High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. We investigated the prospective associations be Show more
High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. We investigated the prospective associations between HDL subspecies containing and lacking apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment. Show less
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed Show more
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at Show less
We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence. Th Show more
We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence. This study included a cross-sectional analysis of the RISC Study, a multicenter European clinical investigation in 1,017 healthy volunteers balanced in sex (women 54%) and age strata (range 30-60 years). Insulin sensitivity (M/I in µmol ⋅ min(-1) ⋅ kgFFM(-1) ⋅ nM(-1)) was measured by the clamp technique and apolipoproteins (ApoB, -C3, -A1, and -E) by Multiplex Technology. The center-, sex-, and age-adjusted standardized regression coefficients (STDβ) with M/I were similar for HDL and triglycerides (+19.9 ± 1.9 vs. -20.0 ± 2.0, P < 0.0001). Further adjustment for triglycerides (or HDL), BMI, and adiponectin (or nonesterified fatty acid) attenuated the strength of the association of M/I with both HDL (STDβ +6.4 ± 2.3, P < 0.01) and triglycerides (-9.5 ± 2.1, P < 0.001). Neither ApoA1 nor ApoE and ApoB showed any association with M/I independent from plasma HDL cholesterol and triglycerides. ApoC3, in contrast, in both men and women, was positively associated with M/I independently of plasma lipids. A relative enrichment of plasma lipids with ApoC3 is associated with lower body fat percentage and lower plasma alanine amino transferase. Our results suggest that HDL cholesterol modulates insulin sensitivity through a mechanism that is partially mediated by BMI and adiponectin but not by ApoA1. Similarly, the influence of triglycerides on insulin sensitivity is in part mediated by BMI and is unrelated to ApoE or ApoB, but it is significantly modulated by ApoC3, which appears to protect from the negative effect of plasma lipids. Show less