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Is methylglyoxal a causative factor for the pathogenesis of type 2 diabetes mellitus and endothelial dysfunction?



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The number of people having diabetes mellitus is increasing worldwide at an alarming rate. An unbalanced diet rich in carbohydrates and saturated fats, obesity and lack of physical activity, are being blamed. The worldwide prevalence of diabetes for all age-groups has been estimated to be 2.8% in 2000 and projected to be 4.4% by the year 2030. The pathogenesis of diabetes, especially the recent epidemic increase in type 2 diabetes, is still far from clear. Endothelial dysfunction, commonly defined as reduced endothelium-dependent relaxation due to reduced availability of the vasodilator mediator nitric oxide (NO), is a hallmark of diabetes mellitus. Methylglyoxal (MG) is a highly reactive dicarbonyl compound mainly formed as an intermediate during glycolysis. MG is also formed to a lesser extent from protein and amino acid metabolism. However, the relative contribution of various metabolic precursors to MG formation is not known. Levels of MG have been found to be elevated in diabetic and hypertensive conditions but it is not known whether MG is the cause or the effect of these pathological conditions. The aim of my project was (i) to quantify the amount of MG and oxidative stress produced from various substrates in cultured A10 vascular smooth muscle cells (VSMCs), (ii) to investigate the acute in vivo effects of a single dose of MG on glucose tolerance in male Sprague-Dawley (SD) rats, (iii) to investigate the effects of MG on endothelial function and (iv) to investigate the effects, and the underlying molecular mechanisms, of chronic administration of MG on glucose homeostasis in male SD rats. The results show that aminoacetone, a protein metabolism intermediate, is the most potent substrate for MG formation on a molar basis, whereas D-glucose and fructose are equipotent. I also established optimum sample preparation protocols for reproducible measurement of MG in biological samples by high performance liquid chromatography (HPLC). In normal SD rats a single acute dose of MG induced glucose intolerance, reduced adipose tissue glucose uptake and impaired the insulin signalling pathway, which was prevented by the MG scavenger and advanced glycation end product (AGE) breaking compound, alagebrium (ALT-711). MG and high glucose (25 mM) induced endothelial dysfunction in rat aortic rings and cultured endothelial cells by reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177, activity and NO production. MG and high glucose also increased oxidative stress and further reduced NO availability in rat aortic rings and cultured endothelial cells. Chronic administration of MG in normal SD rats by continuous infusion with a subcutaneously implanted minipump for 28 days (60 mg/kg/day), induced metabolic and biochemical abnormalities of glucose homeostasis and insulin regulation that are characteristic of type II diabetes. In MG treated rats, insulin stimulated glucose uptake in adipose tissue, and glucose stimulated insulin release from freshly isolated pancreas, were significantly reduced as compared to saline treated control rats. At a molecular level, insulin gene transcription was significantly impaired and apoptosis and DNA fragmentation were more prevalent in the pancreas of MG treated rats as compared to untreated control rats. All of these in vivo effects of MG were attenuated by the MG scavenger, alagebrium. Our data strongly indicate that MG is a causative factor in the pathogenesis of endothelial dysfunction and type 2 diabetes mellitus.



Methylglyoxal, insulin resistance, endothelial dysfunction, type 2 diabetes



Doctor of Philosophy (Ph.D.)






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