Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content.
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.
Coen
Paul M
PM
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Dubé
John J
JJ
Amati
Francesca
F
Stefanovic-Racic
Maja
M
Ferrell
Robert E
RE
Toledo
Frederico G S
FG
Goodpaster
Bret H
BH
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
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