Plasma lipidomics and 15-year risk of incident diabetes: a coronary artery risk development in young adults study

Lipid metabolism has long been implicated in diabetes, but there has been a paucity of population-based studies of the plasma lipidome and incident diabetes in cohorts of early middle age. We used data from the US-based Coronary Artery Risk Development in Young Adults (CARDIA) Study to identify lipidomics associated with 15-year incident diabetes (n = 1,094; n = 162 incident diabetes; [mean (SD) age: 45 (3.6); 58% women; and 59% White race]). Plasma lipidomics was conducted using liquid-chromatography and infusion-mass spectrometry. Diabetes was defined at 5-, 10- and 15-year follow-ups as fasting glucose ≥ 126 mg/dl, 2-h glucose tolerance test ≥ 200 mg/dl, HbA1c ≥ 6.5%, or reported diabetic medication use. We tested associations between individual lipids and incident diabetes with interval-censored, multivariable-adjusted Cox proportional hazards regression, accounting for multiple comparisons. We used differential expression analysis to identify pathways upregulated and downregulated in participants who developed diabetes over the 15-year period. Finally, we used penalized regression (LASSO) to generate a lipid risk score for incident diabetes (0.7 training, 0.3 testing). In hazards regression, 156 lipids including glycerolipids, glycerophospholipids, and sphingolipids, were associated with incident diabetes. Of these, 56 lipids were also selected by LASSO regression as distinguishing participants who developed diabetes from those who did not. The lipid risk score's ability to improve prediction of 15-year incident diabetes past sociodemographic, behavioral, and clinical covariates was limited to the training set. Pathways leading to diacylglycerols and ceramides were upregulated, while pathways leading to hexosylceramides, lysophosphatidylethanolamines, triacylglycerols, and lysophosphatidylcholines were downregulated in incident diabetes cases. Our results in this cohort of early middle-aged adults, supports further investigation into the roles of glycerophospholipid and sphingolipid metabolism in diabetes development, particularly for ceramides and hexosylceramides.