Troglitazone and related compounds - Therapeutic potential beyond diabetes

Troglitazone and structurally related compounds (pioglitazone, rosiglitazon e etc.) containing thiazolidinediones (TZD) are a novel class of antidiabet ic agents which decrease blood glucose in diabetic animal models and in pat ients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) through alleviat ing insulin resistance. A large body of evidence is now accumulating indica ting that insulin resistance and/or resulting hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome call ed "syndrome X" or "insulin resistance syndrome" which includes hypertensio n, dislipidemia and hypercoagulation. Therefore, TZD class of insulin sensi tizers seem to have therapeutic potential to improve this clustering syndro me in addition to diabetes. Moreover, it was demonstrated that the TZD clas s of insulin sensitizers including troglitazone bind and activate the perox isome proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor. Although PPAR gamma is pre dominantly expressed in adipose tissu e, one of the target tissues for insulin, it have been subsequently found t o be expressed in macrophages, vascular smooth muscle cells (VSMC), endothe lial cells and several cancer cell lines. PPAR gamma activation by PPAR gam ma agonists such as TZD class of insulin sensitizers in these cells modulat es these cell functions such as the production of inflammatory cytokine by macrophages, proliferation and migration of VSMC, and growth or differentia tion in cancer cells. In addition, troglitazone has potent antioxidant effe ct, and suppresses both L-type and receptor operated Ca2+ channel and prote in kinase C. Thus since TZD class of insulin sensitizers has many kind of t herapeutic effect in addition to lowering blood glucose, these agents expec t to have therapeutic potential beyond diabetes. (C) 2000 Elsevier Science Inc. All rights reserved.