Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Abstract

Background: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

Objectives: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

Methods: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

Results: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031).

Conclusions: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.

Keywords: Hispanic Americans; diabetes; lipids; risk factors; sphingolipids.

Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.

Figures

FIGURE 1

Correlations between sphingolipid scores and cardiometabolic traits. CRP, C-reactive protein; db, double bond; DBP, diastolic blood pressure; FI, fasting insulin; FPG, fasting plasma glucose; GlyCer, glycosylceramide; HbA1c, hemoglobin A1c; LacCer, lactosylceramide; OGTT, oral-glucose-tolerance test; SBP, systolic blood pressure; SM, sphingomyelin; WC, waist circumference; TG, triglycerides. Data are partial Pearson correlation coefficients with adjustment for age, sex, study field center, and Hispanic/Latino background.

FIGURE 2

Association of individual sphingolipids with incident diabetes. Results were from multivariable survey Poisson regression models with adjustment for field center, age, sex, Hispanic/Latino background, US native, education, annual household income, AHEI-2010 score, total energy intake, smoking status, drinking status, physical activity, use of hypertensive or lipid-lowering drugs, fasting time for blood drawn, and family history of diabetes. * 0.05 P ≤0.01, ** 0.05 < P ≤0.01, *** P <0.001 after correction for multiple testing. AHEI, Alternative Healthy Eating Index; db, double bonds; FA, fatty acids; GlyCer, glycosylceramide; LacCer, lactosylceramide; SM, sphingomyelin.