Xu L, Badr M Z
Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, USA.
Horm Metab Res. 1999 Apr;31(4):278-82. doi: 10.1055/s-2007-978733.
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 beta-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 beta-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.
氧化应激与衰老及年龄相关疾病有关。在高胰岛素血症的情况下，已观察到几种类似于衰老和年龄相关疾病中出现的代谢改变。令人惊讶的是，这种代谢紊乱减少了肝脏过氧化物酶体β-氧化，而肝脏过氧化物酶体β-氧化是肝脏中过氧化氢产生的主要来源，提示对氧化应激有保护作用。然而，高胰岛素血症对肝脏中过氧化氢产生与清除平衡的影响尚不清楚。因此，本研究旨在评估持续高血清胰岛素水平对肝脏过氧化氢酶活性的影响，过氧化氢酶是一种参与过氧化氢分解的过氧化物酶体抗氧化酶。雄性Sprague-Dawley大鼠静脉输注30%葡萄糖、30%半乳糖或生理盐水，持续7天。与输注半乳糖或生理盐水的动物相比，输注葡萄糖的大鼠肝脏过氧化物酶体β-氧化活性和过氧化氢酶活性分别降低了58%和74%。当与葡萄糖同时输注时，二氮嗪可阻断葡萄糖增强的胰岛素分泌，并防止过氧化物酶体酶活性降低，而不改变血糖浓度。单独使用二氮嗪或不改变血清胰岛素水平的半乳糖对酶活性均无影响。这些结果表明，高胰岛素血症是输注葡萄糖大鼠中观察到的酶活性降低的原因。事实上，血清胰岛素水平与肝脏过氧化物酶体酶活性之间存在很强的负相关。为了研究胰岛素调节过氧化氢酶活性的机制，我们研究了输注生理盐水和葡萄糖的大鼠中过氧化氢酶的合成和降解速率。数据显示，胰岛素降低了过氧化氢酶的合成速率，而对其降解没有影响。打破细胞产生和清除过氧化氢能力之间的平衡可能是高胰岛素血症已知有害作用的一个促成因素。
