Zucker diabetic fatty (ZDF) rats are a standard animal model for the study of type 2 diabetes and for pharmacological characterization of insulin-sensitizing drugs. To analyze the age-dependent development of their metabolic derangements and the associated changes in their responses to treatment with the insulin sensitizer pioglitazone, groups of 7, 10.5, or 15.5-week-old ZDF rats were treated orally with vehicle or pioglitazone (12 mg/kg/day). Metabolic parameters including circulating concentrations of glucose, insulin, lipids, and adiponectin as well as body weight, tissue glycogen content, and the activity of p70S6 kinase in skeletal muscle were determined. Blood glucose of ZDF rats rose steeply from 5.9 +/- 0.4 to 23.7 +/- 0.5 mM between 7 and 13 weeks of age and then reached a new steady state, which was associated with increased tissue glycogen content (in 15-week-old ZDF rats versus lean littermates: skeletal muscle, 18.0 +/- 0.9 versus 10.5 +/- 1.4 micromol/g; liver, 181 +/- 6 versus 109 +/- 14 micromol/g; both p < 0.001). Early intervention with pioglitazone at 7 weeks of age fully prevented the development of hyperglycemia (blood glucose, 6.4 +/- 0.4 versus 18.7 +/- 1.5 mM after 5.5 weeks of treatment), which was accompanied by a 40% (p = 0.01) reduction of the activity of p70S6 kinase in skeletal muscles. These beneficial effects of pioglitazone were progressively lost, if treatment was initiated at later stages of disease development. Thus, ZDF rats are suitable for preclinical characterization of insulin-sensitizing thiazolidinediones in many aspects, but several important differences versus human type 2 diabetes exist and are to be considered in the use of this animal model.