Amerindians, particularly Pima Indians, are at high risk for type 2 diabetes (T2D). Our previous studies have shown that lipid levels (high triglycerides or TG, and low HDL-cholesterol, or HDL-C) are important predictors of T2D incidence. There are few data on the extent to which apolipoprotein levels, particularly apolipoprotein CIII (apoC-III), which is a potential therapeutic target to treat high TG, predict T2D. Thus, we examined whether circulating apolipoprotein levels predict T2D risk in addition to known risk factors. We measured serum TG, HDL-C and 5 apolipoprotein levels (apoA-I, apoA-V, apoB100, apoC-III, apoE), in 1,916 nondiabetic Pima Indians at baseline (mean age=31.2±10 years, 43% male). After mean follow-up of 6.26 years, ∼24% of subjects (n=454) developed T2D.

BMI, HDL-C and TG predicted T2D, when adjusted for sex and age (hazard ratio [HR] per s.d. unit was 1.05, 0.74 and 1.18, respectively; all p<0.0005). TG had moderate correlation with apoC-III (r=0.68), apoE (r=0.56) and HDL-C (r=-0.31). With adjustment for age and sex, only apoA-V predicted T2D incidence (HR=1.12 P=0.02). When effects of BMI, HDL-C, TG and each one of 5 apoliproteins were evaluated together, the apoA-V effect was attenuated (HR=1.09, p=0.08). However, higher apoC-III was protective for T2D incidence (HR for apoC-III=0.83, p=0.007; HR=1.43, 0.87, and 1.29 for BMI, HDL-C, and TG, respectively, all p<0.05). Formal significance testing for apoC-III effect showed that it has distinct predictive value for T2D incidence in addition to TG (0.008). As TG and apoC-III are positively correlated, apoC-III may be a risk factor for T2D. However, our findings suggest that, controlled for BMI, TG and HDL-C levels, apoA-I, apoA-V, apoB100 and apoE add little information about T2D risk prediction, whereas higher apoC-III is associated with reduced T2D risk. The mechanisms underlying this association are not presently known.


W. Hsueh: None. M. Walter: None. R. Nelson: None. W.C. Knowler: None. R.L. Hanson: None.


National Institutes of Health

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