Insulin resistance (IR) precedes the onset of Type 2 diabetes, but its impact on preconditioning against myocardial ischemia-reperfusion injury is unexplored. We examined the effects of diazoxide and ischemic preconditioning (IPC; 5-min ischemia and 5-min reperfusion) on ischemia (30 min)-reperfusion (240 min) injury in young IR Zucker obese (ZO) and lean (ZL) rats. ZO hearts developed larger infarcts than ZL hearts (infarct size: 57.3 +/- 3% in ZO vs. 39.2 +/- 3.2% in ZL; P < 0.05) and also failed to respond to cardioprotection by IPC or diazoxide (47.2 +/- 4.3% and 52.5 +/- 5.8%, respectively; P = not significant). In contrast, IPC and diazoxide treatment reduced the infarct size in ZL hearts (12.7 +/- 2% and 16.3 +/- 6.7%, respectively; P < 0.05). The mitochondrial ATP-activated potassium channel (K(ATP)) antagonist 5-hydroxydecanoic acid inhibited IPC and diazoxide-induced preconditioning in ZL hearts, whereas it had no effect on ZO hearts. Diazoxide elicited reduced depolarization of isolated mitochondria from ZO hearts compared with ZL (73 +/- 9% in ZL vs. 39 +/- 9% in ZO; P < 0.05). Diazoxide also failed to enhance superoxide generation in isolated mitochondria from ZO compared with ZL hearts. Electron micrographs of ZO hearts revealed a decreased number of mitochondria accompanied by swelling, disorganized cristae, and vacuolation. Immunoblots of mitochondrial protein showed a modest increase in manganese superoxide dismutase in ZO hearts. Thus obesity accompanied by IR is associated with the inability to precondition against ischemic cardiac injury, which is mediated by enhanced mitochondrial oxidative stress and impaired activation of mitochondrial K(ATP).
Abstract-This study assessed the effect of metformin treatment on insulin, mean arterial pressure (MAP), and endothelial function in insulin-resistant (IR) rats. In addition, we assessed the direct effect of metformin in vitro. Sprague-Dawley rats were randomized to control (nϭ28) or IR (nϭ28) groups. Rats were further randomized to receive metformin (300 mg/kg) or placebo for 2 weeks. MAP and insulin were measured. Subsequently, a third-order branch of the superior mesenteric artery was isolated, and endothelial function was assessed. Specifically, dose-response experiments of acetylcholine (ACh) with or without N-nitro-L-arginine (LNNA) were performed. For in vitro experiments, mesenteric arteries were removed from untreated control and IR rats and treated with metformin (100 mol/L) before AChϮLNNA. MAP and insulin levels were improved in IR-metformin compared with IR-placebo rats. Maximal relaxation (E max ) to ACh was enhanced in IR-metformin (92Ϯ2%) compared with IR-placebo rats (44Ϯ4%) (PϽ0.05). Relaxation in response to AChϩLNNA was greater in IR-metformin (33Ϯ4%) than in IR-placebo rats (12Ϯ4%) but remained depressed compared with control rats (E max ϭ68Ϯ5%). The control group was not affected by metformin. In vitro treatment of arteries with metformin in response to ACh produced results similar to those in the experiments with metformin-treated rats. Although metformin improves metabolic abnormality in IR rats, this action does not appear to mediate its effect on vascular function. Both in vivo and in vitro metformin improved ACh-induced relaxation in IR rats to control levels, apparently through nitric oxide-dependent relaxation. These data suggest that metformin improves vascular function through a direct mechanism rather than by improving metabolic abnormalities. Key Words: insulin resistance Ⅲ relaxation Ⅲ metformin Ⅲ nitric oxide Ⅲ blood pressure E xcess cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus) is not explained by the presence of traditional cardiovascular risk factors. 1,2 In addition, glucose control with traditional agents, such as sulfonylureas or insulin, does not alter the risk of macrovascular complications. 3 Epidemiological and observational studies suggest that insulin resistance (IR) may play a role in the development of vascular disease in type 2 diabetes mellitus. 4 -6 Moreover, a recent study has shown that treatment of obese type 2 diabetes mellitus patients with metformin, an insulinsensitizing agent, improves cardiovascular sequelae. 7 Taken together, these data suggest that IR is an important risk factor for the development of cardiovascular disease. Unfortunately, the underlying mechanism(s) by which IR promotes vascular disease remains unknown. Previous data from our laboratory and others suggest endothelial dysfunction as a possible mechanism linking IR to vascular disease. 8,9 Specifically, we have shown that endothelium-dependent relaxation is impaired in IR rats because of a defect in nitric o...
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