Enhanced potential for oxidative stress in hyperinsulinemic rats: Imbalance between hepatic peroxisomal hydrogen peroxide production and decomposition due to hyperinsulinemia

Oxidative stress is involved in aging and age-related diseases. Several met abolic alterations similar to those encountered with aging and age-related diseases have been observed in response to hyperinsulinemia. Surprisingly, this metabolic derangement diminished hepatic peroxisomal beta-oxidation wh ich is a major source of H2O2 production in the liver, suggesting a protect ive effect against oxidative stress. However, the impact of hyperinsulinemi a on the balance between H2O2 production and elimination in the liver is no t known. Consequently, this study was undertaken to evaluate the effect of sustained high serum insulin levels on the activity of hepatic catalase, a peroxisomal antioxidant enzyme involved in the decomposition of H2O2. Male Sprague-Dawley rats received intravenous infusion of either 30 % glucose, 3 0 % galactose or normal saline for seven days. Activity of hepatic peroxiso mal beta-oxidation and catalase decreased 58% and 74%, respectively, in glu cose-infused rats compared with galactose- or saline-infused animals. When infused simultaneously with glucose, diazoxide blocked glucose-enhanced ins ulin secretion and prevented the decrease in peroxisomal enzyme activities, without altering blood glucose concentration. Neither diazoxide alone nor galactose, which did not alter serum insulin levels, had any effect on enzy me activities. These results suggest that hyperinsulinemia is responsible f or the decreased enzyme activities observed in glucose-infused rats. Indeed , a strong negative correlation between serum insulin levels and hepatic pe roxisomal enzyme activities was found. To investigate the mechanism by whic h insulin modulates catalase activity, we studied rates of synthesis and de gradation of catalase in saline- and glucose-infused rats. Data show that i nsulin diminishes rates of catalase synthesis, while exhibiting no effect o n its degradation. Upsetting the balance between the cellular capacity to p roduce and eliminate H2O2 may be a contributing factor to the known deleter ious effects of hyperinsulinemia.