Modeling Disease Progression and Rosiglitazone Intervention in Type 2 Diabetic Goto-Kakizaki Rats

Abstract

The pharmacokinetics (PK) and pharmacodynamics (PD) of rosiglitazone were studied in type 2 diabetic (T2D) Goto-Kakizaki (GK) rats that received daily doses of 0, 5, or 10 mg/kg for 23 days followed by 60 days of washout. Blood glucose, plasma insulin, and hemoglobin A1c were determined over time. Oral glucose tolerance tests were performed before and at the end of treatment and after 20 days of washout to determine insulin sensitivity and β-cell function. Rosiglitazone effectively lowered glucose by inhibiting hepatic glucose production and enhancing insulin sensitivity. The glucose-insulin inter-regulation was characterized by a feedback model: glucose and insulin have their own production (k(in)) and elimination (k(out)) rate constants, whereas glucose stimulates insulin production (k(inI)) and insulin, in turn, promotes glucose utilization (k(outG)). Animal handling and placebo treatment affected glucose turnover with k(pl) = 0.388 kg/mg/day. The PK of rosiglitazone was fitted with a one-compartment model with first-order absorption. The effect of rosiglitazone was described as inhibition of k(inG) with I(max) = 0.296 and IC(50) = 1.97 μg/ml. Rosiglitazone also stimulated glucose utilization by improving insulin sensitivity with a linear factor S(R) = 0.0796 kg/mg. In GK rats, 23 days of treatment increased body weight but did not cause hemodilution. Weight gain was characterized with body weight input (k(s)(w)) and output (k(d)(w)), and rosiglitazone inhibited k(d)(w) with ID(50) = 96.8 mg/kg. The mechanistic PK/PD model quantitatively described the glucose-insulin system and body weights under chronic rosiglitazone treatment in T2D rats.