Lipidomic markers of habitual physical activity and risk of type 2 diabetes in American Indians

Research is needed to identify lipidomic markers associated with habitual physical activity (PA) among American Indian adults and examine their associations with diabetes risk. We performed LC-MS to quantify 1,542 fasting plasma lipids from 1,779 participants at baseline and 1,406 at follow-up (about 5.5-year apart). PA was objectively measured using pedometers at both visits. We identified lipids associated with PA using mixed-effects linear regression, adjusting for BMI and other covariates. Logistic and linear regression was used to evaluate the associations of PA-related lipids with incident diabetes/prediabetes and glucose/insulin metrics. Mediation role of lipids was examined. Among 1,047 participants with normal fasting glucose at baseline, 68 developed diabetes and 178 developed prediabetes. PA was associated with 127 lipids (q < 0.05), including positive associations with glycerophospholipids and inverse associations with triacylglycerols. Eighteen of the 36 annotated lipids were associated with incident diabetes/prediabetes, with 16 linked to lower PA and higher diabetes risk. Most PA-related lipids were also associated with changes in glucose/insulin metrics, and 28 lipids mediated the positive association between PA and insulin sensitivity. Overall, we identified lipidomic signatures of PA among American Indians. These lipids were associated with diabetes risk, potentially through mediating the protective effects of PA on insulin sensitivity.