CONTEXT: HDL in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects.

OBJECTIVE: We investigated the prospective associations between HDL subspecies containing and lacking apoC-III at baseline and insulin sensitivity at year 3.

DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 864 healthy volunteers drawn from the RISC study, a multi-center European clinical investigation, whose recruitment initiated in 2002 with a follow-up of 3 years.

MAIN MEASURES: Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT) at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich ELISA-based method.

RESULTS: The two 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 VLDL and 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.

CONCLUSION: 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.