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

Abstract

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 O 2 - and H 2 O 2, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcat tg mice. The goal of the current study was to test the hypothesis that increased O 2 - scavenging alone or in combination with increased H 2 O 2 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 hyperinsulinemic-euglycemic clamps (insulin clamps) combined with radioactive glucose tracers following 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 our previous 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 muscle from clamped mice was consistent with glucose flux measurements. These results demonstrate that increased O 2 .- scavenging does not improve muscle insulin action in the HF-fed mouse alone or when coupled to increased H 2 O 2 scavenging.