Plasma Ceramides and Other Sphingolipids in Relation to Incident Prediabetes in a Longitudinal Biracial Cohort

J Clin Endocrinol Metab. 2024 Mar 19:dgae179. doi: 10.1210/clinem/dgae179. Online ahead of print.


Context: Sphingolipids are linked to the pathogenesis of type 2 diabetes (T2D).

Objective: To test the hypothesis that plasma sphingolipid profiles predict incident prediabetes.

Design: A case-control study nested in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study, a 5-year follow-up study.

Setting: Academic health center.

Participants: Normoglycemic adults enrolled in the POP-ABC study. Assessments included OGTT, insulin sensitivity and insulin secretion. Participants with incident prediabetes were matched in age, sex, and ethnicity with non-progressors.

Interventions: We assayed 58 sphingolipid species (ceramides, monohexosyl ceramides, sphingomyelins, and sphingosine) using LC/tandem mass spectrometry in baseline plasma levels from participants and determined association with prediabetes risk.

Main outcome measure: The primary outcome was progression from normoglycemia to prediabetes, defined as impaired fasting glucose or impaired glucose tolerance.

Results: The mean age of participants (N = 140; 50% Black, 50% female) was 48.1 ± 8.69 y, BMI 30.1 ± 5.78 kg/m2, fasting plasma glucose (FPG) 92.7 ± 5.84 mg/dl, and two-hour plasma glucose (2hrPG) 121 ± 23.3 mg/dl. Of the 58 sphingolipid species assayed, higher ratios of sphingomyelin C26:0/C26:1 (OR 2.73 [95% CI 1.172-4.408], P = 0.015) and ceramide C18:0/C18:1 (OR 1.236 [95% CI 1.042-1.466], P = 0.015) in baseline plasma specimens were significantly associated with progression to prediabetes during the 5-year follow-up period, after adjustments for age, race, sex, BMI, FPG, 2hPG, insulin sensitivity, and insulin secretion.

Conclusions: We conclude that the saturated-to-monounsaturated ratios of long-chain ceramide C18:0/C18:1 and very-long-chain sphingomyelin C26:0/C26:1 are potential biomarkers of prediabetes risk among individuals with parental history of T2D.

Keywords: Biomarkers; Impaired Fasting Glucose; Impaired Glucose Tolerance; Race/Ethnicity; Sphingomyelins.