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  • Review Article
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SIRT1 and insulin resistance

Nature Reviews Endocrinology volume 5, pages 367–373 (2009)Cite this article

Abstract

Sirtuin 1 (SIRT1), the mammalian homolog of SIR2, was originally identified as a NAD-dependent histone deacetylase, the activity of which is closely associated with lifespan under calorie restriction. Growing evidence suggests that SIRT1 regulates glucose or lipid metabolism through its deacetylase activity for over two dozen known substrates, and has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. SIRT1 stimulates a glucose-dependent insulin secretion from pancreatic β cells, and directly stimulates insulin signaling pathways in insulin-sensitive organs. Furthermore, SIRT1 regulates adiponectin secretion, inflammatory responses, gluconeogenesis, and levels of reactive oxygen species, which together contribute to the development of insulin resistance. Moreover, overexpression of SIRT1 and several SIRT1 activators has beneficial effects on glucose homeostasis and insulin sensitivity in obese mice models. These findings suggest that SIRT1 might be a new therapeutic target for the prevention of disease related to insulin resistance, such as metabolic syndrome and diabetes mellitus, although direct evidence from clinical studies in humans is needed to prove this possibility. In this Review, we discuss the potential role and therapeutic promise of SIRT1 in insulin resistance on the basis of the latest experimental studies.

Key Points

  • SIRT1 upregulates adiponectin expression by deacetylating FoxO1, and thus protects against insulin resistance

  • SIRT1 attenuates tumor-necrosis-factor-induced inflammation, potentially by deacetylating NFκB

  • SIRT1 has a largely positive role in the insulin-signaling pathway by inducing insulin secretion, repressing Ptpn1, and by regulating insulin-receptor substrates (IRS) 1 and 2 and Akt activation

  • SIRT1 mediates mitochondrial biogenesis by deacetylating PGC1α, upregulates antioxidant enzyme expression by deacetylating FoxO3a and thereby reduces the levels of reactive oxygen species

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Figure 1: SIRT1-mediated regulation of insulin secretion and insulin signaling.
Figure 2: SIRT1-mediated regulation of mitochondrial biogenesis, lipolysis, and ROS levels.
Figure 3: Proposed roles and targets of SIRT1 in insulin resistance.

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Acknowledgements

The authors express their sincere appreciation to Professor Ryuichi Kikkawa, Professor Masakazu Haneda, and Professor Atsunori Kashiwagi for their contribution to the discussion of the role of SIRT1 in insulin resistance.

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Authors and Affiliations

  1. Department of Endocrinology & Metabolism, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan

    Fengxia Liang & Daisuke Koya

  2. Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

    Shinji Kume

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Correspondence to Daisuke Koya.

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Liang, F., Kume, S. & Koya, D. SIRT1 and insulin resistance. Nat Rev Endocrinol 5, 367–373 (2009). https://doi.org/10.1038/nrendo.2009.101

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