Advance Glycation End Products

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Extended exposure of proteins to hyperglycemia can result in nonenzymatic reactions, in which the condensation of glucose with primary amines forms Schiff bases. These products can rearrange to form Amadori products and advanced glycation end-products (AGE). The glycation process occurs both intracellularly and extracellularly. It has been reported that the glycation modification target to intracellular signaling molecules and extracellular structure proteins alike, and furthermore, alter cellular functions. Multiple forms of proteins subjected to glycation have been identified with W£-(carboxymethyl)lysine (CML), pentosidine, and pyralline being the major form of AGEs presented in diabetic states.

A significant role for AGE in diabetic vascular complications is supported by their increased serum concentration in diabetic states (45,46). Infusion of AGE into animals without diabetes reproduces some pathological abnormalities in vasculature similar to that in diabetes (47). Furthermore, inhibition of AGE formation can partly prevent pathological changes in diabetic animals. Treatment of diabetic rats with aminoguanidine, an inhibitor of AGE formation and inducible nitric oxide synthase, can prevent the progression of both diabetic nephropathy (48) and retinopathy (49), evidenced by the reduction of albuminuria; mesangial expansion; endothelial cell proliferation; pericyte loss; and even the formation of microaneurysms. Other inhibitors of protein glycation, such as OPB-9195 (50) or ALT-711 (51) have yielded similar results in animals with diabetes.

Recently, receptor for advanced glycation end-products (RAGE) has received substantial attention in its role in endothelial cell dysfunction in diabetes, especially in the development of atherosclerosis (52). RAGE belongs to the immunoglobulin superfamily and has been reported to express in vascular cells including endothelial cells and SMCs (53). Accumulation of RAGE has been reported in the vasculature in diabetic states (46,47). Infusion of RAGE is associated with vascular hyperpermeability similar to that in diabetes and these changes can be neutralized in the presence of soluble RAGE (sRAGE) (47), the extracellular domain of RAGE that disrupt AGE-RAGE interaction. Additionally, when mice deficient for apolipoprotein (apo)E (apoE-/-) were induced to have type 1-like diabetes by streptozotocin injection, they developed much more advanced atherosclerotic lesions in their aorta as compared to the apoE-/- mice without diabetes (46) and the progression of the atherosclerotic lesion can be reversed by intraperitoneal injection of sRAGE (46). Although the molecular and cellular mechanisms underlying RAGE-induced vascular permeability change is still not fully understood, it is postulated that the induction of vascular oxidative stress (54); activation of PKC and other intracellular signaling events (55); and inflammation (56).

These results provide supportive evidence suggesting an important role for AGE formation and RAGE activation in the development of diabetic vascular complications. The AGE-RAGE axis could therefore potentially be a target for clinical interventions. Indeed, aminoguanidine is currently being evaluated in a clinical trial for its effect on the progression of nephropathy in type 2 diabetes in 599 patients across United States and Canada (57). However, majority of the results were obtained from animal studies and an affirmative role for AGE in the pathogenesis of diabetic vascular complications require further clinical evaluations.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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