Resveratrol treatment restores peripheral insulin sensitivity in diabetic mice in a sirt1-independent manner

Mol Nutr Food Res. 2015 Aug;59(8):1431-42. doi: 10.1002/mnfr.201400933. Epub 2015 Apr 28.


Scope: Mice with deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis. Protein tyrosine phosphatase 1B (PTP1B) inhibition by resveratrol improves peripheral insulin sensitivity of these mice. Although resveratrol activates Sirtuin1 (Sirt1), the mechanisms underlying its beneficial effects are not totally elucidated. In this study, we have investigated whether Sirt1 mediates the effects of resveratrol in controlling insulin resistance in diabetic mice.

Methods and results: We attempted to ameliorate peripheral insulin resistance in two diabetic models, Irs2-deficient (Irs2(-/-)) mice and streptozotocin (STZ)-injected mice by resveratrol treatment or Sirt1 overexpression. Resveratrol improved systemic insulin sensitivity of Irs2-deficient mice. Irs2-deficient mice are characterized by high levels of PTP1B expression in liver and muscle. Interestingly, resveratrol decreased PTP1B in both tissues, thereby restoring IRS1-mediated insulin signaling. Moreover, resveratrol also restored insulin sensitivity and hepatic insulin signaling in STZ-diabetic mice. In contrast, moderate overexpression of Sirt1 neither normalized PTP1B levels nor restored insulin signaling in Irs2-deficient mice or STZ-diabetic mice.

Conclusion: Resveratrol improves peripheral insulin signaling independently of Sirt1 in diabetic mice in association with the inhibition of PTP1B and, therefore, this polyphenol could be an effective adjuvant for the treatment of diabetes.

Keywords: Hyperglycaemia; Insulin resistance; PTP1B; Resveratrol; Sirt1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / therapeutic use*
  • Crosses, Genetic
  • Diabetes Mellitus, Experimental / diet therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / diet therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Dietary Supplements*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Hypoglycemic Agents / therapeutic use
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Resveratrol
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Stilbenes / therapeutic use*


  • Antioxidants
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Stilbenes
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Resveratrol