PMID- 19966184
OWN - NLM
STAT- MEDLINE
DCOM- 20100226
LR  - 20201209
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 151
IP  - 2
DP  - 2010 Feb
TI  - Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic 
      db/db mice.
PG  - 513-9
LID - 10.1210/en.2009-0661 [doi]
AB  - The binding of thrombin to its receptor stimulates inflammatory cytokines 
      including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are 
      associated with the development of insulin resistance. Because increased 
      adiposity enhanced the expression of coagulation factor VII that stimulates the 
      coagulation pathway in adipose tissue, we tested whether the inhibition of 
      thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) 
      mice. The 4-wk administration of argatroban, a selective thrombin inhibitor, 
      reduced fasting plasma glucose and ameliorated insulin resistance in these mice. 
      It also reduced adipocyte size and macrophage infiltration into adipose tissue. 
      The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and 
      suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db 
      mice were reversed by argatroban treatment. These results demonstrate that 
      increased adiposity enhances the production of thrombin in adipose tissue by 
      stimulating factor VII expression and suggest that increased thrombin activity in 
      adipose tissue plays an important role in the development of insulin resistance 
      via enhancing MCP-1 production, leading to macrophage infiltration and insulin 
      receptor substrate-1-Akt pathway inactivation.
FAU - Mihara, Masatomo
AU  - Mihara M
AD  - Department of Medicine and Bioregulatory Sciences, The University of Tokushima 
      Graduate School of Medical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, 
      Japan.
FAU - Aihara, Ken-ichi
AU  - Aihara K
FAU - Ikeda, Yasumasa
AU  - Ikeda Y
FAU - Yoshida, Sumiko
AU  - Yoshida S
FAU - Kinouchi, Mizuho
AU  - Kinouchi M
FAU - Kurahashi, Kiyoe
AU  - Kurahashi K
FAU - Fujinaka, Yuichi
AU  - Fujinaka Y
FAU - Akaike, Masashi
AU  - Akaike M
FAU - Matsumoto, Toshio
AU  - Matsumoto T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091204
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Adiponectin)
RN  - 0 (Anticoagulants)
RN  - 0 (Blood Glucose)
RN  - 0 (Insulin)
RN  - 0 (Interleukin-6)
RN  - 0 (Pipecolic Acids)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Sulfonamides)
RN  - 63231-63-0 (RNA)
RN  - 9001-25-6 (Factor VII)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 3.4.21.5 (Thrombin)
RN  - IY90U61Z3S (argatroban)
SB  - IM
MH  - 3T3-L1 Cells/cytology/drug effects/physiology
MH  - Adipocytes/cytology/drug effects
MH  - Adiponectin/genetics
MH  - Adipose Tissue/drug effects/*physiology
MH  - Animals
MH  - Anticoagulants/pharmacology
MH  - Arginine/analogs & derivatives
MH  - Blood Glucose/drug effects/metabolism
MH  - Diabetes Mellitus, Type 2/*physiopathology
MH  - Drug Tolerance
MH  - Factor VII/genetics/physiology
MH  - Humans
MH  - Insulin/pharmacology
MH  - Insulin Resistance/*physiology
MH  - Interleukin-6/genetics
MH  - Macrophages/drug effects/physiology
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Pipecolic Acids/pharmacology
MH  - Platelet Aggregation Inhibitors/pharmacology
MH  - RNA/genetics/isolation & purification
MH  - Receptors, CCR2/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sulfonamides
MH  - Thrombin/*antagonists & inhibitors/physiology
EDAT- 2009/12/08 06:00
MHDA- 2010/02/27 06:00
CRDT- 2009/12/08 06:00
PHST- 2009/12/08 06:00 [entrez]
PHST- 2009/12/08 06:00 [pubmed]
PHST- 2010/02/27 06:00 [medline]
AID - en.2009-0661 [pii]
AID - 10.1210/en.2009-0661 [doi]
PST - ppublish
SO  - Endocrinology. 2010 Feb;151(2):513-9. doi: 10.1210/en.2009-0661. Epub 2009 Dec 4.