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

L Kang, C Dai, ME Lustig, JS Bonner, WH Mayes… - Diabetes, 2014 - Am Diabetes Assoc
L Kang, C Dai, ME Lustig, JS Bonner, WH Mayes, S Mokshagundam, FD James…
Diabetes, 2014Am Diabetes Assoc
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) …
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.
Am Diabetes Assoc