title: Resveratrol prevents insulin resistance caused by short-term elevation of free fatty acids in vivo.
abstract: Elevated levels of plasma free fatty acids (FFA), which are commonly found in obesity, induce insulin resistance. FFA activate protein kinases including the proinflammatory IκBα kinase β (IKKβ), leading to serine phosphorylation of insulin receptor substrate 1 (IRS-1) and impaired insulin signaling. To test whether resveratrol, a polyphenol found in red wine, prevents FFA-induced insulin resistance, we used a hyperinsulinemic-euglycemic clamp with a tracer to assess hepatic and peripheral insulin sensitivity in overnight-fasted Wistar rats infused for 7 h with saline, Intralipid plus 20 U·mL(-1) heparin (IH; triglyceride emulsion that elevates FFA levels in vivo; 5.5 μL·min(-1)) with or without resveratrol (3 mg·kg(-1)·h(-1)), or resveratrol alone. Infusion of IH significantly decreased glucose infusion rate (GIR; P < 0.05) and peripheral glucose utilization (P < 0.05) and increased endogenous glucose production (EGP; P < 0.05) during the clamp compared with saline infusion. Resveratrol co-infusion, however, completely prevented the effects induced by IH infusion: it prevented the decreases in GIR (P < 0.05 vs. IH), peripheral glucose utilization (P < 0.05 vs. IH), and insulin-induced suppression of EGP (P < 0.05 vs. IH). Resveratrol alone had no effect. Furthermore, IH infusion increased serine (307) phosphorylation of IRS-1 in soleus muscle (∼30-fold, P < 0.001), decreased total IRS-1 levels, and decreased IκBα content, consistent with activation of IKKβ. Importantly, all of these effects were abolished by resveratrol (P < 0.05 vs. IH). These results suggest that resveratrol prevents FFA-induced hepatic and peripheral insulin resistance and, therefore, may help mitigate the health consequences of obesity.
authors.affiliation: a Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pereira
authors.affiliation: a Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Park
authors.affiliation: b Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada.
authors.forename: Jessy
authors.initials: J
authors.lastname: Moore
authors.affiliation: b Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada.
authors.forename: Brandon
authors.initials: B
authors.lastname: Faubert
authors.affiliation: a Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Danna M
authors.initials: DM
authors.lastname: Breen
authors.affiliation: c Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Oprescu
authors.affiliation: a Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Nahle
authors.affiliation: a Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Kwan
authors.affiliation: a Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.|c Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.|d Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.affiliation: b Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Tsiani
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D004655:Emulsions; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D015309:Glucose Clamp Technique; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010743:Phospholipids; D010766:Phosphorylation; D017208:Rats, Wistar; D000077185:Resveratrol; D012694:Serine; D013024:Soybean Oil; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D004655:Emulsions; D005230:Fatty Acids, Nonesterified; D020672:I-kappa B Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C000606206:Nfkbia protein, rat; D010743:Phospholipids; D013267:Stilbenes; C545823:soybean oil, phospholipid emulsion; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine; D013024:Soybean Oil; D051550:I-kappa B Kinase; D000077185:Resveratrol
keywords: dyslipidemia; dyslipidémie; insulin resistance; insulinorésistance; metabolism; muscle squelettique; métabolisme; obesity; obésité; skeletal muscle