PMID- 17977956
OWN - NLM
STAT- MEDLINE
DCOM- 20080321
LR  - 20220316
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 57
IP  - 3
DP  - 2008 Mar
TI  - Insulin signaling stimulates insulin transport by bovine aortic endothelial 
      cells.
PG  - 540-7
AB  - OBJECTIVE: In vivo evidence suggests that insulin entry into skeletal muscle is 
      rate limiting for its overall metabolic action. Although there has been 
      controversy regarding whether insulin crosses the endothelium by a passive 
      (transcellular or paracellular) or mediated process, accumulating data favor the 
      latter. Here, we addressed whether insulin signaling within the endothelial cell 
      is required for the first step of transendothelial insulin transport: its uptake 
      by the endothelial cell. RESEARCH DESIGN AND METHODS: Bovine aortic endothelial 
      cells (bAECs) were incubated in serum-free medium for 6 h before addition of 50 
      nmol/l fluoroisothiocyanate (FITC)-labeled insulin for 30 min, and uptake of FITC 
      insulin was quantified by confocal immunocytochemistry. RESULTS: Cellular insulin 
      uptake was temperature dependent, being greater at 37 vs. 4 degrees C (P < 0.05). 
      Inhibiting phosphatidylinositol 3-kinase (PI 3-kinase) (wortmannin), 
      mitogen-activated protein kinase kinase (MEK) (PD98059), the cSrc-family tyrosine 
      kinase (PP1), or the insulin receptor tyrosine kinase (genistein) markedly 
      diminished FITC insulin uptake (P < 0.05 for each). In contrast, inhibiting the 
      phosphotyrosine phosphatase protein tyrosine phosphatase 1B further stimulated 
      insulin uptake (P < 0.05). Addition of the inflammatory cytokine 5 ng/ml tumor 
      necrosis factor-alpha (TNF-alpha) for 6 h before adding 50 nmol/l FITC insulin 
      diminished insulin uptake significantly (P < 0.05). This inhibitory effect of 
      TNF-alpha could be partially reversed by a specific p38 MAPK inhibitor 
      (SB203580). CONCLUSIONS: Insulin uptake by bAECs requires intact insulin 
      signaling via both the PI 3-kinase and MEK signaling cascades and the cSrc-family 
      tyrosine kinases, and endothelial cell insulin uptake is sensitive to 
      cytokine-induced insulin resistance.
FAU - Wang, Hong
AU  - Wang H
AD  - Department of Medicine, University of Virginia, Box 801410, Charlottesville, VA 
      22908, USA.
FAU - Wang, Aileen X
AU  - Wang AX
FAU - Liu, Zhenqi
AU  - Liu Z
FAU - Barrett, Eugene J
AU  - Barrett EJ
LA  - eng
GR  - ADA 7-07-CR-34/PHS HHS/United States
GR  - DK-057878/DK/NIDDK NIH HHS/United States
GR  - DK-073059/DK/NIDDK NIH HHS/United States
GR  - P30-DK-063609/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20071031
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine)
RN  - 0 (Androstadienes)
RN  - 0 (Caveolin 1)
RN  - 0 (Flavonoids)
RN  - 0 (Insulin)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - DH2M523P0H (Genistein)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Aorta/*cytology
MH  - Cattle
MH  - Caveolin 1/metabolism
MH  - Cells, Cultured
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Flavonoids/pharmacology
MH  - Genistein/pharmacology
MH  - Insulin/*metabolism
MH  - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Transport
MH  - Pyrazoles/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Signal Transduction/drug effects/*physiology
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Wortmannin
MH  - src-Family Kinases/antagonists & inhibitors/metabolism
EDAT- 2007/11/06 09:00
MHDA- 2008/03/22 09:00
CRDT- 2007/11/06 09:00
PHST- 2007/11/06 09:00 [pubmed]
PHST- 2008/03/22 09:00 [medline]
PHST- 2007/11/06 09:00 [entrez]
AID - db07-0967 [pii]
AID - 10.2337/db07-0967 [doi]
PST - ppublish
SO  - Diabetes. 2008 Mar;57(3):540-7. doi: 10.2337/db07-0967. Epub 2007 Oct 31.