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Diabetes 54:3274-3281, 2005
© 2005 by the American Diabetes Association, Inc.

Susceptibility to Diabetic Nephropathy Is Related to Dicarbonyl and Oxidative Stress

Paul J. Beisswenger1, Keith S. Drummond2, Robert G. Nelson3, Scott K. Howell1, Benjamin S. Szwergold1, and Michael Mauer4

1 Department of Medicine, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Hanover and Lebanon, New Hampshire
2 Department of Pediatrics, McGill University, Montreal, Quebec, Canada
3 Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
4 Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota

Dicarbonyl and oxidative stress may play important roles in the development of diabetes complications, and their response to hyperglycemia could determine individual susceptibility to diabetic nephropathy. This study examines the relationship of methylglyoxal, 3-deoxyglucosone (3DG), and oxidative stress levels to diabetic nephropathy risk in three populations with diabetes. All subjects in the Overt Nephropathy Progressor/Nonprogressor (ONPN) cohort (n = 14), the Natural History of Diabetic Nephropathy study (NHS) cohort (n = 110), and the Pima Indian cohort (n = 45) were evaluated for clinical nephropathy, while renal structural measures of fractional mesangial volume [Vv(Mes/glom)] and glomerular basement membrane (GBM) width were determined by electron microscopy morphometry in the NHS and Pima Indian cohorts. Methylglyoxal and 3DG levels reflected dicarbonyl stress, while reduced glutathione (GSH) and urine 8-isoprostane (8-IP) measured oxidative stress. Cross-sectional measures of methylglyoxal production by red blood cells incubated in 30 mmol/l glucose were increased in nephropathy progressors relative to nonprogressors in the ONPN (P = 0.027) and also reflected 5-year GBM thickening in the NHS cohort (P = 0.04). As nephropathy progressed in the NHS cohort, in vivo levels of methylglyoxal (P = 0.036), 3DG (P = 0.004), and oxidative stress (8-IP, P = 0.007 and GSH, P = 0.005) were seen, while increased methylglyoxal levels occurred as nephropathy progressed (P = 0.0016) in the type 2 Pima Indian cohort. Decreased glyceraldehyde-3-phosphate dehydrogenase activity also correlated with increased methylglyoxal levels (P = 0.003) in the NHS cohort. In conclusion, progression of diabetic nephropathy is significantly related to elevated dicarbonyl stress and possibly related to oxidative stress in three separate populations, suggesting that these factors play a role in determining individual susceptibility.

Address correspondence and reprint requests to Paul J. Beisswenger, MD, Department of Medicine, Diabetes, Endocrinology and Metabolism, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr., Lebanon, NH 03756. E-mail: paul.j.beisswenger{at}dartmouth.edu

Abbreviations: 3DG, 3-deoxyglucosone; 8-IP, 8-isoprostane; AGE, advanced glycation end product; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GBM, glomerular basement membrane; GFR, glomerular filtration rate; GSH, reduced glutathione; HPLC, high-performance liquid chromatography; NHS, Natural History Study; ONPN, Overt Nephropathy Progressor/Nonprogressor; PCA, perchloric acid; RBC, red blood cell; UAE, urinary albumin excretion


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