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 metabolic 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 β-oxidation which is a major source of H₂O₂ production in the liver, suggesting a protective effect against oxidative stress. However, the impact of hyperinsulinemia on the balance between H₂O₂ production and elimination in the liver is not 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, 30% galactose or normal saline for seven days. Activity of hepatic peroxisomal β-oxidation and catalase decreased 58% and 74%, respectively, in glucose-infused rats compared with galactose- or saline-infused animals. When infused simultaneously with glucose, diazoxide blocked glucose-enhanced insulin 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 enzyme activities. These results suggest that hyperinsulinemia is responsible for the decreased enzyme activities observed in glucose-infused rats. Indeed, a strong negative correlation between serum insulin levels and hepatic peroxisomal enzyme activities was found. To investigate the mechanism by which insulin modulates catalase activity, we studied rates of synthesis and degradation of catalase in saline- and glucose-infused rats. Data show that insulin diminishes rates of catalase synthesis, while exhibiting no effect on its degradation. Upsetting the balance between the cellular capacity to produce and eliminate H₂O₂ may be a contributing factor to the known deleterious effects of hyperinsulinemia.

Key words

Syndrome X - Oxidative Stress - Antioxidants - Peroxisomal Metabolism - Obesity