The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including α-oxoaldehydes, which are inherently toxic as well as serving as presursors for advanced glycation end-products. Protective mechanisms exist to control this unavoidable glycation, and these are determined by genetic or environmental factors that can regulate the concentrations of the reactive sugars or end-products. In diabetes these protective mechanisms become more important, since glycation stress increases, and less efficient defence systems against this stress could lead to diabetic complications. Some of these enzymatic control mechanisms, including those that regulate α-oxoaldehydes, have been identified. We have observed significant increases in production of the α-oxoaldehydes methylglyoxal and 3-deoxyglucosone in three human populations with biopsy-proven progression of nephropathy. The increase in methylglyoxal could be secondary to defects in downstream glycolytic enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) that regulate its production, or in detoxification mechanisms such as glyoxalase. Other mechanisms, however, appear to be responsible for the observed increase in 3-deoxyglucosone levels. We present results of our studies on the mechanisms responsible for variable production of α-oxoaldehydes by measuring the activity and characteristics of these enzymes in cells from complication-prone and -resistant diabetic patients. New therapeutic interventions designed to control these endogenous mechanisms could potentially enhance protection against excessive glycation and prevent or reverse complications of long-term diabetes.
Conference Article| December 01 2003
α-Oxoaldehyde metabolism and diabetic complications
P.J. Beisswenger 1
*Department of Medicine, Diabetes, Endocrinology and Metabolism, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, U.S.A.
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Biochem Soc Trans (2003) 31 (6): 1358–1363.
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P.J. Beisswenger, S.K. Howell, R.G. Nelson, M. Mauer, B.S. Szwergold; α-Oxoaldehyde metabolism and diabetic complications. Biochem Soc Trans 1 December 2003; 31 (6): 1358–1363. doi: https://doi.org/10.1042/bst0311358
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