title: Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content.
abstract: OBJECTIVE
  We tested the primary hypotheses that sphingolipid and diacylglycerol (DAG) content is higher within insulin-resistant muscle and that the association between intramyocellular triglycerides (IMTG) and insulin resistance is muscle fiber type specific.
  
  
  METHODS
  A nested case-control analysis was conducted in 22 obese (BMI >30 kg/m(2)) women who were classified as insulin-resistant (IR; n = 12) or insulin-sensitive (IS; n = 10), determined by hyperinsulinemic-euglycemic clamp (>30% greater in IS compared with IR, P < 0.01). Sphingolipid and DAG content was determined by high-performance liquid chromatography-tandem mass spectrometry. Fiber type-specific IMTG content was histologically determined. Gene expression was determined by quantitative PCR.
  
  
  RESULTS
  Total (555 +/- 53 vs. 293 +/- 54 pmol/mg protein, P = 0.004), saturated (361 +/- 29 vs. 179 +/- 34 pmol/mg protein, P = 0.001), and unsaturated (198 +/- 29 vs. 114 +/- 21 pmol/mg protein, P = 0.034) ceramides were higher in IR compared with IS. DAG concentrations, however, were similar. IMTG content within type I myocytes, but not type II myocytes, was higher in IR compared with IS subjects (P = 0.005). Insulin sensitivity was negatively correlated with IMTG within type I myocytes (R = -0.51, P = 0.026), but not with IMTG within type II myocytes. The proportion of type I myocytes was lower (41 vs. 59%, P < 0.01) in IR subjects. Several genes involved in lipid droplet and fatty acid metabolism were differentially expressed in IR compared with IS subjects.
  
  
  CONCLUSIONS
  Human skeletal muscle insulin resistance is related to greater IMTG content in type I but not type II myocytes, to greater ceramide content, and to alterations in gene expression associated with lipid metabolism.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Coen
authors.forename: John J
authors.initials: JJ
authors.lastname: Dubé
authors.forename: Francesca
authors.initials: F
authors.lastname: Amati
authors.forename: Maja
authors.initials: M
authors.lastname: Stefanovic-Racic
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Frederico G S
authors.initials: FG
authors.lastname: Toledo
authors.forename: Bret H
authors.initials: BH
authors.lastname: Goodpaster
mesh_terms: D000199:Actins / Q000235:genetics; D001706:Biopsy; D001823:Body Composition; D002518:Ceramides / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015870:Gene Expression; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D032342:Muscle Cells / Q000378:metabolism* / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000235:genetics
chemical_list: D000199:Actins; D002518:Ceramides; D004075:Diglycerides; D005230:Fatty Acids, Nonesterified; D013107:Sphingolipids; D014280:Triglycerides; D001613:beta 2-Microglobulin; D012313:RNA; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D007041:Hypoxanthine Phosphoribosyltransferase