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

Nature volume 457, pages 1146–1149 (2009)Cite this article

Abstract

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.

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Figure 1: Downregulation of β-arrestin-2 in diabetic mice.
Figure 2: β-arrestin-2 affects the development of insulin resistance.
Figure 3: Insulin stimulated the formation of Receptor/Akt/β-arrestin-2/Src signal complex.
Figure 4: Mutation of β-arrestin-2 contributes to insulin resistance in vivo.

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Acknowledgements

We are grateful to R. J. Lefkowitz for providing us with β-arr2-KO mice. We thank J.-L. Guan for discussions and comments on the manuscripts. We thank all members of the laboratory for sharing reagents and advice. This research was supported by the Ministry of Science and Technology (2005CB522406, 2006CB943900, 2007CB947904, 2007CB947100, 2007CB948000 and 2009CB941100), National Natural Science Foundation of China (30621091, 30625014, 30623003, 30871285 and 90713047), Shanghai Municipal Commission for Science and Technology (07PJ14099 and 06DZ22032), Chinese Academy of Sciences (KSCX2-YW-R-56 and 2007KIP204).

Author Contributions This study was designed by B.L., J.Z. and G.P. The experiments were performed by B.L., B.D. and G.S. H.W. and W.J. contributed to the hyperinsulinaemic–euglycaemic clamp experiments. X.W. provided type 2 diabetes clinic samples. G.P. supervised the project. B.L. and J.Z. contributed to the writing of the paper. D.L. helped with the manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, and Graduate School of the Chinese Academy of Sciences,,

    Bing Luan, Jian Zhao, Baoyu Duan, Guangwen Shu, Jiuhong Kang & Gang Pei

  2. Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China ,

    Dangsheng Li

  3. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital; Shanghai Clinical Center of Diabetes, 200233, Shanghai, China,

    Haiya Wu & Weiping Jia

  4. Shanghai Diabetes Institute,

    Haiya Wu & Weiping Jia

  5. Fudan University Affiliated Zhongshan Hospital, 200032, Shanghai, China ,

    Xiaoying Wang

  6. School of Life Science and Technology, Tongji University, 200092, Shanghai, China ,

    Gang Pei

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  1. Bing Luan
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Correspondence to Gang Pei.

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Luan, B., Zhao, J., Wu, H. et al. Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance. Nature 457, 1146–1149 (2009). https://doi.org/10.1038/nature07617

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