Arterial insulin resistance in Yucatan micropigs with diet-induced obesity and metabolic syndrome

J Diabetes Complications. Jul-Aug 2013;27(4):307-15. doi: 10.1016/j.jdiacomp.2013.02.009. Epub 2013 Apr 2.

Abstract

Aim: Metabolic syndrome affects a large proportion of the population and increases cardiovascular disease risk. Because metabolic syndrome often co-exists clinically with atherosclerosis, it is difficult to distinguish the respective contributions of the components to vascular abnormalities. Accordingly, we utilized a porcine dietary model of metabolic syndrome without atherosclerosis to investigate early abnormalities of vascular function and signaling.

Methods: Thirty-two Yucatan micropigs were fed either a high-fat, high-simple-sugar, high-calorie (HFHS) or standard chow diet (STD) for 6 months. Neither diet contained added cholesterol. Blood pressure and flow-mediated vasodilatation were assessed at baseline and 6 months. Aortas were harvested at 6 months to assess histology, insulin signaling, and endothelial nitric oxide (eNOS) phosphorylation.

Results: HFHS pigs developed characteristics of metabolic syndrome including obesity, dyslipidemia, and insulin resistance, but without histologic evidence of atherosclerosis. Although arterial intima-media thickness did not differ between groups, vascular dysfunction in HFHS was manifest by increased blood pressure and impaired flow-mediated vasodilation of the femoral artery. Compared with STD, aortas from HFHS exhibited increased p85α expression and Ser307 IRS-1 phosphorylation, and blunted insulin-stimulated IRS-1-associated phosphatidylinositol (PI) 3-kinase activity. In the absence of insulin stimulation, aortic Akt Ser473-phosphorylation was greater in HFHS than in STD. With insulin stimulation, Akt phosphorylation increased in STD, but not HFHS. Insulin-induced Ser1177-phosphorylation of eNOS was decreased in HFHS, compared with STD.

Conclusions: Pigs with metabolic syndrome develop early vascular dysfunction and aortic insulin signaling abnormalities, and could be a useful model for early human vascular abnormalities in this condition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arteries / metabolism
  • Diet
  • Disease Models, Animal
  • Female
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / physiology*
  • Male
  • Metabolic Syndrome / complications*
  • Metabolic Syndrome / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Obesity / complications*
  • Obesity / etiology
  • Obesity / metabolism*
  • Phosphorylation
  • Swine
  • Swine, Miniature*
  • Vasodilation

Substances

  • Insulin Receptor Substrate Proteins
  • Nitric Oxide Synthase Type III