Sphingosine 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. Levels 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. Comparison 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). Circulating 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.

中文翻译：

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鉴定循环鞘氨醇激酶相关代谢物以预测 2 型糖尿病

将鞘氨醇 (Sph) 催化为 1-磷酸鞘氨醇 (S1P) 的鞘氨醇激酶 (SphK) 在鞘脂代谢和细胞信号传导中都起着关键作用。虽然 SphK 与 2 型糖尿病 (T2DM) 有关联，但尚未在人类中进行探索。在此，我们在已建立的前瞻性队列中研究了循环 SphK 相关代谢物是否与 T2DM 发病率相关。通过靶向脂质组学分析测量血清中 SphK 相关鞘脂代谢物的水平，包括 Sph、S1P、二氢鞘氨醇 (dhSph) 和二氢-S1P (dhS1P)。通过访问一个既定的前瞻性队列，该队列在基线时涉及总共 2486 名非糖尿病成人，100 名在平均随访 4.2 年后发展为 T2DM 的受试者，以及 100 名对照受试者严格匹配年龄、性别、BMI 和空腹血糖，被随机纳入本研究。与对照组相比，基线时血清 dhS1P 和 dhS1P/dhSph 比值的中位数在 T2DM 发病前显着升高。dhS1P 和 dhS1P/dhSph 比率的每个 SD 增量分别与 53.5% 和 54.1% 的糖尿病发病风险增加相关。循环 dhS1P 和 dhS1P/dhSph 比值对 T2DM 发病率的预测作用与多元回归模型中的常规风险因素无关。此外，血清 dhS1P 和 dhS1P/dhSph 比值与常规临床指标的结合显着提高了 T2DM 预测的准确性（AUROC，0.726），尤其是对于血糖正常的受试者（AUROC，0.859）。dhS1P 的循环水平和 dhS1P/dhSph 比率与 T2DM 风险增加密切相关，