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 ( < 0.0001). Associations between sphingomyelin species carrying 18:0, 20:0, 22:0, or 24:0 and insulin were modified by BMI ( < 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.

Metabolomic Profiles Associated with BMI, Waist Circumference, and Diabetes and Inflammation Biomarkers in Women

“…Thus, most studies have focused on the more prevalent SMs and ceramides containing the double bond in the sphingoid base backbone. In fact, ceramides with C16:0, C18:0, C20:0, and C24:1 acyl chains are currently the subject of considerable interest because they have been linked to insulin resistance and risk of cardiovascular disease and mortality . While our association between dihydro‐SM and CRP is novel, the association with c‐peptide is consistent with findings for other sphingolipids and suggests that the dihydrosphingolipids may affect insulin secretion and metabolic health as well.…”

“…One approach to identify those that do is to examine their relationship to parameters used to define metabolic health. The parameters that have been investigated to date include blood pressure , cholesterol, lipoprotein, and triglyceride levels , body composition , glucose, insulin and insulin sensitivity , adipokine levels , and inflammation markers . These studies have provided support for the involvement of some metabolites in processes related to metabolic diseases, such as the BCAAs in the development of insulin resistance , but the role of many of the metabolites associated with BMI remains undefined.…”

Ceramides and diabetes mellitus: an update on the potential molecular relationships

“…A recent large prospective study confirmed the significant and independent role of ceramides, in particular, the Cer(18:1/18:0)/Cer(18:1/16:0) ceramide ratio, in the prediction of Type 2 diabetes up to 10 years before the onset of the disease . Furthermore, specific ceramides are associated early with insulin resistance, prior to its progression to diabetes . This is intriguing given the fact that the early stages of diabetes are usually asymptomatic.…”

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

“…These data as well as the lipidomic data previously mentioned (Gonzalez‐Covarrubias et al, ; Montoliu et al, ; Wong et al, ) nicely justify further exploring the relationship between blood sphingolipids and human aging. Indeed, a recent study in nondiabetic patients found that higher levels of plasma insulin and an increased HOMA of insulin resistance score were associated with an elevation in plasma ceramides (Lemaitre et al, ).…”