Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes

Background: Although the association between insulin resistance and cardiov ascular risk is well established, the underlying molecular mechanisms are p oorly understood. The antifibrinolytic molecule plasminogen activator inhib itor 1 (PAI-I) is a cardiovascular risk factor that is consistently elevate d in insulin-resistant states such as obesity and noninsulin-dependent diab etes mellitus (NIDDM). The strong positive correlation between this elevate d PAI-1 and the degree of hyperinsulinemia not only implicates insulin itse lf in this increase, but also suggests that PAI-I is regulated by a pathway that does not become insulin resistant. The data in this report supports t his hypothesis. Materials and Methods: We show that insulin stimulates PAI-I gene expressio n in metabolically insulin-resistant ob/ob mice and in insulin-resistant 3T 3-L1 adipocytes. Moreover, we provide evidence that glucose transport and P AI-1 gene expression are mediated by different insulin signaling pathways. These observations suggest that the compensatory hyperinsulinemia that is f requently associated with insulin-resistant states, directly contribute to the elevated PAI-I. Conclusions: These results provide a potential mechanism for the abnormal i ncreases in cardiovascular risk genes in obesity, NIDDM, and polycystic ova ry disease.