream kinases, Akt and Src, to the insulin receptor. Without beta-arrestin-2 insulin resistance develops. Insulin resistance, a hallmark of type 2 diabetes, is a defect of insulin in stimulating insulin receptor signalling1,2, which has become one of the most serious public health threats. Upon stimulation by insulin, insulin receptor recruits and phosphorylates insulin receptor substrate proteins3, leading to activation of the phosphatidylinositol-3-OH kinase (PI(3)K)–Akt pathway. Activated Akt phosphorylates downstream kinases and transcription factors, thus mediating most of the metabolic actions of insulin4,5,6. β-arrestins mediate biological functions of G-protein-coupled receptors by linking activated receptors with distinct sets of accessory and effecter proteins, thereby determining the specificity, efficiency and capacity of signals7,8,9,10,11. Here we show that in diabetic mouse models, β-arrestin-2 is severely downregulated. Knockdown of β-arrestin-2 exacerbates insulin resistance, whereas administration of β-arrestin-2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a new β-arrestin-2 signal complex, in which β-arrestin-2 scaffolds Akt and Src to insulin receptor. Loss or dysfunction of β-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.