The thiazolidinediones are highly selective and potent agonists for the PPAR-g (Fig. 1) (5,6). These receptors are important regulators of adipocyte differentiation, lipid homeostasis, insulin action, and vascular endothelial function and are found not only in key target tissues for insulin action, such as adipose tissue, skeletal muscle, and liver, but also in the vascular endothelium, macrophages and other cell types (5,6). The thiazolidinediones act, at least in part, by binding with PPAR-g in various tissues to influence/alter the expression of a number of genes encoding proteins involved in glucose and lipid metabolism, endothelial function and atherogenesis (5-7). The glucose-lowering effects of the thiazolidinediones involve the alteration of the expression of several genes involved in glucose and lipid metabolism, including glucose transporter (GLUT)1, GLUT4, leptin, tumor necrosis factor-a, hepatic glucokinase, Phosphoenolpyruvate carboxykinase (PEPCK), fatty acid (FA) binding protein, FA transport protein, and acyl CoA oxidase. These changes lead to improved metabolic effects, such as improved adipose tissue insulin sensitivity resulting in decreased free fatty acid (FFA) release and increased adiponectin release; improved hepatic insulin sensitivity, decreased gluconeogenesis and decreased hepatic glucose production; and improved muscle insulin sensitivity with increased tissue glucose uptake. Perhaps the most exciting development in the field of adipocyte biology and thiazolidinedione action has been the identification and characterization of the adipocyte-derived hormone
FIGURE 1 Cellular effects of the thiazolidinediones on the PPAR receptor.
adiponectin (8). Adipose tissue expression of adiponectin is lower in insulin-resistant states and lower plasma levels of adiponectin have been documented in human subjects with obesity, type 2 diabetes, or coronary artery disease (CAD). Studies in humans demonstrate a close correlation between changes in plasma levels of adiponectin after thiazolidinedione treatment and measures of insulin-mediated glucose metabolism and adipose tissue distribution (8).
Currently, it is still not clear if the thiazolidinediones produce in vivo insulin-sensitizing effects by altering expression of adipocyte genes, which, in turn, convey some signal (metabolic or non-metabolic) to other insulin-sensitive tissues, and/or they exert direct effects on these tissues. Since the thiazolidinediones potently induce adipocyte differentiation, it is possible that the primary action of thiazolidinediones is in fat cells, with secondary effects on skeletal muscle and other insulin-sensitive tissue to improve insulin action, possibly through a thiazolidinedione-mediated changes in circulating FFA levels, adiponectin secretion, or some other signal (Fig. 2).
Was this article helpful?