Unraveling the mechanism of action of thiazolidinediones

Thiazolidinediones (TZDs) are a new class of antidiabetic agents and include three compounds that have come to clinical use — troglitazone (Rezulin®), rosiglitazone (Avandia®), and pioglitazone (Actos®) — as well as several others that have been limited to pre-clinical study. TZDs were initially discovered by screening compounds for a hypoglycemic action in the ob/ob mouse (1), and subsequently they were shown to improve insulin action in a variety of obese and diabetic animal models with insulin resistance (2). In these model systems, TZDs reduce plasma glucose and insulin levels and improve some of the abnormalities of lipid metabolism. Consistent with animal studies, clinical studies have shown that treatment of type 2 diabetic patients with TZDs can lower serum glucose and insulin levels, increase peripheral glucose uptake, and decrease triglyceride levels (3). In euglycemic clamp studies, this is associated with an increase in insulin sensitivity in peripheral tissues (mainly represented by muscle in clamp studies), with relatively little effect on hepatic glucose output (4).