Heterozygous SOD2 Deletion Impairs Glucose-Stimulated Insulin Secretion, but not Insulin Action in High Fat-Fed Mice
- Li Kang1,2,3⇑,
- Chunhua Dai4,
- Mary E. Lustig1,
- Jeffrey S. Bonner1,
- Wesley H. Mayes1,
- Shilpa Mokshagundam1,
- Freyja D. James1,
- Courtney S. Thompson4,
- Chien-Te Lin5,
- Christopher G. R. Perry5,
- Ethan J. Anderson5,
- P. Darrell Neufer5,
- David H. Wasserman1,2 and
- Alvin C. Powers1,4,6
- 1Department of Molecular Physiology and Biophysics and
- 2Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN 37232;
- 3Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK;
- 4Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN 37232;
- 5East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC 27858;
- 6Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232
- Address correspondence to: Li Kang, E-mail:
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.
- © 2014 by the American Diabetes Association.
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