The Extra-Glycemic Effect of Pioglitazone

Pioglitazone was demonstrated to have efficacy and durability of glycemic control in type 2 diabetes through several studies, and evidence has accumulated for its cardiovascular safety, as well as well as some positive, yet inconclusive results to prove its cardioprotective effect. Several other actions of pioglitazone beyond its glycemic effect are appreciable. The major side effects of pioglitazone are edema (with the potential of leading to chronic heart failure), weight gain, increased incidence of bone fractures and decreased hematocrit and hemoglobin. Its molecular action on the skeletal muscle, especially its anti-inflammatory effect, is a worthwhile, novel finding of out studies, considering its independence from the glucose-lowering effect. Thus, it is plausible that its anti-inflammatory effect precedes, and possibly leads to, insulin sensitization. In our study, we demonstrated that treatment with pioglitazone causes a normalization of inflammation at the molecular level in skeletal muscle of nondiabetic, insulin resistant women and showed, to the best of our knowledge, for the first time, that the improved insulin action which occurs after treatment with TZDs is associated to their anti-inflammatory action in polycystic ovarian syndrome. Moreover, despite the failure of troglitazone due its hepatotoxicity, we not only proved pioglitazone safe in terms of hepatic liver function tests, but -for the first time in a randomized, double-blind, placebo-controlled trial- demonstrated a positive effect of pioglitazone on metabolic and histological indexes of liver steatosis. Also, the positive effect of pioglitazone was shown also in patients with polycystic ovarian syndrome, who -despite having liver transaminases value within the normal range before being treated with TZD- consistently demonstrated a further lowering of transaminases levels after treatment with pioglitazone. Finally, the mechanism of TZD-induced mild anemia was carefully investigated, both among patients with type 2 diabetes and in a special population of insulin resistant, nondiabetic women characterized by hyperandrogenemia. The latter findings warrant further studies in male type 2 diabetic patients, in order to explore their hormonal status and dependence on pioglitazone. In summary, pioglitazone was shown to hold a pleiotropic mechanism of action, which grants not only the well-known anti-hyperglycemic effect, but also several other actions, independent from the glycemic efficacy, some of which make pioglitazone a valuable compound in the armamentarium of diabetologists, as well as gastroenterologists and gynecologists.