Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes.
BACKGROUND
Although the association between insulin resistance and cardiovascular risk is well established, the underlying molecular mechanisms are poorly understood. The antifibrinolytic molecule plasminogen activator inhibitor 1 (PAI-1) is a cardiovascular risk factor that is consistently elevated in insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). The strong positive correlation between this elevated PAI-1 and the degree of hyperinsulinemia not only implicates insulin itself in this increase, but also suggests that PAI-1 is regulated by a pathway that does not become insulin resistant. The data in this report supports this hypothesis.


METHODS
We show that insulin stimulates PAI-1 gene expression in metabolically insulin-resistant ob/ob mice and in insulin-resistant 3T3-L1 adipocytes. Moreover, we provide evidence that glucose transport and PAI-1 gene expression are mediated by different insulin signaling pathways. These observations suggest that the compensatory hyperinsulinemia that is frequently associated with insulin-resistant states, directly contribute to the elevated PAI-1.


CONCLUSIONS
These results provide a potential mechanism for the abnormal increases in cardiovascular risk genes in obesity, NIDDM, and polycystic ovary disease.
Samad
F
F
The Scripps Research Institute, Department of Vascular Biology, La Jolla, California 92037, USA.
Pandey
M
M
Bell
P A
PA
Loskutoff
D J
DJ
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003847:Deoxyglucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D006946:Hyperinsulinism / Q000150:complications / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
D001786:Blood Glucose; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D003847:Deoxyglucose