Pioglitazone ameliorates high glucose induced desensitization of insulin receptor kinase in Rat 1 fibroblasts in culture.

A new oral agent, pioglitazone, increases insulin sensitivity by activating receptor kinase in insulin-resistant rats. To clarify the mechanism, we studied in vitro effects of glucose and pioglitazone on the insulin receptor function using Rat 1 fibroblasts which expressed human insulin receptors. Insulin receptor kinase activity was impaired by incubating cells for 4 days in the presence of 27mM D-glucose. The glucose effect was time- and dose-dependent and also specific for D-glucose, since D-raffinose incubation had no effect. Pioglitazone treatment did not have any effect on intact receptor kinase. However, exposure of both 27mM D-glucose and 0.1 microM pioglitazone to the cells completely prevented the glucose-induced impairment of insulin receptor kinase activity, suggesting that pioglitazone might reverse the processes which are critical for the glucose-induced desensitization of insulin receptor kinase.