Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice.
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.
Mihara
Masatomo
M
Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Medical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Aihara
Ken-ichi
K
Ikeda
Yasumasa
Y
Yoshida
Sumiko
S
Kinouchi
Mizuho
M
Kurahashi
Kiyoe
K
Fujinaka
Yuichi
Y
Akaike
Masashi
M
Matsumoto
Toshio
T
D041721:3T3-L1 Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004361:Drug Tolerance; D005167:Factor VII / Q000235:genetics / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D010875:Pipecolic Acids / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D054390:Receptors, CCR2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000502:physiology
D052242:Adiponectin; D000925:Anticoagulants; D001786:Blood Glucose; D007328:Insulin; D015850:Interleukin-6; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D054390:Receptors, CCR2; D013449:Sulfonamides; D012313:RNA; D005167:Factor VII; D001120:Arginine; D013917:Thrombin; C031942:argatroban