Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance
Rui-Hong Wang, … , Oksana Gavrilova, Chu-Xia Deng
Rui-Hong Wang, … , Oksana Gavrilova, Chu-Xia Deng
Published October 3, 2011
Citation Information: J Clin Invest. 2011;121(11):4477-4490. https://doi.org/10.1172/JCI46243.
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Research Article Metabolism

Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance

Abstract

Insulin resistance is a major risk factor for type 2 diabetes mellitus. The protein encoded by the sirtuin 1 (Sirt1) gene, which is a mouse homolog of yeast Sir2, is implicated in the regulation of glucose metabolism and insulin sensitivity; however, the underlying mechanism remains elusive. Here, using mice with a liver-specific null mutation of Sirt1, we have identified a signaling pathway involving Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and Foxo1 that regulates gluconeogenesis. We found that Sirt1 positively regulates transcription of the gene encoding Rictor, triggering a cascade of phosphorylation of Akt at S473 and Foxo1 at S253 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (Pepck). Liver-specific Sirt1 deficiency caused hepatic glucose overproduction, chronic hyperglycemia, and increased ROS production. This oxidative stress disrupted mTorc2 and impaired mTorc2/Akt signaling in other insulin-sensitive organs, leading to insulin resistance that could be largely reversed with antioxidant treatment. These data delineate a pathway through which Sirt1 maintains insulin sensitivity and suggest that treatment with antioxidants might provide protection against progressive insulin resistance in older human populations.

Authors

Rui-Hong Wang, Hyun-Seok Kim, Cuiying Xiao, Xiaoling Xu, Oksana Gavrilova, Chu-Xia Deng

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Figure 1

Liver-specific deletion of SIRT1 causes increased hepatic glucose production.

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Liver-specific deletion of SIRT1 causes increased hepatic glucose produc...
(A) Sirt1LKO animals contain higher blood glucose under fed, 6-hour, and 24-hour fasting conditions than wild-type mice (n = 39 pairs of males) measured at 2 months of age. *P < 0.01, Student t test. (B) PTT shows Sirt1LKO mice (n = 12) produce more glucose than wild-type mice (n = 11) at 2 month of age. *P < 0.05. (C) The expression of gluconeogenesis genes (G6pase and Pepck) is increased at the mRNA level (n ≥ 6). *P < 0.02. (D) G6pase and Pepck protein levels are also elevated. Twenty pairs of mice were used. The bar graph on right is the quantification of Western blots from all the samples. (E and F) Sirt1LKO animals display glucose intolerance. (E) GTT assay was performed in 2-month-old males, and (F) the corresponding blood insulin level during GTT time course was determined (n = 15 pairs). *P < 0.01.