PIOGLITAZONE-INDUCED INCREASE OF INSULIN SENSITIVITY IN THE MUSCLES OF THE OBESE ZUCKER FA FA RAT CANNOT BE EXPLAINED BY LOCAL ADIPOCYTE DIFFERENTIATION/

Thiazolidinediones are potent antidiabetic compounds, which act by enh ancing peripheral insulin sensitivity. They are also activators of the peroxisome proliferator activated receptor gamma in adipose tissue. P ioglitazone induces in vivo adipocyte differentiation in the obese Zuc ker fa/fa rat and hence the capacity of adipose tissue to utilize gluc ose. Nevertheless, muscles are the major site for insulin-mediated glu cose disposal. The increase of muscle glucose utilization under thiazo lidinedione treatment could be secondary to local adipose tissue diffe rentiation. This possibility is supported by the fact that a thiazolid inedione-induced myoblast conversion into adipocytes has been describe d in vitro. To address this problem, we have studied the in vivo effec t of a pioglitazone treatment on insulin-induced glucose utilization a nd the expression of genes exclusively expressed in mature adipocytes in three muscles differing by their fibre composition in Zucker (fa/fa ) rats. Whereas pioglitazone treatment increased insulin-stimulated gl ucose utilization to the same extent in all muscle types, an adipocyte differentiation was only present in the oxidative muscle, the soleus. Soleus muscle was also the only one in which the presence of genes sp ecific for adipose tissue could be detected before the pioglitazone tr eatment. There was no detectable expression of adipocyte specific gene s in the extensor digitorum longus or in the epitrochlearis muscles be fore or after the drug treatment. We conclude that pioglitazone effect s on muscle glucose metabolism cannot be due to a local adipocyte diff erentiation, and that the conversion of myoblasts into adipocytes unde r thiazolidinedione stimulation observed in vitro is, if it exists, a marginal phenomenon in vivo.