Troglitazone and structurally related compounds (
pioglitazone,
rosiglitazone etc.) containing
thiazolidinediones (TZD) are a novel class of
antidiabetic agents which decrease
blood glucose in diabetic animal models and in patients with
Non-Insulin-Dependent Diabetes Mellitus (
NIDDM) through alleviating
insulin resistance. A large body of evidence is now accumulating indicating that
insulin resistance and/or resulting
hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome called "syndrome X" or "
insulin resistance syndrome" which includes
hypertension, dislipidemia and hypercoagulation. Therefore, TZD class of
insulin sensitizers seem to have therapeutic potential to improve this clustering syndrome in addition to diabetes. Moreover, it was demonstrated that the TZD class of
insulin sensitizers including
troglitazone bind and activate the
peroxisome proliferator-activated receptor gamma (
PPARgamma), a
nuclear hormone receptor. Although
PPARgamma is predominantly expressed in adipose tissue, one of the target tissues for
insulin, it have been subsequently found to be expressed in macrophages, vascular smooth muscle cells (VSMC), endothelial cells and several
cancer cell lines.
PPARgamma activation by
PPARgamma agonists such as TZD class of
insulin sensitizers in these cells modulates these cell functions such as the production of inflammatory
cytokine by macrophages, proliferation and migration of VSMC, and growth or differentiation in
cancer cells. In addition,
troglitazone has potent
antioxidant effect, and suppresses both L-type and receptor operated Ca2+ channel and
protein kinase C. Thus since TZD class of
insulin sensitizers has many kind of
therapeutic effect in addition to lowering
blood glucose, these agents expect to have therapeutic potential beyond diabetes.