The interaction between glucose levels and body mass index on the regulation of circulating sphingolipidome in humans

<b>Background.</b> Circulating sphingolipids have been associated with diabetes risk and chronic complications. This study characterized the sphingolipidome in a subset of the CA.ME.LI.A. cohort to identify lipid signatures related to sex, body mass index (BMI), and fasting glucose levels. <b>Methods.</b> 367 subjects (217 men) were stratified into six groups based on BMI (normal weight or overweight/obese) and fasting glucose levels (normal, impaired, or diabetes). Circulating sphingolipids were measured by LC-MS/MS. The effects of BMI, glucose levels, and their interaction on the sphingolipidome were analyzed using a two-way ANOVA model. <b>Results.</b> Women showed higher circulating sphingolipid levels than men, except for ganglioside GM3. Glucose levels produced relevant changes on hexosyl- and lactosylceramides, which were significantly reduced in subjects with diabetes, independently of BMI. Some ceramide and sphingomyelin species also varied only according to glucose levels. Dihydroceramide 18:0 and 24:1 were higher in overweight/obese subjects, whereas sphingomyelin 18:1 and GM3 24:0 were higher in normal-weight individuals. Gangliosides GM3 were higher in normal body weight with normal glucose levels and impaired fasting glucose as compared to overweight obese of the same categories. Sphingomyelin 18:1, GM3 24:1, sphingosine, and dihydrosphingosine-1-phosphate levels were significantly regulated by both BMI and glucose. In overweight/obese individuals, sphingosine-1-phosphate and dihydrosphingosine-1P levels were reduced in impaired fasting glucose and diabetes. <b>Conclusions.</b> The circulating sphingolipidome differs in men and women, being modulated by BMI and glucose levels. These data support the concept that sphingolipids could be novel biomarkers for obesity, diabetes and associated complications.