ORALLY ABSORBED REACTIVE GLYCATION PRODUCTS (GLYCOTOXINS) - AN ENVIRONMENTAL RISK FACTOR IN DIABETIC NEPHROPATHY

Endogenous advanced glycation endproducts (AGEs) include chemically cr osslinking species (glycotoxins) that contribute to the vascular and r enal complications of diabetes mellitus (DM), Renal excretion of the c atabolic products of endogenous AGEs is impaired in patients with diab etic or nondiabetic kidney disease (KD), The aim of this study was to examine the oral absorption and renal clearance kinetics of food AGEs in DM with KD and whether circulating diet-derived AGEs contain active glycotoxins. Thirty-eight diabetics (DM) with or without KD and five healthy subjects (NL) received a single meal of egg white (56 g protei n), cooked with (AGE-diet) or without fructose (100 g) (CL-diet). Seru m and urine samples, collected for 48 hr, were monitored for AGE immun oreactivity by ELISA and for AGE-specific crosslinking reactivity, bas ed on complex formation with I-125-labeled fibronectin, The AGE-diet, but not the CL-diet, produced distinct elevations in serum AGE: levels in direct proportion to amount ingested (r = 0.8, P < 0.05): the area under the curve for serum (approximate to 10% of ingested AGE) correl ated directly with severity of KD; renal excretion of dietary AGE, alt hough normally incomplete (only approximate to 30% of amount absorbed) , in DM it correlated inversely with degree of albuminuria, and direct ly with creatinine clearance (r = 0.8, P < 0.05), reduced to <5% in DM with renal failure, Post-AGE-meal serum exhibited increased AGE-cross linking activity (two times above baseline serum AGE, three times abov e negative control), which was inhibited by aminoguanidine, In conclus ion, (i) the renal excretion of orally absorbed AGEs is markedly suppr essed in diabetic nephropathy patients, (ii) daily influx of dietary A GEs includes glycotoxins that may constitute an added chronic risk for renal-vascular injury in DM, and (iii) dietary restriction of AGE foo d intake may greatly reduce the burden of AGEs in diabetic patients an d possibly improve prognosis.