HDL and reverse cholesterol transport in diabetes

Despite the fact that numerous epidemiological studies and clinical experience have documented the very high incidence of macrovascular disease in diabetes, conventional risk factors account for no more than similar to 25% of this excess risk, It is therefore clear that a number of other processes, some of which are unique to the diabetic state, are operative that accelerate atherogenesis. Among the fruitful avenues of investigation of the pathophysiology of diabetic vascular disease has been the recognition that the transfer of neutral lipids (GET) among the lipoproteins in plasma, a process mediated by a 74-kDa transfer protein (CETP), is pathologically increased in both IDDM and NIDDM, and the severity of this defect correlates directly with glycemic central and plasma triglyceride concentrations, One consequence of this disturbance is that subpopulations of triglyceride-rich lipoproteins become enriched with cholesteryl ester (CE) and resemble postprandial particles that are believed to be highly atherogenic. Because CETP also has the capacity to transfer lipoprotein phospholipids, its actions can significantly alter lipoprotein composition and possibly predispose affected particles to further modifications, This defect in CET appears to be related to iatrogenic hyperinsulinemia associated with conventional subcutaneous insulin treatment, because it is fully reversed in insulin-requiring IDDM and NIDDM subjects when insulin levels are lowered by administering insulin directly into the portal circulation from an implanted pump with an intraperitoneal catheter. Since the placement of pancreas allografts in the pel iis results in systemic hyperinsulinemia, CET remains abnormally increased after pancreas transplantation in IDDM. CET is normal, however, when the transplanted pancreas drains into the portal circulation, which normalizes insulin levels, In both IDDM and NIDDM, this disturbance in CET results from abnormal behavior of qualitatively altered lipoproteins and not from changes in CETP mass, Evidence supporting the mechanism is that treatment with marine lipids (i.e., fish oil) containing omega-3 fatty acids and the antioxident probucol, both of which are lipophilic and alter the lipoprotein core and surface composition, corrects the abnormality in GET. Because CET is pathologically increased when glycemic control is poor, plasma triglyceride is elevated, and hyperinsulinemia is present, this disturbance occurs frequently in diabetic patients and may be a major pathway fur increasing populations of lipoprotein particles with enhanced atherogenicity.