[Pharmacological effects of a thiazolidinedione derivative, pioglitazone]

Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models and our chemical research on lipid-lowering agents. In clinical studies, pioglitazone at doses of 15-45 mg/man/day produced 1.0-1.6% reduction in HbA1c for 6 months. Moreover, pioglitazone produced about 14% reduction in plasma triglyceride levels and 4-11% increase in HDL-cholesterol(HDL-C) levels without the significant changes in total cholesterol and LDL-C levels. Although the exact molecular mechanism of reducing insulin resistance still remains obscure, pioglitazone normalizes abnormalities in the cellular insulin signal transduction. This effect seems to be due to the inhibitory action of pioglitazone on TNF-alpha production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator activated receptor(PPAR)-gamma, that is related to differentiation of adipocytes, and the relationship between TNF-alpha production and PPAR-gamma has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-gamma may be involved in the mechanism for reducing insulin resistance. Recently, it was demonstrated that pioglitazone is also an agonist of PPAR-alpha, which plays a central role in lipid metabolism through enhancing the synthesis of apo AI, apo AII and reverse cholesterol transporters, such as fatty acid transporter molecules, and SR-B1 and ABCA1 reverse cholesterol transport receptors. Therefore, these findings suggest that pioglitazone has a benefit for prevention of both diabetic micro-angiopathy and macro-angiopathy.