Adiponectin mediates the suppressive effect of rosiglitazone on plasminogen activator inhibitor-1 production.
OBJECTIVE
The purpose of this study was to examine the effects of PPAR-gamma agonist rosiglitazone, relative to sulfonylureas, on circulating levels of adiponectin and the prothrombotic factor, plasminogen activator inhibitor (PAI)-1, in type 2 diabetic patients, and to investigate, in animal models, whether the antithrombotic action of rosiglitazone was mediated through adiponectin.


RESULTS
Our clinical study (n=64) showed that after 24-week add-on therapy, the rosiglitazone group had a greater mean reduction in plasma PAI-1 levels (25%, versus 12% in sulfonylurea group, P=0.002). Stepwise multiple linear regression analysis identified the reduction in plasma fasting glucose and the rise in adiponectin levels to be independently associated with the reduction in PAI-I concentration in the rosiglitazone-treated patients. Rosiglitazone (20 mg/kg/d) reduced adipose tissue PAI-1 mRNA expression and its plasma levels in wild-type C57 mice with diet-induced obesity (P<0.001), but this suppressive effect was attenuated in adiponectin knockout mice. Adenovirus-mediated overexpression of adiponectin led to a significant suppression of adipose tissue PAI-1 expression and its circulating concentrations in db/db diabetic mice. Our in vitro study demonstrated that recombinant adiponectin directly inhibited PAI-1 production in 3T3-L1 adipocytes.


CONCLUSIONS
The antithrombotic effect of rosiglitazone is mediated, at least in part, through the suppressive effect of adiponectin on PAI-1 production.
Hoo
Ruby L C
RL
Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
Chow
W S
WS
Yau
M H
MH
Xu
A
A
Tso
Annette W K
AW
Tse
H F
HF
Fong
Carol H Y
CH
Tam
Sidney
S
Chan
Lawrence
L
Lam
Karen S L
KS
D041721:3T3-L1 Cells; D000256:Adenoviridae / Q000235:genetics; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005822:Genetic Vectors; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000077154:Rosiglitazone; D058258:Serpin E2; D015843:Serpins / Q000097:blood / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014161:Transduction, Genetic; D016896:Treatment Outcome
C499918:ADIPOQ protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D001786:Blood Glucose; D004041:Dietary Fats; D005343:Fibrinolytic Agents; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D000077154:Rosiglitazone