PMID- 18983503
OWN - NLM
STAT- MEDLINE
DCOM- 20090227
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 7
IP  - 1
DP  - 2009 Jan
TI  - Insulin inhibits tissue factor expression in monocytes.
PG  - 198-205
LID - 10.1111/j.1538-7836.2008.03206.x [doi]
AB  - OBJECTIVES: Platelets from healthy subjects are inhibited by insulin but type 2 
      diabetes mellitus (T2DM) platelets have become insulin-resistant, which might 
      explain their hyperactivity. In the present study we investigated whether 
      monocytes are responsive to insulin. METHODS AND RESULTS: LPS-induced tissue 
      factor (TF) upregulation was measured in human monocytes and monocytic THP-1 
      cells in a factor Xa generation assay. Insulin (0.1-100 nmol L(-1)) induced a 
      dose-dependent inhibition in both cell types and in monocytes 100 nmol L(-1) 
      insulin inhibited cytosolic, membrane-bound and microparticle TF by 32 +/- 2, 27 
      +/- 3 and 52 +/- 4% (n = 3). Insulin induced Tyr phosphorylation of the insulin 
      receptor (INS-R) and formation of an INS-R - G(i)alpha(2) complex, suggesting 
      interference with LPS-induced cAMP control. Indeed, insulin interfered with 
      LPS-induced cAMP decrease and TF upregulation in a manner similar to an inhibitor 
      of G(i) (pertussis toxin) and agents that raise cAMP (iloprost, forskolin, IBMX) 
      reduced TF upregulation. Although LPS failed to raise cytosolic Ca(2+), quenching 
      of Ca(2+) increases (BAPTA-AM) reduced and induction of Ca(2+) entry (ionophore, 
      P2X7 activation) enhanced upregulation of TF mRNA and procoagulant activity. 
      Insulin interfered with MCP-1-induced Ca(2+) mobilization but not with 
      ATP-induced Ca(2+) rises. CONCLUSIONS: Insulin inhibits TF expression in 
      monocytes and monocyte-derived microparticles through interference with 
      G(i)alpha(2)-mediated cAMP suppression, which attenuates Ca(2+)-mediated TF 
      synthesis.
FAU - Gerrits, A J
AU  - Gerrits AJ
AD  - Department of Clinical Chemistry and Haematology, University Medical Center 
      Utrecht, Utrecht, The Netherlands.
FAU - Koekman, C A
AU  - Koekman CA
FAU - Yildirim, C
AU  - Yildirim C
FAU - Nieuwland, R
AU  - Nieuwland R
FAU - Akkerman, J W N
AU  - Akkerman JW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081028
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Insulin)
RN  - 0 (Lipopolysaccharides)
RN  - 9035-58-9 (Thromboplastin)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium
MH  - Cell-Derived Microparticles/metabolism
MH  - Cyclic AMP/antagonists & inhibitors
MH  - GTP-Binding Protein alpha Subunits, Gi-Go
MH  - Humans
MH  - Insulin/*pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - Monocytes/*metabolism
MH  - Phosphorylation
MH  - Receptor, Insulin/metabolism
MH  - Thromboplastin/*antagonists & inhibitors/*biosynthesis
EDAT- 2008/11/06 09:00
MHDA- 2009/02/28 09:00
CRDT- 2008/11/06 09:00
PHST- 2008/11/06 09:00 [pubmed]
PHST- 2009/02/28 09:00 [medline]
PHST- 2008/11/06 09:00 [entrez]
AID - S1538-7836(22)12502-X [pii]
AID - 10.1111/j.1538-7836.2008.03206.x [doi]
PST - ppublish
SO  - J Thromb Haemost. 2009 Jan;7(1):198-205. doi: 10.1111/j.1538-7836.2008.03206.x. 
      Epub 2008 Oct 28.