PMID- 18303120
OWN - NLM
STAT- MEDLINE
DCOM- 20080619
LR  - 20211203
IS  - 0193-1849 (Print)
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Linking)
VI  - 294
IP  - 5
DP  - 2008 May
TI  - Mechanisms of high-glucose/insulin-mediated desensitization of acute 
      insulin-stimulated glucose transport and Akt activation.
PG  - E870-81
LID - 10.1152/ajpendo.00644.2007 [doi]
AB  - High-glucose/low-dose insulin-mediated insulin resistance of glucose transport 
      was studied in 3T3-L1 adipocytes. In this model, proximal insulin signaling, 
      including insulin receptor substrate (IRS)-1-bound phosphatidylinositol 3-kinase 
      (PI 3-kinase) activation, is preserved, but insulin-stimulated protein kinase B 
      (Akt) activation is markedly impaired. To assess a difference in acute 
      insulin-stimulated production of phosphatidylinositol 3,4,5-trisphosphate 
      [PtdIns(3,4,5)P3], cells were labeled with [32P]orthophosphate, and 
      glycerophosphoinositides were quantified by HPLC. Although basal PtdIns(3,4,5)P3 
      was similar, insulin stimulated its production 33.6% more in controls (P < 0.03) 
      than in insulin-resistant cells. Phosphatase and tensin homolog deleted on 
      chromosome 10 (PTEN) protein, a lipid phosphatase that dephosphorylates 
      PtdIns(3,4,5)P3 in the 3-position, was significantly and specifically increased 
      in insulin-resistant cells. Treatment with rapamycin [a specific inhibitor of 
      mammalian target of rapamycin complex 1 (mTORC1)] inhibited the increased PTEN 
      expression and partially restored insulin-stimulated glucose transport and Akt 
      activation to insulin-resistant cells. Acute insulin markedly stimulated 
      Ser(636/639) phosphorylation of IRS-1; this was rapamycin inhibited but was 
      significantly decreased in cells that had been preexposed to insulin, whereas 
      total IRS-1 was unaffected. These findings were essentially paralleled by changes 
      in the activation of p70 S6 kinase and S6-ribosomal protein. Overexpression of 
      uncoupling protein-1 or manganese superoxide dismutase did not prevent the 
      development of insulin-resistant glucose transport and impaired Akt activation in 
      high-glucose/low-insulin-pretreated cells. The insulin resistance associated with 
      glucotoxicity in our model reflects in part decreased availability of 
      PtdIns(3,4,5)P3, which correlates with increased PTEN protein expression. Chronic 
      activation of mTORC1 plays a role in stimulating PTEN expression and possibly in 
      activation or induction of a phosphoprotein phosphatase. No evidence was found 
      for a role for increased mitochondrial superoxide production in this model.
FAU - Robinson, Katherine A
AU  - Robinson KA
AD  - Division of Endocrinology, Department of Medicine, Medical University of South 
      Carolina, Charleston, SC, USA.
FAU - Buse, Maria G
AU  - Buse MG
LA  - eng
GR  - R01 DK002001/DK/NIDDK NIH HHS/United States
GR  - R56 DK002001/DK/NIDDK NIH HHS/United States
GR  - R01 DK002001-47/DK/NIDDK NIH HHS/United States
GR  - R56 DK002001-48/DK/NIDDK NIH HHS/United States
GR  - DK02001/DK/NIDDK NIH HHS/United States
GR  - R01 DK002001-46/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080226
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Glucose Transport Proteins, Facilitative)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Ion Channels)
RN  - 0 (Irs1 protein, mouse)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphatidylinositols)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Ucp1 protein, mouse)
RN  - 0 (Uncoupling Protein 1)
RN  - 11062-77-4 (Superoxides)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
EIN - Am J Physiol Endocrinol Metab. 2008 Jul;295(1): E223
MH  - 3T3 Cells
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Adipocytes/drug effects/metabolism
MH  - Animals
MH  - Biotransformation/drug effects
MH  - Blotting, Western
MH  - Electroporation
MH  - Glucose/*pharmacology
MH  - Glucose Transport Proteins, Facilitative/*metabolism
MH  - Green Fluorescent Proteins
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulin/*pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - Insulin Resistance/physiology
MH  - Ion Channels/metabolism
MH  - Lipid Metabolism/drug effects
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mitochondrial Proteins/metabolism
MH  - Multiprotein Complexes
MH  - Oncogene Protein v-akt/*metabolism
MH  - PTEN Phosphohydrolase/biosynthesis/genetics
MH  - Phosphatidylinositols/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - Proteins
MH  - Superoxides/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/biosynthesis/genetics
MH  - Uncoupling Protein 1
PMC - PMC2703196
MID - NIHMS58198
EDAT- 2008/02/28 09:00
MHDA- 2008/06/20 09:00
PMCR- 2009/06/29
CRDT- 2008/02/28 09:00
PHST- 2008/02/28 09:00 [pubmed]
PHST- 2008/06/20 09:00 [medline]
PHST- 2008/02/28 09:00 [entrez]
PHST- 2009/06/29 00:00 [pmc-release]
AID - 00644.2007 [pii]
AID - 10.1152/ajpendo.00644.2007 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2008 May;294(5):E870-81. doi: 
      10.1152/ajpendo.00644.2007. Epub 2008 Feb 26.