Effect of a Low Volume Exercise Intervention on the Plasma Lipidome in People with Normal Glucose, Prediabetes or Type 2 Diabetes: A Randomised Controlled Trial.

High-intensity interval training (HIIT) may improve metabolic outcomes in people with type 2 diabetes (T2D) and prediabetes (PD). This randomised controlled trial assessed plasma lipidomic differences between overweight participants (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-weeks. 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 to 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 utilise 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-week HIIT+PRT protocol significantly reduces deoxyceramides in individuals with T2D independently of the plasma L-alanine:L-serine ratio.