Abstract
BackgroundSphingosine Kinase (SphK) that catalyzes sphingosine (Sph) to sphingosine 1-phosphate (S1P), plays a key role in both sphingolipid metabolism and cellular signaling. While SphK has been implicated in type 2 diabetes mellitus (T2DM), it is unexplored in humans. Herein, we investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort.MethodsLevels of SphK-related sphingolipid metabolites, including Sph, S1P, dihydrosphingosine (dhSph) and dihydro-S1P (dhS1P) in serum were measured by targeted-lipidomic analyses. By accessing to an established prospective cohort that involves a total of 2486 non-diabetic adults at baseline, 100 subjects who developed T2DM after a mean follow-up of 4.2-years, along with 100 control subjects matched strictly with age, sex, BMI and fasting glucose, were randomly enrolled for the present study.ResultsComparison with the control group, medians of serum dhS1P and dhS1P/dhSph ratio at baseline were elevated significantly prior to the onset of T2DM. Each SD increment of dhS1P and dhS1P/dhSph ratio was associated with 53.5% and 54.1% increased risk of incident diabetes, respectively. The predictive effect of circulating dhS1P and dhS1P/dhSph ratio on T2DM incidence was independent of conventional risk factors in multivariate regression models. Furthermore, combination of serum dhS1P and dhS1P/dhSph ratio with conventional clinical indices significantly improved the accuracy of T2DM prediction (AUROC, 0.726), especially for normoglycemic subjects (AUROC, 0.859).ConclusionCirculating levels of dhS1P and dhS1P/dhSph ratio are strongly associated with increased risk of T2DM, and could serve as a useful biomarker for prediction of incident T2DM in normoglycemic populations.
Highlights
Type 2 diabetes mellitus (T2DM) is a major global health problem that currently affects 463 million people over the world [1]
Circulating levels of the Sphingosine Kinase (SphK)‐related sphingolipid metabolites in mice Because no established methodology currently available for measuring SphK activity in vivo, we applied Sphk1-deficient (Sphk1−/−) and Sphk2-deficient (Sphk2−/−) mice to measure circulating levels of the key sphingolipid metabolites that are mostly relevant to SphK activity, including Sph, dhSph, sphingosine 1-phosphate (S1P) and dhS1P, using HPLC–MS/MS-based targeted-lipidomic analyses
The circulating dhS1P/dhSph ratio was not significant altered by Sphk1−/−, a decrease trend existed (Fig. 1)
Summary
Type 2 diabetes mellitus (T2DM) is a major global health problem that currently affects 463 million people over the world [1]. We have recently reported that global deletion of Sphk in mice resulted in a significant loss of pancreatic β-cell mass and promoted the onset of diabetes [9], whereas Sphk deficiency ameliorated diabetic phenotype by protecting β-cells against lipoapoptosis [10] These findings indicate that both SphK1 and SphK2 are critically involved in the regulation of β-cell viability and function in opposite directions. We have reported that hepatocytespecific deficiency of SphK2 in mice increased hepatic glucose production, impaired glucose homeostasis and caused insulin resistance [12] It appears that SphK is critically involved in both insulin resistance and β-cell failure, suggesting a crucial role in diabetes. We investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort
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