A peroxovanadium compound stimulates muscle glucose transport as powerfully as insulin and contractions combined.
Stimulation of glucose transport by insulin involves tyrosine phosphorylation of the insulin receptor (IR) and IR substrates (IRSs). Peroxovanadates inhibit tyrosine phosphatases, also resulting in tyrosine phosphorylation of the IRSs. Muscle contractions stimulate glucose transport by a mechanism independent of the insulin-signaling pathway. We found that the peroxovanadate compound bis-peroxovanadium,1,10-phenanthrolene [bpV(phen)] stimulates glucose transport to the same extent as the additive effects of maximal insulin and contraction stimuli. Translocation of GLUT4 to the cell surface mediates stimulation of glucose transport. There is evidence suggesting there are separate insulin- and contraction-stimulated pools of GLUT4-containing vesicles. We tested the hypothesis that bpV(phen) stimulates both the insulin- and the contraction-activated pathways. Stimulation of glucose transport and GLUT4 translocation by bpV(phen) was completely blocked by the phosphatidylinositol 3-kinase (PI 3-K) inhibitors wortmannin and LY294002. The combined effect of bpV(phen) and contractions was no greater than that of bpV(phen) alone. Activation of the IRS-PI 3-K signaling pathway was much greater with bpV(phen) than with insulin. Our results suggest that the GLUT4 vesicles that are normally translocated in response to contractions but not insulin can respond to the signal generated via the IRS-PI 3-K pathway if it is sufficiently powerful.
Nolte
Lorraine A
LA
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Han
Dong-Ho
DH
Hansen
Polly A
PA
Hucker
Kathleen A
KA
Holloszy
John O
JO
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000493:pharmacokinetics*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology*; D010618:Phenanthrolines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D005082:Physical Exertion / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009025:Morpholines; D009942:Organometallic Compounds; D010618:Phenanthrolines; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D014443:Tyrosine; D014638:Vanadates; D000077191:Wortmannin; C526296:Irs1 protein, rat; C069276:peroxovanadate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-)