Enhanced mitochondrial superoxide scavenging does not Improve muscle insulin action in the high fat-fed mouse

Improving mitochondrial oxidant scavenging may be a viable strategy for the treatment of insulin resistance and diabetes. Mice overexpressing the mitochondrial matrix isoform of superoxide dismutase (sod2^tg mice) and/or transgenically expressing catalase within the mitochondrial matrix (mcat^tg mice) have increased scavenging of O₂^.ˉ and H₂O₂, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcat^tgmice. The goal of the current study was to test the hypothesis that increased O₂^.ˉ scavenging alone or in combination with increased H₂O₂ scavenging (mtAO mice) enhances in vivo muscle insulin action in the HF-fed mouse. Insulin action was examined in conscious, unrestrained and unstressed wild type (WT), sod2^tg , mcat^tg and mtAO mice using hyperinsuline-mic-euglycemic clamps (insulin clamps) combined with radioactive glucose tracersfollowing sixteen weeks of normal chow or HF (60% calories from fat) feeding. Glucose infusion rates, whole body glucose disappearance, and muscle glucose uptake during the insulin clamp were similar in chow- and HF-fed WT and sod2^tg mice. Consistent with ourprevious work, HF-fed mcat^tg mice had improved muscle insulin action, however, an additive effect was not seen in mtAO mice. Insulin-stimulated Akt phosphorylation in musclefrom clamped mice was consistent with glucose flux measurements. These results demonstrate that increased O₂^.ˉ scavenging does not improve muscle insulin action in the HF-fedmouse alone or when coupled to increased H₂O₂ scavenging.