Heterozygous SOD2 Deletion Impairs Glucose-Stimulated Insulin Secretion, but not Insulin Action in High Fat-Fed Mice

  1. Alvin C. Powers1,4,6
  1. 1Department of Molecular Physiology and Biophysics and
  2. 2Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN 37232;
  3. 3Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK;
  4. 4Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
  5. 5East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC 27858;
  6. 6Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232
  1. Address correspondence to: Li Kang, E-mail: l.kang{at}dundee.ac.uk


Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2+/+) and heterozygous knockout mice (sod2+/-) were fed chow or high fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2+/- and sod2+/+ but was markedly decreased in HF-fed sod2+/-. Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2+/- was associated with increased ROS, such as O2˙ˉ. Surprisingly, insulin action determined by HI clamps, did not differ between sod2+/- and sod2+/+ of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2+/- was due to increased glucose effectiveness. Increased GLUT1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2+/- support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action.

  • Received December 4, 2013.
  • Accepted June 10, 2014.

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  1. Diabetes
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