Effect of a low-volume exercise intervention on the plasma lipidome in people with normal glucose, prediabetes or type 2 diabetes: a randomized controlled trial.

High-intensity interval training (HIIT) may improve metabolic outcomes in people with type 2 diabetes (T2D) and prediabetes (PD). This randomized controlled trial assessed plasma lipidomic differences between overweight participants [body mass index (BMI) > 25 kg/m2] with normal glucose tolerance (NGT) (n = 74), PD (n = 60) or newly-diagnosed T2D (n = 26), and the effects of a combined HIIT and progressive resistance training (PRT) intervention on circulating lipids. Participants were randomized to either a stretching or HIIT + PRT protocol. Fasted plasma was collected at baseline and after 12 wk. Plasma lipids, d- and l-serine, and d- and l-alanine were quantified with liquid chromatography-tandem mass spectrometry. Plasma lipidomics revealed significantly lower levels of sphingomyelin and lysophosphatidylcholine (LPC) and higher diacylglycerol and deoxyceramide species in T2D compared with NGT or PD. The HIIT + PRT intervention significantly reduced circulating deoxyceramides in the T2D group. We investigated the basis for elevated atypical deoxyceramides in T2D, which use l-alanine rather than l-serine as biosynthetic substrates. Serine levels were unchanged; however, l-alanine and d-alanine were increased in T2D. Total diacylglycerol, l-alanine, and d-alanine positively correlated with fasting glucose, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), glycated hemoglobin, and liver fat, whereas sphingomyelin and LPC inversely correlated with fasting glucose and HOMA-IR. The l-alanine:l-serine ratio positively correlated with deoxyceramide levels, but was unaltered by the HIIT + PRT intervention. This study reveals plasma lipidomic perturbations in T2D, establishing that excess l-alanine may underpin elevated metabolically-adverse deoxyceramide levels in T2D, and demonstrates that a 12-wk HIIT + PRT protocol significantly reduces deoxyceramides in individuals with T2D independently of the plasma l-alanine:l-serine ratio.NEW & NOTEWORTHY We have found that the baseline plasma lipidome differs substantially between people who are overweight with normal glucose tolerance or prediabetes, compared with type 2 diabetes, and that the 12-wk exercise protocol instituted reduces levels of metabolically adverse potentially toxic deoxyceramide species in type 2 diabetes. Moreover, excess plasma l-alanine levels may account for the baseline elevated deoxyceramides. This study thus identifies that low-volume exercise can improve novel aspects of the lipidome in metabolic health.