Effects of glucose and insulin on the development of oxidative stress and hypertension in animal models of type 1 and type 2 diabetes.

摘要

OBJECTIVES: To investigate whether glucose or insulin is the cause of increases in oxidative stress and blood pressure in insulin-resistant animals, and to evaluate the effects of alpha-lipoic acid (LA) on the production of the superoxide anion (O2) in the aorta and blood pressure elevations in various models of diabetes. METHODS: Two models of arterial hypertension combined with insulin resistance state and one model of insulin-dependent diabetes were studied in chronically glucose-fed rats (10% in drinking water), in animals chronically treated simultaneously with insulin (9 mU/kg per min with osmotic pumps) and glucose, and in rats initially treated with streptozotocin (50 mg/kg) and glucose during 4 weeks. These three groups of rats were treated either with a normal chow diet or with LA-supplemented diet. The oxidative stress was evaluated by the O2 production using the lucigenin-enhanced chemiluminescence method either in aortic or cultured smooth muscle cells from 12-week-old normotensive rats. Fasting blood glucose and insulin levels were measured after 4 weeks. RESULTS: At the end of the study, plasma levels of insulin and glucose as well as the insulin resistance index were found to be significantly higher in glucose-fed rats or in rats treated with insulin plus glucose compared with control rats (P < 0.01). Plasma glucose levels were elevated (P < 0.01) but plasma insulin levels were not modified in streptozotocin- and glucose-treated rats. Systolic blood pressure and aorta O2 production were found to be significantly higher in either glucose-fed rats (+20%) or in insulin plus glucose-treated rats (+24%) as compared with control rats (P < 0.01). Streptozotocin-induced diabetes with glucose treatment was not accompanied by increases in systolic blood pressure or in aortic O2 production. Rises in systolic blood pressure and in aortic O2 production were significantly attenuated either in glucose-fed (+10.3%) or in insulin plus glucose-fed (+8.7%) rats treated with LA. The simultaneous treatment with LA also attenuated the rise in insulin levels as well as in insulin resistance either in glucose-fed rats or in insulin plus glucose-treated rats. Moreover, LA was found to prevent the marked increases in O2 production in cultured smooth muscle cells chronically treated with high insulin combined or not with high glucose levels. CONCLUSIONS: These findings demonstrate that elevated plasma glucose levels alone do not induce vascular oxidative stress and hypertension unless it is combined with high level of insulin. The finding that the treatment with LA, a potent antioxidant, was efficacious in preventing oxidative stress and hypertension in diabetic models of insulin resistance suggests an important participation of oxidative stress in the development of hypertension in type 2 diabetes.