Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network

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Abstract

Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes1,2,3,4,5, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD+)–dependent deacetylase sirtuin 1 (SIRT1) in various tissues1,3,6,7,8. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues9,10. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)–induced reduction in duodenal–mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut–brain–liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD–fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance—a 28 d HFD–induced model of obesity and a nicotinamide (NA)–streptozotocin (STZ)–HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.

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Figure 1: Duodenal Sirt1 regulates insulin action.
Figure 2: Intraduodenal resveratrol triggers a duodenal Ampk–Sirt1 axis to improve insulin sensitivity.
Figure 3: Intraduodenal resveratrol requires a vagal gut–brain neuronal axis to remotely improve hypothalamic insulin sensitivity.
Figure 4: Intraduodenal resveratrol improves insulin sensitivity in obese rats and lowers HGP and plasma glucose levels in hyperglycemic rats.

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Acknowledgements

The authors are grateful to E. Burdett for technical assistance and to L. Schäffer (Novo Nordisk) for providing us with the insulin receptor antagonist (S961). This work is supported by a research grant to T.K.T.L. from the Canadian Institute of Health Research (MOP-82701). C.D.C. is supported by a Banting and Best Diabetes Centre graduate studentship. B.A.R. is supported by a Canadian Institute of Health Research Doctoral Vanier Canada scholarship. F.A.D. is a Banting Fellow. M.Z.-T. is supported by a Banting and Best Diabetes Centre graduate studentship. D.M.B. is supported by a Canadian Diabetes Association postdoctoral fellowship. T.K.T.L. holds the John Kitson McIvor (1915–1942) Endowed Chair in Diabetes Research and the Canada Research Chair in Obesity at the Toronto General Research Institute and the University of Toronto.

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C.D.C., B.A.R. and F.A.D. conducted and designed experiments, performed data analyses and wrote the manuscript; M.Z.-T., M.D., D.M.B. and B.M.F. assisted with experiments; J.A.B. assisted with the in vitro Sirt1 activity experiments; and T.K.T.L. supervised the project, designed experiments and edited the manuscript.

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Correspondence to Tony K T Lam.

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The authors declare no competing financial interests.

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Côté, C., Rasmussen, B., Duca, F. et al. Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network. Nat Med 21, 498–505 (2015). https://doi.org/10.1038/nm.3821

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