Association of Ceramide and Sphingolipid Species with Incident Prediabetes among Offspring of Parents with Type 2 Diabetes

Objective: Sphingolipids (SPL) have been associated with type 2 diabetes (T2D) risk. Here, we examined plasma SPL profiles in relation to prediabetes risk in Black and White adults. Methods: Assessments included OGTT, insulin sensitivity (Si-clamp) and insulin secretion (AIRg) . Baseline plasma levels of 54 SPL species (ceramides {CER}, monohexosyl ceramides, sphingomyelins {SM}, and sphingosine {SO}) were assayed using LC/mass spectrometry. The initially normoglycemic adult with parental T2D were followed for 5y for the occurrence of prediabetes. Results: The subjects' mean age was 48.1 + 8.69 y, BMI 30.1 + 5.78 kg/m2, fasting plasma glucose (FPG) 92.7 + 5.84 mg/dl and 2-hrPG 121 + 23.3 mg/dl. We analyzed SPL data from 70 progressors to prediabetes (P) and 70 nonprogressors (NP) . After full adjustments, the levels of SO and saturated (Sat) SPLs (C26:0 CER, C26:0 SM) were higher, and unsaturated (Unsat) SPLs (C18:1 CER; C18:1 SM) and SM% of SPL were lower in P vs.NP (Table 1) . CER and SM levels correlated with Si-clamp and AIRg. The Sat/Unsat SPL ratios were higher in P vs. NP. The C18:0/C18:1 CER (OR 1.22, 95%CI [1.07 - 1.39], P=0.0028) and C26:0/C26:1 SM (OR 2.65, 95%CI [1.39 - 5.06], P=0.0032) ratios predicted prediabetes risk after adjusting for age, race, sex, BMI, FPG and 2hPG. Conclusion: The Sat/Unsat ratios of CER and SM C18 and C26 predicted incident prediabetes in a diverse cohort, and may be potential biomarkers of prediabetes risk. Disclosure N. Mandal: None. J. Y. Wan: None. F. B. Stentz: None. S. Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. Funding National Institutes of Health (5R01DK128129)