1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, and Graduate School of the Chinese Academy of Sciences,
2. Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
3. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, 200233, Shanghai, China
4. Fudan University Affiliated Zhongshan Hospital, 200032, Shanghai, China
5. School of Life Science and Technology, Tongji University, 200092, Shanghai, China

Correspondence to: Gang Pei^1,5 Correspondence and requests for materials should be addressed to G.P. (Email: gpei@sibs.ac.cn).

Abstract

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 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 insulin^{4, 5, 6}. -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 signals^{7, 8, 9, 10, 11}. Here we show that in diabetic mouse models, -arrestin-2 is severely downregulated. Knockdown of -arrestin-2 exacerbates insulin resistance, whereas administration of -arrestin-2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a new -arrestin-2 signal complex, in which -arrestin-2 scaffolds Akt and Src to insulin receptor. Loss or dysfunction of -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.

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