Circulating Sphingolipids, Insulin, HOMA-IR, and HOMA-B: The Strong Heart Family Study

Abstract

Experimental studies suggest ceramides may play a role in insulin resistance. However, the relationships of circulating ceramides and related sphingolipids with plasma insulin have been underexplored in humans. We measured 15 ceramide and sphingomyelin species in fasting baseline samples from the Strong Heart Family Study (SHFS), a prospective cohort of American Indians. We examined sphingolipid associations with both baseline and follow-up measures of plasma insulin, HOMA of insulin resistance (HOMA-IR), and HOMA of β-cell function (HOMA-B) after adjustment for risk factors. Among the 2,086 participants without diabetes, higher levels of plasma ceramides carrying the fatty acids 16:0 (16 carbons, 0 double bond), 18:0, 20:0, or 22:0 were associated with higher plasma insulin and higher HOMA-IR at baseline and at follow-up an average of 5.4 years later. For example, a twofold higher baseline concentration of ceramide 16:0 was associated with 14% higher baseline insulin (P < 0.0001). Associations between sphingomyelin species carrying 18:0, 20:0, 22:0, or 24:0 and insulin were modified by BMI (P < 0.003): higher levels were associated with lower fasting insulin, HOMA-IR, and HOMA-B among those with normal BMI. Our study suggests lowering circulating ceramides might be a target in prediabetes and targeting circulating sphingomyelins should take into account BMI.

Trial registration: ClinicalTrials.gov NCT00005134.

© 2018 by the American Diabetes Association.

Figures

Figure 1

Synthesis of ceramide and other measured sphingolipids. Shown are simplified pathways leading to ceramide, sphingomyelin, glucosyl ceramide, and lactosyl ceramide, the four sphingolipids measured in the study. In the de novo synthesis pathway and the salvage pathway, ceramide is formed by acylation of a fatty acid (FA) to a “sphingoid” backbone, dihydrosphinganine and sphingosine, respectively. There are six ceramide synthases in humans with different fatty acid specificities, resulting in multiple ceramide species carrying different fatty acids. Synthesis of ceramide by the two pathways occurs in the endoplasmic reticulum. Ceramide can also be formed by sphingomyelinases on the plasma membrane. Sphingomyelin is synthesized by sphingomyelin synthase by addition of a choline head group to ceramide transported to the Golgi. Glucosyl ceramide is synthesized by addition of a glucose head group to ceramide, and lactosyl ceramide by further addition of galactose to glucosyl ceramide, also in the Golgi.

Figure 2

Association of plasma ceramides with plasma fasting insulin and change in plasma fasting insulin. Shown is the ratio of insulin geometric means associated with twofold higher ceramide. Within each ceramide, top estimate represents the association with insulin at baseline, middle estimate the association with insulin at follow-up, and bottom estimate the association with change in insulin between baseline and follow-up.

Figure 3

Geometric mean ratio of insulin levels associated with twofold difference in sphingomyelin species as a function of BMI (kg/m2). Each plot shows the ratio of baseline insulin geometric means associated with twofold higher sphingomyelin species as a function of BMI (solid line) and 95% CI (shaded area). A geometric mean ratio of 1.0 indicates no association. Values less than 1 indicate an association with lower insulin, and values above 1 indicate an association with higher insulin. The density plot shows the distribution of BMI values in the cohort.