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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