Distribution of apolipoprotein E in the plasma of insulin-dependent and noninsulin-dependent diabetics and its relation to cholesterol net transport.

Noninsulin-dependent diabetics, whose plasma contained no detectable beta-VLDL (very low density lipoprotein), had a proportion (0.23 +/- 0.04) of plasma apolipoprotein E in the form of an abnormal lipoprotein not recognized by antibodies to apoB-100 from LDL (low density lipoprotein) or apoA-I from HDL (high density lipoprotein). This lipoprotein, abnormally rich in free cholesterol and apoE, had a calculated particle density within the low density lipoprotein range. It competed with LDL at the apoB,E receptor of normal fibroblasts and stimulated cholesteryl ester accumulation in mouse peritoneal macrophages. However, it did not compete with the binding of labeled rabbit beta-VLDL to macrophages. A much lower proportion of apoE (0.04 +/- 0.03) was in this form in the plasma of patients with insulin-dependent diabetes who had a comparable degree of hyperglycemia. The diabetic lipoprotein was absent in normoglycemic control subjects. The net transport of cholesterol from cell membranes to the plasma of noninsulin-dependent diabetics (and to a lesser extent, insulin-dependent diabetics) was inhibited relative to control values, and the magnitude of this inhibition was well correlated with the concentration of the abnormal lipoprotein of diabetes in plasma (r = 0.66 and 0.75, respectively). These findings suggest that diabetic plasma contains an abnormal and novel low density lipoprotein that mediates the abnormal cholesterol transport characteristic of human diabetes mellitus.