Increased Plasma Levels of Remnant Lipoproteins in Diabetes

Although a high prevalence of atherosclerotic diseases is observed in patients with diabetes mellitus, the precise mechanism has been unclear. In order to clarify the contribution of lipoprotein metabolism to the development of atherosclerosis in diabetes, we focussed on the metabolism of plasma remnant lipoproteins.First, lipoprotein profiles in survivors of myocardial infarction (MI) were investigated. A high prevalence of mid-band in lipoprotein electro-phoresis, and increased cholesterol/triglyceride ratio in VLDL and elevated lipid contents in IDL were shown in them. These changes were seen exclusively in patients with MI whose glucose tolerance were impaired.Second, lipoprotein profiles were also analysed in newly-diagnosed patients with diabetes or IGT, who has not yet suffered from atherosclerotic diseases. It revealed that IDL levels in patients with diabetes or IGT were higher than those in age- and sex-matched controls. Furthermore, 5 patients had elevated IDL levels to the extent of familial type 3 hyperlipoproteinemia. But phenotype of apolipoprotein E isoform of them were not E2/2 (E 3/3 in 2 cases, E4/3 in 2, and E 4/2 in 1). Thus, elevation of remnant lipoprotein was seen in diabetes, and plays an important role in occurrence of atherosclerotic diseases.Finally, the mechanism of the remnant accumulation was investigated in experimental animal model. Streptozotocin-diabetic rats showed a marked hyperlipoproteinemia after an exogenous cholesterol load. The degree of elevation of remnants lipoproteins, especially that of chylomicron remnants, in diabetic rats fed a high-cholesterol diet was greatly higher than in non-diabetic rats fed it. When cholesterol-fed animals were treated with 17α-ethinyl estradiol or T3, remnant lipoproteins were disappeared from plasma. These data suggest that some disorder exists in exogenous cholesterol transport in diabetes, and this disorder could be improved by the agents which are known to induce lipoprotein receptors.In conclusion, increased remnant lipoprotein plays important role in coronary atherosclerotic disease in Japan, to which diabetes is closely related. The major mechanism of elevated remnant lipoprotein levels in diabetes might be explained by impaired exogenous cholesterol transport.