HYPERHOMOCYST(E)INEMIA AND ENDOTHELIAL DYSFUNCTION IN IDDM

OBJECTIVE - While elevated blood levels of homocyst(e)ine represent an independent risk factor for macrovascular disease, we assessed the li nk between hyperhomocyst(e)inemia and diabetic microvascular diseases, RESEARCH DESIGN AND METHODS - Plasma levels of homocyst(e)ine and thr ombomodulin (TM), markers of endothelial cell damage, were measured be fore and 3 h after oral methionine loading in 75 patients with IDDM an d 40 healthy control subjects matched for ser and age. Exclusion crite ria were hyperlipidemia, hypertension, smoking, or positive family his tory for cardiovascular disease. RESULTS - IDDM patients had higher pr e-and postload plasma levels of homocyst(e)ine than did healthy contro l subjects (12.0 vs. 7.7 mu mol/l and 27.6 vs. 16.0 mu mol/l; P < 0.00 1). Of 75 IDDM patients, 26 had plasma homocyst(e)ine levels above the normal range (means +/- 2 SD of values obtained in the control group) . These IDDM patients with hyperhomocyst(e)inemia had higher plasma TM levels (62.2 vs. 38.2 ng/ml, P < 0.001), higher albumin excretion rat es (485 vs. 115 mg/l, P < 0.005), and a higher prevalence of late diab etic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs, 51%; neuropathy, 57 vs. 41%; and macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells showed an increased release of TM int o the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might cont ribute to vascular complications in patients with diabetes. CONCLUSION S - Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardi ovascular diseases characteristically observed in IDDM patients with d iabetic nedhropathy.