Reduction in Mn‐superoxide dismutase (SOD2) corrects insulin resistance due to high fat feeding in oxidative tissues of mice

Abstract

SOD2 is a mitochondrial antioxidant enzyme responsible for converting superoxide radical to H2O2. Certain levels of H2O2 are essential while excessive levels are harmful to normal metabolic function. We hypothesized that reducing the formation of H2O2 by decreasing SOD2 expression by 50% would improve metabolic function. SOD2+/−mice and wild type (WT) littermates (n=14/13) were chow or high fat fed (HF) for 3 months. Catheters were placed in the jugular vein and carotid artery. 5 days later a hyperinsulinemic glucose clamp was performed. 2‐deoxyglucose was given for analysis of tissue glucose uptake. Body weight, 5 h fasted blood glucose or insulin levels were not different between SOD2+/− and WT on either diet. Glucose infusion rate (mg/kg/min) to maintain euglycemia was similar in SOD2+/− and WT on chow (49±4 vs 49±6) and HF (32±3 vs 35±4). The rates of glucose uptake (Rg; μmol/100gtissue/min) in vastus lateralis muscle were not different between SOD2+/−and WT on either diet. Heart Rg was significantly higher in SOD2+/−compared to WT (174±9 vs 130±13) but there was no difference in diaphragm Rg (46±19 vs 46±8) on chow. WT mice on HF had impaired insulin stimulated glucose uptake in heart (71±9) and diaphragm (22 ± 3). Heart Rg (167±26) and diaphragm Rg (157±12) were not impaired by HF in SOD2+/−. A 50% reduction in SOD2 activity corrects the HF induced insulin resistance that occurs in highly oxidative tissues, such as diaphragm and heart. Supported by DK 54902 and DK 59637