Serum ceramides are related to insulin resistance, decrease after insulin sensitizing lifestyle interventions, and are linked to CVD risk in humans. To what extent other serum sphingolipids may serve to regulate insulin sensitivity remains unknown. We performed this study to quantify a broad range of serum sphingolipids in individuals spanning the physiologic range of insulin sensitivity, and to determine if specific sphingolipid species promote insulin resistance in vitro. We evaluated serum sphingolipid content in lean (n=15), endurance trained athletes (n=16), obese (n=15), and people with type 2 diabetes (T2D; n=12). Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps and serum sphingolipids measured using targeted lipidomics. Quantitative sphingolipid analysis revealed no differences between sphinganine, sphingosine, glucosyl- and lactosyl-ceramides, gangliosides, sphingomyelins, and sulfatides. Total serum ceramides were significantly increased in obese compared to lean individuals (p=0.01), with significant inverse relationships between C18:0 (p=0.002), C20:0 (p=0.02), and C22:0 (p-0.009) species and insulin sensitivity. Total serum dihydroceramides (p=0.0007) and most individual species were significantly greater in obese and T2D compared to lean and athletes, with C18:0 dihydroceramide showing the strongest inverse relationship to insulin sensitivity (p=0.002). We administered C18:0 dihydroceramide in liposomes to primary cultured myocytes and found that it significantly decreased insulin sensitivity in vitro by 36 +/- 6% (p=0.002), measured by insulin-stimulated glycogen synthesis. These data extend what is known regarding ceramides and insulin resistance and show a novel potential role for serum dihydroceramides, especially C18:0 species, in predicting and promoting insulin resistance in humans.
S. Zarini: None. J.T. Brozinick: Employee; Self; Eli Lilly and Company. L. Perreault: Advisory Panel; Self; Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. S.A. Newsom: None. D.E. Kahn: None. A. Kerege: None. K.A. Harrison: None. B.C. Bergman: Consultant; Spouse/Partner; Novo Nordisk Inc., Sanofi US. Research Support; Self; Eli Lilly and Company. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc.
National Institutes of Health (R01DK089170, T32DK07658, P30DK048520, RR-00036)