Sex Differences in Insulin Sensitivity Are Related to Muscle Tissue Acylcarnitines and Serum Lysophosphatidylcholines but Not Subcellular Lipid Distribution in Humans

Abstract

Sex differences in insulin sensitivity are present throughout the lifespan, though mechanisms that account for these differences are unclear. Accumulation of diacylglycerol (DAG) and sphingolipids in skeletal muscle are thought to promote insulin resistance, and localization plays an important role. Other lipids and lipid intermediates found in muscle and plasma such as acylcarnitines also relate to insulin sensitivity. However, it is not known whether there are sex differences in accumulation of these lipids that may affect insulin sensitivity. We evaluated insulin sensitivity and sub-cellular localization of skeletal muscle DAG and sphingolipids, as well as muscle acylcarnitines and serum lipidomics, in 25 obese, nondiabetic men and women (13F). Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Muscle biopsies were taken during basal and insulin stimulated conditions and fractionated into sub-cellular compartments. Lipids were measured using LC/MS/MS. Insulin sensitivity was significantly lower in men (p=0.05), however we found no sex-differences in localization of DAG or sphingolipids in skeletal muscle. Men had higher total acylcarnitines in muscle tissue (p<0.05) and higher serum lysophosphatidylcholines (LPCs; p<0.01), and both were correlated with insulin sensitivity (r=-0.42 and -0.43, respectively; p<0.05). After correcting for multiple comparisons, the linoleoylcarnitine species (18:2AC) was significantly elevated in men during insulin stimulation (p=0.001), and was negatively associated with insulin sensitivity (r=-0.43; p<0.05). Combined, these data suggest differences in content of acylcarnitines between sexes consistent with differences in fatty acid processing and oxidation that may impact insulin sensitivity. Further, greater serum LPC species may play an important role in the decreased insulin sensitivity associated with male sex. Disclosure J.L. Broussard: None. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Merck & Co., Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. S.A. Newsom: None. D.E. Kahn: None. A. Kerege: None. K.A. Harrison: None. B. Bergman: Research Support; Self; Eli Lilly and Company. Advisory Panel; Spouse/Partner; Novo Nordisk Inc., Merck & Co., Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company.