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

摘要

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 a 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 superoxide ion. 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 GLUT-1, 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.