Selective association of plasma sphingolipid species with insulin sensitivity and secretion in normoglycemic Black and White American adults

Ceramides and other sphingolipids are associated with diabetes risk. Here, we examined the association of plasma sphingolipids with insulin sensitivity and secretion in people without diabetes. We enrolled adults without diabetes based on 75-g oral glucose tolerance test. Assessments included clinical examination, insulin sensitivity (hyperinsulinemic euglycemic clamp), and insulin secretion (intravenous glucose tolerance test). Plasma levels of 58 sphingolipid species (including ceramides, monohexosylceramides, sphingomyelins, and sphingosine) were assayed using liquid chromatography tandem mass spectrometry. The study participants (N = 240; 129 Black, 111 White) had a mean age of 43.1 ± 12.0 y, body mass index (BMI) 29.4 ± 6.23 kg/m², fasting plasma glucose 91.4 ± 6.91 mg/dL, and 2-h plasma glucose 123 ± 26.3 mg/dL. Several of the 58 SPLs species assayed showed variable associations with insulin sensitivity (r = 0.17-0.35, P = 0.039 - <0.0001) and secretion (r = 0.14-0.27; P = 0.038 - <0.0001). After correction for multiple testing, plasma levels of very-long-chain (VLC) monohexosylceramide C34:0 (r = 0.31 - 0.43, P < 0.0001) and VLC sphingomyelins C28-C34 (r = 0.31-0.35, P = 0.0004 - <0.0001) were significantly associated with insulin sensitivity. Plasma VLC sphingomyelin level were inversely associated with insulin secretion, plasma glucose, BMI, and waist circumference. We conclude that circulating VLC sphingomyelins are associated positively with insulin action and inversely with insulin secretion and adiposity in normoglycemic adults, indicating a possible link to glucoregulation that precedes the development of dysglycemia.