Plasma sphingosine 1-phosphate concentrations and cardiovascular autonomic neuropathy in individuals with type 2 diabetes

Abstract

The aim of this study was to test the hypothesis that plasma sphingosine 1-phosphate (S1P) levels are associated with the risk of cardiovascular autonomic neuropathy (CAN) in type 2 diabetes patients. This cross-sectional study included 287 individuals with type 2 diabetes. CAN was evaluated using cardiovascular reflex tests. Logistic regression analyses were conducted to assess the relationship between plasma S1P levels and CAN. Plasma S1P concentrations were significantly lower in individuals with CAN than in those without CAN. There was a significant interaction between plasma S1P levels and sex with respect to CAN (p for interaction = 0.003). When stratified by sex, the association between plasma S1P levels and CAN exhibited a sex difference; in multivariable analysis, plasma S1P levels were significantly associated with CAN in women (odds ratio per standard deviation increase in the log-transformed value, 0.40; 95% confidence interval, 0.23-0.70, p = 0.001). However, there was no significant association between plasma S1P and CAN in men. Plasma S1P concentrations were inversely associated with CAN only in women with type 2 diabetes. Cardiovascular autonomic neuropathy (CAN) is a common but overlooked complication of diabetes mellitus (DM) 1. CAN involves damage to the autonomic nervous system that innervate the heart and blood vessels 2 , and it is thought to be implicated in silent myocardial ischemia, hemodynamic instability, stroke, cardiovascular mortality, and perioperative cardiovascular liability in individuals with type 2 DM 2,3. While poor glycemic control, diabetes duration, and hypertension play important roles in the pathogenesis of CAN 4 , CAN risk cannot be entirely explained by these conventional risk factors, suggesting that other factors may also have an influence on its pathogenesis. Sphingosine 1-phosphate (S1P), a metabolite of sphingolipids, is a bioactive lipid mediator which regulates cell differentiation, proliferation, apoptosis, and inflammation 5. Accumulating evidence indicates that S1P plays important physiologic roles in the central and peripheral nervous systems 6,7. Furthermore, S1P plays a crucial role in neural development 6. In addition, several investigations have shown that decreased S1P levels may be related to neurodegenerative disease, suggesting that it also plays a neuroprotective role 8. However, although S1P has been implicated in neurological disorders, the relationship between S1P and CAN in individuals with type 2 DM has not been clarified. In the present study, we tested the hypothesis that plasma S1P levels are associated with CAN risk in individuals with type 2 DM. Methods Study population. This cross-sectional study included 287 individuals with type 2 DM. We consecutively enrolled individuals with type 2 DM who visited the diabetes clinic at our hospital. Type 2 DM was diagnosed based on the "Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus" 9. Individuals were regarded as having hypertension if they had a blood pressu...

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