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

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. Three hundred sixty-seven 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. Women showed highercirculating 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 sphingomyelinspecies 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 bodyweight with normal glucose levels and impaired fasting glucose as compared with overweight obese individuals of the same categories. Sphingomyelin 18:1, GM3 24:1, sphingosine, and dihydrosphingosine-1-phosphate levels were significantly regulated by both BMIand glucose. In overweight/obese individuals, sphingosine-1-phosphate and dihydrosphingosine-1P levels were reduced in impairedfasting glucose and diabetes. 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.NEW & NOTEWORTHY Sphingolipid glycosylation is an enzymatic process that does not follow the pattern of nonenzymatichemoglobin glycosylation. Unexpectedly, hexosyl- and lactosylceramides decreased in impaired fasting glucose and diabetes,with and without obesity. On the other hand, dihydroceramides increased in overweight/obesity with prediabetes/diabetes. Thecirculating sphingolipidome is differentially regulated in humans according to sex, glucose, and BMI.