Improving Glucose Metabolism With Resveratrol in a Swine Model of Metabolic Syndrome Through Alteration of Signaling Pathways in the Liver and Skeletal Muscle | JAMA Surgery | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Flegal  KMCarroll  MDOgden  CLCurtin  LR Prevalence and trends in obesity among US adults, 1999-2008.  JAMA 2010;303 (3) 235- 241PubMedGoogle Scholar
Haslam  DWJames  WP Obesity.  Lancet 2005;366 (9492) 1197- 1209PubMedGoogle Scholar
Malik  SWong  NDFranklin  SS  et al.  Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults.  Circulation 2004;110 (10) 1245- 1250PubMedGoogle Scholar
Turcotte  LPFisher  JS Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise.  Phys Ther 2008;88 (11) 1279- 1296PubMedGoogle Scholar
Petersen  KFShulman  GI Etiology of insulin resistance.  Am J Med 2006;119 (5 (suppl 1)) S10- S16PubMedGoogle Scholar
Lovejoy  JC The influence of dietary fat on insulin resistance.  Curr Diab Rep 2002;2 (5) 435- 440PubMedGoogle Scholar
Schattenberg  JMSchuchmann  M Diabetes and apoptosis: liver.  Apoptosis 2009;14 (12) 1459- 1471PubMedGoogle Scholar
Harris  EH Elevated liver function tests in type 2 diabetes.  Clin Diabetes2005233115119doi:10.2337/diaclin.23.3.115Google Scholar
Sigal  RJKenny  GPBoulé  NG  et al.  Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial.  Ann Intern Med 2007;147 (6) 357- 369PubMedGoogle Scholar
O’Brien  PEDixon  JBLaurie  C  et al.  Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding or an intensive medical program: a randomized trial.  Ann Intern Med 2006;144 (9) 625- 633PubMedGoogle Scholar
Dixon  JBO’Brien  PEPlayfair  J  et al.  Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial.  JAMA 2008;299 (3) 316- 323PubMedGoogle Scholar
Breen  DMSanli  TGiacca  ATsiani  E Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK.  Biochem Biophys Res Commun 2008;374 (1) 117- 122PubMedGoogle Scholar
Roccaro  AMLeleu  XSacco  A  et al.  Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenström's macroglobulinemia.  Clin Cancer Res 2008;14 (6) 1849- 1858PubMedGoogle Scholar
Lagouge  MArgmann  CGerhart-Hines  Z  et al.  Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.  Cell 2006;127 (6) 1109- 1122PubMedGoogle Scholar
González-Rodríguez  AMas Gutierrez  JASanz-González  SRos  MBurks  DJValverde  AM Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice.  Diabetes 2010;59 (3) 588- 599PubMedGoogle Scholar
Chaudhary  NPfluger  PT Metabolic benefits from Sirt1 and Sirt1 activators.  Curr Opin Clin Nutr Metab Care 2009;12 (4) 431- 437PubMedGoogle Scholar
Institute of Laboratory Animal Resources; Commission on Life Sciences; National Research Council Guide for the Care and Use of Laboratory Animals  Washington, DC: National Academy Press; 1996. Publication 5377-3
Mattson  MP Perspective: does brown fat protect against diseases of aging?  Ageing Res Rev 2010;9 (1) 69- 76PubMedGoogle Scholar
Baur  JAPearson  KJPrice  NL  et al.  Resveratrol improves health and survival of mice on a high-calorie diet.  Nature 2006;444 (7117) 337- 342PubMedGoogle Scholar
Muoio  DMNewgard  CB Metabolism: A is for adipokine.  Nature 2005;436 (7049) 337- 338PubMedGoogle Scholar
Graham  TEYang  QBlüher  M  et al.  Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.  N Engl J Med 2006;354 (24) 2552- 2563PubMedGoogle Scholar
Higashida  KHiguchi  MTerada  S Dissociation between PGC-1alpha and GLUT-4 expression in skeletal muscle of rats fed a high-fat diet.  J Nutr Sci Vitaminol (Tokyo) 2009;55 (6) 486- 491PubMedGoogle Scholar
O’Brien  RMGranner  DK Regulation of gene expression by insulin.  Biochem J 1991;278 (pt 3) 609- 619PubMedGoogle Scholar
Ueda  SKitazawa  SIshida  K  et al.  Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma.  FASEB J 2010;24 (7) 2254- 2261PubMedGoogle Scholar
Cheng  ZJSingh  RDWang  TK  et al.  Stimulation of GLUT4 (glucose transporter isoform 4) storage vesicle formation by sphingolipid depletion.  Biochem J 2010;427 (1) 143- 150PubMedGoogle Scholar
Shepherd  PRKahn  BB Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus.  N Engl J Med 1999;341 (4) 248- 257PubMedGoogle Scholar
Berger  JMoller  DE The mechanisms of action of PPARs.  Annu Rev Med 2002;53409- 435PubMedGoogle Scholar
Cheatham  WW Peroxisome proliferator-activated receptor translational research and clinical experience.  Am J Clin Nutr 2010;91 (1) 262S- 266SPubMedGoogle Scholar
Neuschwander-Tetri  BACaldwell  SH Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.  Hepatology 2003;37 (5) 1202- 1219PubMedGoogle Scholar
Roghani  MBaluchnejadmojarad  T Mechanisms underlying vascular effect of chronic resveratrol in streptozotocin-diabetic rats.  Phytother Res 2010;24 ((suppl 2)) S148- S154PubMedGoogle Scholar
Sarbassov  DDGuertin  DAAli  SMSabatini  DM Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.  Science 2005;307 (5712) 1098- 1101PubMedGoogle Scholar
Dong  XPark  SLin  XCopps  KYi  XWhite  MF Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth.  J Clin Invest 2006;116 (1) 101- 114PubMedGoogle Scholar
Lipina  CHuang  XFinlay  D McManus  EJAlessi  DRSutherland  C Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3.  Biochem J 2005;392 (pt 3) 633- 639PubMedGoogle Scholar
Gurusamy  NLekli  IMukherjee  S  et al.  Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway.  Cardiovasc Res 2010;86 (1) 103- 112PubMedGoogle Scholar
Poster Session
May 2011May 16, 2011

