Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications.
Protein alteration resulting from a nonenzymatic reaction between ambient glucose and primary amino groups on proteins to form glycated residues called Amadori products is termed the Maillard reaction. By dehydration and fragmentation reactions, Amadori products are transformed to stable covalent adducts called advanced glycosylation end products (AGEs). In diabetes, accelerated synthesis and tissue deposition of AGEs is proposed as a contributing mechanism in the pathogenesis of clinical complications. Uremia in diabetes is associated with both a high serum level of AGEs and accelerated macro- and microvasculopathy. Diabetic uremic patients accumulate advanced glycosylated end products in "toxic" amounts that are not decreased to normal by hemodialysis or peritoneal dialysis but fall sharply to within the normal range within 8 h of restoration of half-normal glomerular filtration by renal transplantation. It follows that the higher mortality of hemodialysis-treated diabetic patients compared with those given a renal transplant may relate, in part, to persistent AGE toxicity. Pharmacologic prevention of AGE formation is an attractive means of preempting diabetic microvascular complications because it bypasses the necessity of having to attain euglycemia, an often unattainable goal. Pimagidine (aminoguanidine) interferes with nonenzymatic glycosylation and reduces measured AGE levels leading to its investigation as a potential treatment. The mechanism by which pimagidine prevents renal, eye, nerve, and other microvascular complications in animal models of diabetes is under investigation. Separate multicenter clinical trials of pimagidine in type 1 and type 2 diabetes, where proteinuria is attributable to diabetic nephropathy, are in progress. The effect of treatment on the amount of proteinuria, progression of renal insufficiency, and the course of retinopathy will be monitored.
Friedman
E A
EA
Department of Medicine, State University of New York, Health Science Center at Brooklyn, NY 11203, USA. elifriedmn@aol.com
D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D002986:Clinical Trials as Topic; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D000449:Aldehyde Reductase; D011493:Protein Kinase C; C004479:pimagedine