Debate over the deleterious effect of hyperglycemia in the pathogenesis of diabetic complications has ended. Large prospective controlled studies of the relationship between glycemic control and progression of diabetic retinopathy, nephropathy, and neuropathy all point in one direction: hyperglycemia is injurious and is directly linked to tissue damage. Exactly how a high ambient glucose concentration causes protein damage is a story that has been progressively told over the past 20 years starting with Cerami’s observation that the level of glycosylated hemoglobin correlated with the degree of glucose regulation. As reviewed by Vlassara, a prime contributor to establishing the central role of advanced glycosylated endproducts (AGEs), these toxic molecules may be incriminated in pathologic changes of aging, atherosclerosis, Alzheimer’s disease as well as diabetes. Nephrologists suspect that AGEs may be linked to the crippling amyloidosis with arthritis that afflicts long-term hemodialysis patients. In this report, a newly recognized threat of AGEs absorbed from cooked foods is assessed. There is hope of muting the damage caused by AGEs in diabetic individuals by at least three strategies: (1) limiting synthesis of AGEs by optimizing glucose regulation; (2) pharmacologic intervention to block the glycoxidation pathway using inhibitors like aminoguanidine; (3) breaking existing AGE-cross-links by administering novel chemical agents now in investigation. Clinical trials to determine whether aminoguanidine will favorably alter the course of nephropathy in type 1 and type 2 diabetes, as well as the high mortality of diabetic patients treated by maintenance hemodialysis, are nearing completion. It is probable that this fresh direction in the therapy — if successful — may reduce the often futile striving to sustain euglycemia as the only means of preserving eyes and kidneys in diabetes.
KeywordsDiabetic Nephropathy Diabetic Retinopathy Advance Glycation Endproducts United States Renal Data System Advanced Glycosylation
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- 5.Diabetes Control & Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 14: 977–986.Google Scholar
- 18.Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker LJ. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci USA 1992; 89: 2873–2877.PubMedCrossRefGoogle Scholar
- 24.Kirstein M, Brett J, Radoff S, Ogawa S, Stern D, Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci USA 1990; 87: 9010–9014.PubMedCrossRefGoogle Scholar
- 26.Schmidt AM, Vianna M, Gerlach M, Brett J, Ryan J, Kao J, Esposito C, Hegarty H, Hurley W, Clauss M et al. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem 1992; 267: 14987–14997.PubMedGoogle Scholar
- 27.Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem !□ □@; 267: 14998–15004.Google Scholar
- 32.Wing AJ, Brunner FP, Brynger HOA, Jacobs C, Kramer P. Comparative review between dialysis and transplantation. In: Drukker W, Parsons FM, Maher JF (eds.), Replacement of Renal Function by Dialysis. Dordrecht, The Netherlands; 1986: 850–871.Google Scholar
- 35.USRDS. United States Renal Data System. NIH, NIDDKD 1992.Google Scholar
- 42.Cho HK, Kozu H, Peyman GA, Parry GJ, Khoobehi B. The effect of aminoguanidine on the blood-retinal barrier in streptozotocin-induced diabetic rats. Ophthal Surg 1991; 22: 44–47.Google Scholar
- 46.Stitt AW, Friedman S, Scher L, Rossi P, Ong H, Founds H, Bucala R, Vlassara H. Carotid Artery Advanced Glycation Endproducts and Their Receptors Correlate with Severity of Lesion and with Plasma AGE-ApoB Levels in Non-Diabetic Patients. 96 FASEB Meeting (Abstract) 1996.Google Scholar
- 47.Cerami C, Founds H, Nicholl I, Mitsuhashi T, Giordano D, VanPatten S, Lee A, Al-Abed Y, Vlassara H, Bucala R, Cerami A. Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci USA 1998; in press.Google Scholar