title: Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation.
abstract: Elevated levels of resistin have been proposed to cause insulin resistance and therefore may serve as a link between obesity and type 2 diabetes. However, its role in skeletal muscle metabolism is unknown. In this study, we examined the effect of resistin on insulin-stimulated glucose uptake and the upstream insulin-signaling components in L6 rat skeletal muscle cells that were either incubated with recombinant resistin or stably transfected with a vector containing the myc-tagged mouse resistin gene. Transfected clones expressed intracellular resistin, which was released in the medium. Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. Furthermore, resistin did not alter the insulin receptor (IR) content and its phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic activity. Insulin-stimulated phosphorylation of Akt/protein kinase B-alpha, one of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also not affected by resistin. Expression of resistin also inhibited insulin-stimulated 2-DG uptake when compared with cells expressing the empty vector (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3-kinase signaling. We conclude that resistin does not alter IR signaling but does affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic activity of cell surface glucose transporters.
authors.affiliation: Diabetes Research Laboratory, Winthrop University Hospital, Mineola, New York 11501, USA.
authors.forename: Byoung
authors.initials: B
authors.lastname: Moon
authors.forename: Jamie Jun-Mae
authors.initials: JJ
authors.lastname: Kwan
authors.forename: Noreen
authors.initials: N
authors.lastname: Duddy
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
authors.forename: Najma
authors.initials: N
authors.lastname: Begum
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003847:Deoxyglucose / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D016259:Genes, myc / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006729:Hormones, Ectopic / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018613:Microscopy, Confocal; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020932:Nerve Growth Factor; D010766:Phosphorylation; D011506:Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D052243:Resistin; D015398:Signal Transduction / Q000187:drug effects*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D018076:DNA, Complementary; D051275:Glucose Transporter Type 4; D006729:Hormones, Ectopic; D007004:Hypoglycemic Agents; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D052243:Resistin; C499623:Retn protein, mouse; C499622:Retn protein, rat; C413576:Retnla protein, mouse; C486575:Retnla protein, rat; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; D020932:Nerve Growth Factor; D003847:Deoxyglucose; D011972:Receptor, Insulin; D005947:Glucose