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 (sod2tg mice) and/or transgenically expressing catalase within the mitochondrial matrix (mcattg mice) have increased scavenging of O2˙ˉ and H2O2, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcattg mice. 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), sod2tg, mcattg 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 sod2tg mice. Consistent with our previous work, HF-fed mcattg 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 O2˙ˉ scavenging does not improve muscle insulin action in the HF-fed mouse alone or when coupled to increased H2O2 scavenging.
Highlights
Overnutrition can lead to the development of insulin resistance and type 2 diabetes
Mice with transgenic expression of catalase, a peroxisomal enzyme, within the mitochondrial matrix are a model of enhanced mitochondrial H2O2 scavenging in striated muscle [13]. mcattg mice have increased lifespan [13] and we have recently demonstrated that mcattg mice are partially protected against diet-induced insulin resistance [3]
We examined the independent and combined effects of enhanced scavenging of O2_ˉ and H2O2 in the muscle of high fat (HF)-fed mice using sod2tg, mcattg and mcattg and double transgenic (mtAO) double transgenic mice generated by crossing sod2tg and mcattg [4]
Summary
Overnutrition can lead to the development of insulin resistance and type 2 diabetes. Increased production of mitochondrial oxidant species has been proposed as central to the etiology of diet-induced insulin resistance [1]. In the presence of overnutrition, the mitochondrial electron transport system (ETS) is overloaded with electrons donated from reducing equivalents (e.g. NADH and FADH2), resulting in the increased production of membrane impermeable superoxide ion (O2_ˉ). O2_ˉ is dismutated by manganese superoxide dismutase (SOD2) to hydrogen peroxide (H2O2). Both O2_ˉ and H2O2 have been proposed to serve as metabolic sensors functionally linking redox biology to insulin sensitivity [2, 3]. Increased O2_ˉ scavenging by increased SOD2 activity has been proposed to have beneficial effects on muscle insulin sensitivity. This proposal is complicated by the fact that O2_ˉ scavenging comes at the expense of increased H2O2 production [4]
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