Introduction
Diabetes mellitus type 2 (T2DM) remains a major cause of mortality and morbidity worldwide, despite the advances in risk prediction, diagnosis, and management. Traditional risk factors such as impaired fasting glucose (IFG) and impaired glucose tolerance fail to predict almost 50% of the patients who will develop T2DM.1 ,2 This fact has fueled an expanding research pursuit to identify risk factors and novel biomarkers to improve risk prediction.3 ,4 With the progress in mass spectrometry and nuclear magnetic resonance spectroscopy, many blind spots in the human plasma metabolome and lipidome are becoming visible and quantifiable. In fact, several metabolites such as acylcarnitines, amino acids, phospholipids, and also sphingolipids have become candidates of biomarkers for the prediction of future T2DM.5–7
Sphingolipids comprise a heterogeneous class of lipids including free sphingoid bases, ceramides, sphingomyelins, and glycosphingolipids. Sphingoid bases are the shared structural element in all sphingolipids and typically formed by the condensation of l-serine and palmitoyl coenzyme A. This reaction is catalyzed by the enzyme serine palmitoyltransferase (SPT)8–10 forming C18-sphinganine (C18SA), which is then subsequently N-acylated to (dihydro)-ceramides. Ceramides are bioactive lipids which serve as building blocks for the synthesis of complex sphingolipids like sphingomyelins or gylcosphingolipids.
There is increasing evidence that sphingolipids are actively involved in the development of T2DM.11 Ceramides were shown to counteract the insulin action on glucose uptake and glycogen synthesis by inhibiting protein kinase B/Akt through different mechanisms,12 and it was demonstrated recently that many of the beneficial effects of adiponectin on β-cell survival in T2DM are linked to its lowering effect on intracellular ceramide levels.13 Moreover, plasma levels of ceramides were found to be elevated in patients with T2DM14 and to correlate with the degree of insulin resistance in these patients. In contrast, sphingomyelin and gylcosphingolipids were found to be decreased in plasma of diabetic monkeys.15 Myriocin, a potent SPT inhibitor, was shown to improve insulin resistance and preclude the development of T2DM in animal models.16 Apart from the canonical substrates, SPT is also able to metabolize other acyl coenzyme As in the range of C12 to C18, which results in a spectrum of sphingoid bases with variable carbon chain length. Under certain conditions, SPT can also use other amino acids such as l-alanine and partly also glycine as alternative substrates.17 This generates an atypical class of neurotoxic 1-deoxysphingolipids (1-deoxySL) which lack the C1 hydroxyl group of canonical sphingolipids. SPT is positioned at a metabolic cross-point which metabolically interconnects fatty acid, amino acid (serine, alanine, and glycine), and thereby indirectly also the carbohydrate metabolism.
We showed previously that 1-deoxyspingolipids (1-deoxySLs) are significantly elevated in the plasma of individuals with metabolic syndrome (MetS)18 and T2DM.19 In this follow-up study, we aimed to investigate the ability of 1-deoxySLs to predict incident diabetes by analyzing the sphingoid base profile in a prospective cohort with 339 individuals.