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

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 hypoth-esis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2+/+) and heterozygous knockout mice (sod2+/2) were fed a chow or high-fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were per-formed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2+/2 and sod2+/+ but was markedly decreased in HF-fed sod2+/2. Remarkably, this impairment was not paralleled by re-duced HG glucose infusion rate (GIR). Decreased GSI