Probucol Normalizes Cholesteryl Ester Transfer in IDDM

Abstract

OBJECTIVE Cholesteryl ester transfer (CET) is pathologically increased in insulin-dependent diabetes mellitus (IDDM), and the resulting enrichment of the apolipoprotein B-containing lipoproteins with cholesteryl ester (CE) is believed to increase their atherogenicity. Because we have shown previously that treatment with the lipid-modifying antioxidant probucol normalizes CET in nondiabetic patients with hypercholesterolemia, we sought to determine whether the same beneficial effects could be achieved in IDDM. RESEARCH DESIGN AND METHODS CET was measured by both mass and isotopic assay in eight normolipidemic (triglyceride, 102; cholesterol, 192; high-density lipoprotein [HDL] cholesterol, 45 mg/dl) IDDM patients (fructosamine 495 ± 146 μmol/l; normal 174–286) before and after 2 months of treatment with probucol (1.0 g/day). RESULTS Before treatment, CET was accelerated abnormally (P < 0.001). As expected, probucol decreased plasma (−13%; P < 0.025) and HDL2 cholesterol levels (−52%; P < 0.025) and the concentration of lipoprotein A-I particles (P < 0.025). In conjunction with these changes, CET fell dramatically in all subjects (mass assay: −94%; isotopic assay: −22%, P < 0.001) with no change in the mass of cholesteryl ester transfer protein (CETP) (pretreatment 2.91 ± 0.97 vs. posttreatment 3.21 ± 1.03 μg/ml). Glycemic control, however, improved significantly (fructosamine 409 ± 85 μmol/l, P < 0.025). CONCLUSIONS Because it is believed that accelerated CET promotes the formation of apolipoprotein B-containing lipoproteins enriched with atherogenic CE, the capacity of probucol to reverse this functional abnormality without adversely affecting glycemic control suggests that it has a place in the therapy of IDDM.