Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action in high fat-fed mice

Li Kang (Lead / Corresponding author), Chunhua Dai, Mary E. Lustig, Jeffrey S. Bonner, Wesley H. Mayes, Shilpa Mokshagundam, Freyja D. James, Courtney S. Thompson, Chien-Te Lin, Christopher G. R. Perry, Ethan J. Anderson, P. Darrell Neufer, David H. Wasserman, Alvin C. Powers

    Research output: Contribution to journalArticlepeer-review

    37 Citations (Scopus)


    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?-. 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.
    Original languageEnglish
    Pages (from-to)3699-3710
    Number of pages12
    Issue number11
    Early online date19 Jun 2014
    Publication statusPublished - Nov 2014


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