Improving Glucose Metabolism With Resveratrol in a Swine Model of Metabolic Syndrome Through Alteration of Signaling Pathways in the Liver and Skeletal Muscle

Author Affiliations

Author Affiliations: Division of Cardiothoracic Surgery, Department of Surgery, and Cardiovascular Research Center, Rhode Island Hospital (Mr Burgess and Drs Robich, Bianchi, and Sellke), and Division of Cardiothoracic Surgery, Department of Surgery, Warren Alpert School of Medicine, Brown University (Drs Robich, Chu, and Sellke), Providence; and Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Drs Robich and Sellke).

Arch Surg. 2011;146(5):556-564. doi:10.1001/archsurg.2011.100

Hypothesis  We hypothesized that supplemental resveratrol would affect glucose metabolism in the skeletal muscle and liver to improve blood glucose control.

Design  Case-control study.

Setting  Hospital laboratory.

Subjects  Yorkshire miniswine.

Intervention  The swine developed metabolic syndrome by consuming a high-calorie, high–fat/cholesterol diet for 11 weeks. Pigs were fed either a normal diet (control) (n = 7), a hypercholesterolemic diet (HCC) (n = 7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d) (HCRV) (n = 7). Animals underwent dextrose challenge prior to euthanasia and tissue collection.

Main Outcome Measures  Measurements of glucose and insulin levels, skeletal muscle and liver protein expression, and liver function test results.

Results  The HCC group had significantly increased blood glucose levels at 30 minutes as compared with the control and HCRV groups. The HCC group demonstrated increased fasting serum insulin levels and levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Oil red O staining demonstrated increased lipid deposition in the livers of the HCC animals. Immunoblotting in the liver showed increased levels of mammalian target of rapamycin, insulin receptor substrate 1, and phosphorylated AKT in the HCRV group. Immunoblotting in skeletal muscle tissue demonstrated increased glucose transporter type 4 (Glut 4), peroxisome proliferating activation receptor γ coactivator 1α, peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor γ, and phosphorylated AKT at threonine 308 expression as well as decreased retinol binding protein 4 in the HCRV group. Immunofluorescence staining for Glut 4 in the skeletal muscle demonstrated increased Glut 4 staining in the HCRV group compared with the HCC or control groups.

Conclusion  Supplemental resveratrol positively influences glucose metabolism pathways in the liver and skeletal muscle and leads to improved glucose control in a swine model of metabolic syndrome.