Persistent abnormalities in lipoprotein composition in noninsulin-dependent diabetes after intensive insulin therapy

Abstract

To determine whether rigorous insulin therapy, which normalized the routinely measured plasma lipids, also reversed qualitative abnormalities in the composition of lipoproteins in noninsulin-dependent diabetes mellitus (NIDDM), we studied 18 NIDDM patients (eight men and 10 women) before and 2 months after intensive insulin therapy. Glycosylated hemoglobin levels (11.7% vs. 8.7%), plasma triglyceride (TG) (250±91 vs. 164±56 mg/dl, p<0.001), and cholesterol (214±43 vs. 198±31 mg/dl, p<0.025) all fell, and both HDL2 cholesterol and HDLg cholesterol increased (59.1% and 10.9%, respectively, p<0.001). However, abnormalities in two indices of lipoprotein surface constituents, which were present before insulin therapy, remained so thereafter. The first of these, the new cardiovascular risk factor, the plasma free cholesterol/lecithin ratio, which was increased before treatment, fell only slightly after therapy (pre-therapy 1.02±0.29 vs. post-therapy 0.90±0.17, p<0.4; reference group, 0.83±0.14), and remained elevated in very low density lipoprotein (VLDL) and low density lipoprotein (LDL). Secondly, the sphingomyelin/lecithin ratio, an index of the surface rigidity of lipoproteins, was abnormal before treatment in VLDL, HDL2, and HDL3, and this alteration persisted after insulin therapy in HDL3 (p<0.001). Lipoprotein core lipid abnormalities were also present before treatment: the TG/cholesteryl ester ratio was reduced in VLDL and increased in LDL, HDL2, and HDL3. Rigorous insulin therapy improved, but failed to fully correct, this disturbance. In HDL2, apolipoprotein (apo) A-I increased significantly (p<0.005), and apo A-II and apo E were unchanged; in contrast, in HDL3, apo A-I was unchanged, and apo A-II and apo E both decreased (p<0.005) after insulin therapy. Since lipoproteins with altered surface and core lipids have been shown to have an impaired capacity to transfer their constituents to other lipoproteins and cells and compromised participation in reverse cholesterol transport, persistence of these qualitative changes may sustain the increased cardiovascular risk in NIDDM even when clinical control is excellent and the routinely measured plasma lipids appear normal.