Apolipoprotein CIII Is Associated With Risk Of Diabetes And Defines A High-density Lipoprotein Subtype That Isn't Protective.

Background: Apolipoprotein CIII (apoCIII) is a proinflammatory protein that may affect insulin sensitivity by promoting β-cell apoptosis. ApoCIII is present on some lipoproteins (HDL, LDL and VLDL). We hypothesized that the presence of apoCIII on HDL may modulate the inverse association of HDL with risk of diabetes. Aim: To investigate relations of concentrations of apoCIII in plasma, the concentration of apoCIII in HDL, and HDL subtypes defined according to presence and absence of apoCIII with risk of diabetes. Methods: Concentrations of total apoCIII, apoCIII in HDL, and HDL-cholesterol in plasma separated according to apoCIII (by immunoaffinity chromatography) were assessed in 3,459 initially healthy women and men from the prospective Danish Diet, Cancer and Health Study. Between 1994 and 2007, 439 incident diabetes events occurred. We used standard inverse probability weighted estimators to resample the original study population (n=57,053). Results: In multivariable Cox regression models, total apoCIII concentration was statistically significantly associated with risk of diabetes (Hazard Ratio [HR] was 3.5, 95% CI=1.9-6.5 comparing extreme quintiles). The concentration of apoCIII within HDL was not associated with risk of diabetes, but when HDL was separated according to presence and absence of apoCIII, only HDL without apoCIII was inversely associated with diabetes (HR= 0.5, 95% CI=0.3-0.9 comparing extreme quintiles), whereas HDL with apoCIII was not associated with diabetes (HR= 1.0, 95% CI= 0.5-2.0)(Figure). The associations of the two HDL fractions were significantly different (p for heterogeneity = 0.002) and added significant information above and beyond the measure of total HDL (p=0.01). Conclusion: ApoCIII is associated with risk of diabetes. Further, while the concentration of apoCIII in HDL is not associated with diabetes risk, the presence of apoCIII on HDL may mark a dysfunctional subtype of HDL that lacks a protective association with diabetes. [ABSTRACT FROM AUTHOR]