Association of serum very long-chain saturated fatty acids with changes in insulin sensitivity and beta-cell function: the PROspective Metabolism and Islet cell Evaluation (PROMISE) cohort.

A unique group of circulating very long-chain saturated fatty acids (VLCSFA), including arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), have been associated with lower risk of type 2 diabetes, although associations with early metabolic risk phenotypes preceding type 2 diabetes have received limited study. We aimed to examine the associations of VLCSFA with longitudinal changes in insulin sensitivity and beta-cell function in a cohort at risk of type 2 diabetes. VLCSFA in the four main serum pools (phospholipid, triacylglycerol, cholesteryl ester, and non-esterified fatty acid) were extracted from fasting baseline samples (n=467). Generalized Estimating Equations were used to determine the associations between VLCSFA and changes over 9 years in validated indices of insulin sensitivity (HOMA2-%S and ISI) and beta-cell function (IGI, IGI/IR and ISSI-2). Associations of VLCSFA with outcomes were strongest in the triacylglycerol lipid pool: 20:0 was positively associated with both insulin sensitivity and beta-cell function (5.01% increase in HOMA2-%S and 4.01-6.28% increase in IGI/IR and ISSI-2 per SD increase in 20:0); 22:0 was positively associated with insulin sensitivity with 6.55% increase in HOMA2-%S and a 5.80% increase in ISI per SD increase in 22:0. Lastly, 24:0 was positively associated with insulin sensitivity and beta-cell function (7.94-8.45% increase in HOMA2-%S and ISI, and 4.61-6.93% increase in IGI/IR and ISSI-2 per SD increase in 24:0). Fewer significant associations were observed in the cholesteryl ester and non-esterified pools. Overall, our results indicate positive longitudinal associations of VLCSFA with insulin sensitivity and beta-cell function, especially within the triacylglycerol pool.