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

Abstract

1 The blood glucose-lowering ecacy 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 71 daily for 21 days. 2 In DIOs, plasma glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg kg 71, respectively. Homeostasis model assessment (HOMA) indicated the threshold for a reduction of insulin resistance was 1 mg kg 71 . Neither glucose nor insulin levels were aected by treatment in chow-fed rats. 3 RSG 0.3 mg kg 71 lowered free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the threshold was 3 mg kg 71 . By contrast, the threshold for reducing packed red cell volume (PCV) and increasing cardiac mass was 10 mg kg 71 . Thus, the therapeutic index for RSG in DIOs was 43 and 410. 4 Energy intake and weight gain increased in treated DIOs (by 20% and 50 g, at 30 mg kg 71) and chow-fed rats (by 25% and 35 g, at 30 mg kg 71 ). In DIOs, these increases coincided with falls in plasma leptin (40% lower at 30 mg kg 71 ) and insulin (43% lower at 30 mg kg 71 ). 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 43 fold below the threshold for causing haemodilution and cardiac hypertrophy in DIO rats.

The Effect of Leptin, Tumor Necrosis Factor-α (TNF-α), and Nitric Oxide (NO) Production on Insulin Resistance in Otsuka Long-Evans Fatty Rats

“…Insulin resistance was expected to be enhanced by the change of leptin, TNF-a and NO [12,18,32,33]. To evaluate insulin resistance, we used the HOMA-R, which is well correlated with M-values obtained by euglycemic hyperinsulinemic clamp [35][36][37]. We demonstrated that leptin played an important role in the regulation of insulin sensitivity.…”

“…Serum leptin levels were measured by an ELISA kit (Amersham Pharmacia Biotech, Tokyo, Japan) with a lower limit of 0.2 ng/ml. HOMA-R was calculated as an indicator of insulin resistance [35][36][37] according to the formula: HOMA-R = Fasting glucose (mM) × Fasting insulin (mU/ml)/22.5…”

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

“…Also, Rosiglitazone has been reported to induce hyperphagia and weight gain in rats, 65 and in both chow-fed (ie nonobese) and dietary obese rats, the size of the weight gain showed a linear correlation to the lowering in plasma FFA levels, but without changes in insulin or leptin levels. 66 Hence, TZDinduced improvement of insulin sensitivity seems to increase appetite and perhaps increase feed efficiency. The concept of adipose tissue functioning as a 'sink' for fatty acids to prevent an overload of lipid supply to other tissues has been suggested, 67 and this hypothesis may seem reasonable.…”

Tempol Reduces Oxidative Stress, Improves Insulin Sensitivity, Decreases Renal Dopamine D1 Receptor Hyperphosphorylation, and Restores D1 Receptor–G-Protein Coupling and Function in Obese Zucker Rats

“…Urinary cGMP was measured with a cGMP ELISA kit (R & D Systems, Minneapolis, MN). Homeostasis model assessment, which incorporates measures of both fasting plasma concentrations of glucose and insulin, was used to calculate an index of insulin resistance as insulin (microunits per milliliter) ϫ glucose (millimoles per liter)/22.5 (26). To evaluate renal function, urine volume was measured gravimetrically, and urine flow (milliliters per minute) was calculated.…”