OBJECTIVE: LDL particles are heterogeneous in terms of size and density; small dense LDL particles are considered more atherogenic than larger LDL particles. The aim of this study was to investigate the interrelationships among LDL size, insulin, proinsulin (intact and split), and insulin sensitivity in a tri-ethnic population with varying degrees of glucose tolerance (n = 1,549) in the Insulin Resistance Atherosclerosis Study. RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test with minimal model analysis. Proinsulin levels were measured using highly sensitive assays without detectable cross-reactivity with insulin, and LDL size was determined by gradient-gel electrophoresis. RESULTS: In univariate analyses, LDL size was related to various features of the insulin resistance syndrome, including fasting insulin (r = -0.18), intact proinsulin (r = -0.24), split proinsulin (r = -0.24), the proinsulin-to-insulin ratio (r = -0.14), and insulin sensitivity (r = 0.21; all P < 0.0001). In a multivariate regression model (adjusted for age, BMI, ethnicity, and clinic), triglyceride levels (P = 0.0001), HDL cholesterol (P = 0.0001), sex (P = 0.002), and proinsulin (P = 0.01) were significantly related to LDL size. In the same model stratified by sex, LDL size was significantly inversely related to proinsulin in men (P = 0.005 and P = 0.04 after further adjustment for the glucose tolerance status), but not in women (P > 0.15). CONCLUSIONS: We found an inverse relation of proinsulin to LDL particle size in a large tri-ethnic population with varying degrees of glucose tolerance. This relation was independent of age, BMI, and triglyceride and HDL cholesterol concentrations, and was more pronounced in men than in women.

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