Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution

1 The blood glucose-lowering efficacy of rosiglitazone (RSG) and the mechanisms of associated weight gain were determined in dietary obese rats (DIOs). DIO and chow-fed rats received RSG 0.3-30 mg kg(-1) daily for 21 days. 2 In DIOs, plasma glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg kg(-1), respectively. Homeostasis model assessment (HOMA) indicated the threshold for a reduction of insulin resistance was 1 mg kg(-1). Neither glucose nor insulin levels were affected by treatment in chow-fed rats. 3 RSG 0.3 mg kg(-1) lowered free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the threshold was 3 mg kg(-1) By contrast, the threshold for reducing packed red cell volume (PCV) and increasing cardiac mass was 10 mg kg(-1).Thus, the therapeutic index for RSG in DIOs was >3 and less than or equal to 10. 4 Energy intake and weight gain increased in treated DIOs (by 20% and 50 g, at 30 mg kg(-1)) and chow-fed rats (by 25% and 35 g, at 30 mg kg(-1)). In DIOs, these increases coincided with falls in plasma leptin (40% lower at 30 mg kg(-1)) and insulin (43% lower at 30 mg kg). By contrast, in chow-fed rats, weight gain and hyperphagia occurred without changes in either leptin or insulin. However, reductions in FFAs below 0.4-0.3 mM were associated with hyperphagia and weight gain in DIO and chow-fed rats. 5 We conclude that increased energy intake and body weight did not :attenuate the improved metabolism evoked by RSG in DIO rats, and that insulin action was enhanced at a dose >3 fold below the threshold for causing haemodilution and cardiac hypertrophy in DIO rats.