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Fatty acid (FA) composition in four serum lipid fractions and the pathogenesis of diabetes: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort

Luke W. Johnston

Background: Evidence suggests specific FAs within serum lipid fractions contribute uniquely to the risk for diabetes. However, limited longitudinal data exist on the role of the FA composition in different lipid fractions and the underlying pathogenesis of diabetes. Our aim was to study the longitudinal associations of FA composition in four lipid fractions with 6-yr changes in insulin sensitivity (IS) and beta-cell function.

Methods: Adults at-risk for diabetes in PROMISE had glucose and insulin measured from an oral glucose tolerance test at 3 visits over 6-yrs (n=477). Baseline fasting FA in phospholipid (PL), cholesteryl ester, triacylglycerol (TAGFA), and non-esterified (NEFA) fractions were quantified using thin-layer-chromatography and gas-chromatography. The inverse of HOMA-IR (1/HOMA-IR) and the Matsuda index assessed IS; the Insulinogenic Index over HOMA-IR (IGI/IR) and the Insulin Secretion-Sensitivity Index-2 (ISSI-2) assessed beta-cell function. Partial least squares and generalized estimating equations was conducted adjusting for visit, sex, ethnicity, baseline age, waist, NEFA, and ALT.

Results: IS and beta-cell function declined by 14-27% over 6-yrs. Total NEFA associated negatively with beta-cell function. In PL, cis-vaccenate associated positively with IS while palmitate associated with declines in beta-cell function. Four TAGFA (14:0, 16:0, 14:1n7, 16:1n17) clustered together to associate with lower IS. Monounsaturated TAGFA tended to associate positively with IS.

Conclusions: These findings reveal fraction and FA specific associations with core abnormalities underlying diabetes, providing a comprehensive view of FA in diabetes pathogenesis. In particular, within the TAGFA, the FA cluster may be indicative of higher de novo lipogenesis of carbohydrates. We hope the results encourage further research on the FA with particularly strong associations, as many of these FA are not well studied.



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