A new oral agent, 5-[4-(2-(5-ethyl 12-pyridyl)ethoxy]- benzoyl]-2,4-thiazolidinedione (pioglitazone), has been developed for treatment of non-insulin-dependent diabetes mellitus (NIDDM). This agent increases insulin sensitivity in vivo in genetically obese Wistar fatty rats. Administration of the agent (3 mg/kg/day) for 10 days to the rats ameliorated hyperglycemia and hyperinsulinemia, indicating that it decreased insulin resistance. To clarify the mechanism of the drug to increase insulin sensitivity, we examined insulin binding and kinase activity of insulin receptors from muscles of both untreated and treated rats. Pioglitazone treatment did not change insulin binding in Wistar fatty rats but increased insulin-stimulated autophosphorylation of insulin receptors to 78% over the level in the control but not the basal state. Kinase activity toward exogenous substrate, poly Glu4Tyr1, was also increased to 87% over the level of untreated control obese rats. In contrast, in lean rats, pioglitazone treatment did not increase autophosphorylation and kinase activity toward exogenous substrates. To further elucidate the mechanism, we incubated insulin receptors with the agent and measured kinase activity. Incubation of solubilized receptors with the agent did not increase kinase activity. However, the receptors from IM-9 cells, which were incubated with 10−8 M pioglitazone for 7 days, showed a 46% increase over the control in insulin-stimulated autophosphorylation and kinase activity. These results suggested that pioglitazone increased insulin sensitivity in part by activating kinase of the receptors through indirect effect on insulin receptors and that the drug may have useful benefits in insulin resistance of NIDDM.

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