title: Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network.
abstract: Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, 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 tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. 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.
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Clémence D
authors: CD
authors: Côté
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Brittany A
authors: BA
authors: Rasmussen
authors: Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors: Frank A
authors: FA
authors: Duca
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Melika
authors: M
authors: Zadeh-Tahmasebi
authors: Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Joseph A
authors: JA
authors: Baur
authors: Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors: Mira
authors: M
authors: Daljeet
authors: Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors: Danna M
authors: DM
authors: Breen
authors: Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors: Beatrice M
authors: BM
authors: Filippi
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada. [3] Department of Medicine, University of Toronto, Toronto, Ontario, Canada. [4] Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors: Tony K T
authors: TK
authors: Lam
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001786:Blood Glucose / Q000737:chemistry; D003920:Diabetes Mellitus / Q000097:blood; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D009415:Nerve Net / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D009536:Niacinamide / Q000737:chemistry; D009765:Obesity / Q000097:blood / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000627:therapeutic use*; D013311:Streptozocin
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D007328:Insulin; D013267:Stilbenes; D009536:Niacinamide; D013311:Streptozocin; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol