Type II diabetes is associated with three basic pathophysiologic abnormalities: impaired insulin secretion, excessive hepatic glucose production, and insulin resistance in skeletal muscle, liver, and adipose tissue.<sup>7 DeFronzo R.A., Bonadonna R.C., Ferrannini E. Pathogenesis of NIDDM: A balanced overview Diabetes Care 1992 ;  15 : 318-368

Cliquez ici pour aller à la section Références</sup> The pharmacologic agents available for the treatment of type II diabetes have focused primarily on delaying gastrointestinal glucose absorption (alpha-glucosidase inhibitors), increasing insulin availability (sulfonylureas, insulin), or suppressing excessive hepatic glucose production (biguanides). Treatment modalities have not acted mechanistically to impact directly on the underlying pathology of insulin resistance.

After its synthesis in 1982,<sup>47 Sohda T., Mizuno K., Imamiya E. , et al. Studies on antidiabetic agents. II. Synthesis of 5-[4-(1-methylcyclohexylmethylmethoxy)benzyl]thiozolidine-2,4-dione(ADD-3878) and its derivatives Chem Pharm Bull 1982 ;  30 : 3580-3585

Cliquez ici pour aller à la section Références</sup> it was discovered that the thiazolidinedione derivative ciglitazone could reduce insulin resistance in obese and diabetic animals.<sup>10 Fujita T., Sugiyama Y., Taketomi S. , et al. Reduction of insulin resistance in obese and/or diabetic animals by 3[-4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3870, U-63,287,ciglitazone), a new antidiabetic agent Diabetes 1983 ;  32 : 804-810

Cliquez ici pour aller à la section Références</sup> Following extensive testing of numerous hindered phenolic compounds, several other agents were developed, including pioglitazone, englitazone, troglitazone, and BRL 49653 (Figure 1). These compounds are orally active and chemically and functionally unrelated to the other oral antidiabetic agents, including sulfonylureas, biguanides, and alpha-glucosidase inhibitors. Clinical development of most of these compounds has not progressed because of their unacceptable side effect profile. A thiazolidine-2-4-dione structure is common to all agents of this class, but they differ in side-chain modifications which influence their pharmacologic actions and potential for adverse effects. Unlike the other thiazolidinediones, troglitazone was designed to contain an alpha-tocopherol moiety to combine potent lipid peroxide inhibition with hypolipidemic and insulin-sensitizing properties.<sup>57 Yoshioka T., Aizawa Y., Fujita T. , et al. Studies on hindered phenols and analogues. V. Synthesis, identification, and antidiabetic activity of the glucuronide of CS-045 Chem Pharm Bull 1991 ;  39 : 2124-2125

Cliquez ici pour aller à la section Références, 58 Yoshioka T., Fujita T., Kanai T. , et al. Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation J Med Chem 1989 ;  32 : 421-428  [cross-ref]

Cliquez ici pour aller à la section Références</sup> Because troglitazone is the only thiazolidinedione to have undergone extensive testing in humans, it is the focus of this review.