Skeletal muscle and plasma lipidomic signatures of insulin resistance and overweight/obesity in humans

OBJECTIVE: Alterations in lipids in muscle and plasma have been documented in insulin‐resistant people with obesity. Whether these lipid alterations are a reflection of insulin resistance or obesity remains unclear. METHODS: Nondiabetic sedentary individuals not treated with lipid‐lowering medications were studied (n = 51). Subjects with body mass index (BMI) > 25 kg/m(2) (n = 28) were stratified based on median glucose infusion rate during a hyperinsulinemic‐euglycemic clamp into insulin‐sensitive and insulin‐resistant groups (above and below median, obesity/insulin‐sensitive and obesity/insulin‐resistant, respectively). Lean individuals (n = 23) served as a reference group. Lipidomics was performed in muscle and plasma by liquid chromatography electrospray ionization‐tandem mass spectrometry. Pathway analysis of gene array in muscle was performed in a subset (n = 35). RESULTS: In muscle, insulin resistance was characterized by higher levels of C18:0 sphingolipids, while in plasma, higher levels of diacylglycerol and cholesterol ester, and lower levels of lysophosphatidylcholine and lysoalkylphosphatidylcholine, indicated insulin resistance, irrespective of overweight/obesity. The sphingolipid metabolism gene pathway was upregulated in muscle in insulin resistance independent of obesity. An overweight/obesity lipidomic signature was only apparent in plasma, predominated by higher triacylglycerol and lower plasmalogen species. CONCLUSIONS: Muscle C18:0 sphingolipids may play a role in insulin resistance independent of excess adiposity.