MODIFICATION OF LOW-DENSITY-LIPOPROTEIN BY ADVANCED GLYCATION END-PRODUCTS CONTRIBUTES TO THE DYSLIPIDEMIA OF DIABETES AND RENAL-INSUFFICIENCY

Atherosclerosis develops rapidly in patients with diabetes or renal in sufficiency. Plasma lipoprotein profiles are frequently abnormal in th ese conditions and reflect an elevation in the level of the apoprotein B (ApoB)-containing components very low density lipoprotein (VLDL) an d low density lipoprotein (LDL), High levels of circulating advanced g lycation end products (AGEs) also occur in diabetes and end-stage rena l disease (ESRD). These products arise from glucose-derived Amadori pr oducts and include AGE-modified peptides (AGE-peptides) which result f rom the catabolism of AGE-modified tissue proteins. AGE-peptides have been shown to crosslink protein amino groups and to accumulate in plas ma as a consequence of renal insufficiency. To address potential mecha nisms for the dyslipidemia of diabetes and ESRD, we investigated the p ossibility that circulating AGEs react directly with plasma lipoprotei ns to prevent their recognition by tissue LDL receptors. AGE-specific ELISA showed a significantly increased level of AGE-modified LDL in th e plasma of diabetic or ESRD patients compared with normal controls. A GE-LDL formed readily in vitro when native LDL was incubated with eith er synthetic AGE-peptides or AGE-peptides isolated directly from patie nt plasma. LDL which had been modified by AGE-peptides in vitro to the same level of modification as that present in the plasma of diabetics with renal insufficiency exhibited markedly impaired clearance kineti cs when injected into transgenic mice expressing the human LDL recepto r. These data indicate that AGE modification significantly impairs LDL -receptor-mediated clearance mechanisms and may contribute to elevated LDL levels in patients with diabetes or renal insufficiency. This hyp othesis was further supported by the observation that the administrati on of the advanced glycation inhibitor aminoguanidine to diabetic pati ents decreased circulating LDL levels by 28%.