PMID- 12800089
OWN - NLM
STAT- MEDLINE
DCOM- 20030711
LR  - 20191210
IS  - 0026-0495 (Print)
IS  - 0026-0495 (Linking)
VI  - 52
IP  - 6
DP  - 2003 Jun
TI  - Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake.
PG  - 666-74
AB  - Tyrosine dephosphorylation, serine phosphorylation, and proteasomal degradation 
      of insulin receptor substrates (IRSs) are implicated in the negative regulation 
      of insulin action. Here we show that simultaneous inhibition of IRS-1 tyrosine 
      dephosphorylation and proteasomal degradation synergistically augments 
      insulin-responsive glucose uptake. L6 skeletal muscle cells (L6 cells) were 
      treated with inhibitors of protein-tyrosine phosphatases, proteasomal 
      degradation, and mammalian target of rapamycin (mTOR), and the effects of insulin 
      on glucose uptake, IRS-1 tyrosine phosphorylation, phosphatidylinositol (PI) 
      3-kinase activity, and IRS-1 mass were examined. Pretreatment of L6 cells with 
      sodium orthovanadate (Na(3)VO(4)) plus the mTOR inhibitor rapamycin caused a 
      5-fold increase in insulin-responsive glucose uptake at 2 hours when compared to 
      insulin alone. Evaluation of IRS-1 associated PI 3-kinase activity, 
      IRS-1-associated p85 mass, and IRS-1 tyrosine phosphorylation showed that 2 hours 
      after insulin addition they were reduced by 70% from maximal activity. Likewise, 
      IRS-1 mass was reduced by 50%. When L6 cells were pretreated with Na(3)VO(4) plus 
      the proteasome inhibitor MG-132 or the mTOR inhibitor rapamycin prior to insulin 
      addition, IRS-1 mass loss as well as IRS-1/PI-3 kinase complex decay was blocked 
      at 2 hours and PI 3-kinase activity was increased 2.5-fold and 4-fold, 
      respectively, over insulin alone. Finally, treatment of L6 cells with 
      subtherapeutic amounts of vanadyl sulfate and rapamycin induced a synergistic 
      3-fold increase in insulin-induced glucose uptake at 2 hours. These findings 
      indicate that vanadium and rapamycin synergize to enhance glucose uptake by 
      preventing IRS-1 mass loss and IRS-1/PI 3-kinase complex decay and may offer a 
      new approach to enhance glucose transport in diabetes.
FAU - O'Connor, Jason C
AU  - O'Connor JC
AD  - Department of Animal Sciences, University of Illinois at Urbana-Champaign, 
      Urbana, IL 61801, USA.
FAU - Freund, Gregory G
AU  - Freund GG
LA  - eng
GR  - CA-61931/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Leupeptins)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Phosphoproteins)
RN  - 3WHH0066W5 (Vanadates)
RN  - 42HK56048U (Tyrosine)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - IY9XDZ35W2 (Glucose)
RN  - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cysteine Endopeptidases
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Drug Synergism
MH  - Glucose/*metabolism
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulin/*pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - Leupeptins/pharmacology
MH  - Multienzyme Complexes/antagonists & inhibitors
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphoproteins/antagonists & inhibitors/metabolism
MH  - Phosphorylation/drug effects
MH  - Proteasome Endopeptidase Complex
MH  - Sirolimus/*pharmacology
MH  - Tyrosine/metabolism
MH  - Vanadates/*pharmacology
EDAT- 2003/06/12 05:00
MHDA- 2003/07/12 05:00
CRDT- 2003/06/12 05:00
PHST- 2003/06/12 05:00 [pubmed]
PHST- 2003/07/12 05:00 [medline]
PHST- 2003/06/12 05:00 [entrez]
AID - S002604950300026X [pii]
AID - 10.1016/s0026-0495(03)00026-x [doi]
PST - ppublish
SO  - Metabolism. 2003 Jun;52(6):666-74. doi: 10.1016/s0026-0495(03)00026-x.