Methylglyoxal (MG) is a reactive dicarbonyl compound mainly formed during glucose and fructose metabolism. Diabetic patients have increased plasma levels of MG. Our laboratory has shown that treatment with MG induces insulin resistance and type II diabetes in male Sprague-Dawley rats. However, the increases in endogenous MG level attained in different organs and its contribution to the pathogenesis of diabetes following the administration of either high glucose or high fructose diet have not been addressed. The present study aims to investigate whether the harmful effects induced by increased consumption of glucose and/or fructose is linked to increased MG generation. In vitro studies have suggested that L-arginine is an effective MG scavenger. Accordingly, another goal is to determine whether L-arginine pretreatment would scavenge MG under in vivo setting and reduce the harmful effects of hyperglycemia. MG and reduced glutathione (GSH) levels were determined in plasma and urine and in different organs of male Sprague-Dawley rats after 12 weeks of treatment with either high fructose or high glucose diet. GSH plays an important role in the degradation of MG and bears an inverse relationship with the levels of MG. The key results obtained suggest that both diets significantly increased blood pressure and plasma MG levels. A high fructose but not a high glucose diet, increased the plasma total cholesterol, triglycerides levels and total cholesterol/HDL ratio in parallel with the increases in MG and GSH levels in the liver. Increased MG levels seen in both aorta and mesenteric artery induced by high glucose or fructose diet was attenuated by pretreatment with L-arginine. These findings suggest that elevated MG level induced by treatment with high carbohydrate diets in both conduit (aorta) and resistance type (mesneteric artery) vessels may be linked to endothelial dysfunction seen in hyerglycemic/diabetic states. High glucose but not high fructose diet significantly increased MG levels in the pancreas. This observation is consistent with the well-known glucotoxicity caused by hyperglycemia in the pancreas. Taken together, these data provide the first evidence that elevated MG levels in certain organs/tissues following consumption of high fructose and/or glucose diet(s) may play a critical role in contributing to the metabolic abnormalities and the endothelial dysfunction that precedes the onset of macro and microvascular complications in either hyperglycemic and/or type II diabetic states. Interestingly, quenching of elevated MG levels in tissues by pretreamtent with L-arginine overcomes MG-induced vascular damage and endothelial dysfunction caused by high fructose and high glucose diet regimens.

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