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

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Fig. 1.
The PK/PD model for rosiglitazone in GK rats. Symbols are defined in the text and tables.
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Fig. 2.
Time courses of rosiglitazone pharmacokinetics after 5 (a) and 10 (b) mg/kg doses in GK rats according to eq. 1. Symbols represent the individual PK observations, and lines are model fittings. In c, lines are simulated rosiglitazone PK profiles during the chronic dosing period.
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Fig. 3.
The time course of glucose (left) and insulin (right) concentrations in the placebo (top), 5 mg/kg-treated (middle), and 10 mg/kg-treated (bottom) rats. Symbols are individual observations and lines are model fittings.
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Fig. 4.
The time course of body weights for the control (left), 5 mg/kg treatment (middle), and 10 mg/kg treatment (right) groups. Symbols are individual observations, and lines are model fittings.
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Fig. 5.
Simulated profiles of insulin sensitivity in GK rats for various dosing regimens.

TABLE 1

Parameters resulting from oral glucose tolerance tests in GK rats

Results shown are mean ± S.D.

Day	Number of Rats	Group	Measurement
Day	Number of Rats	Group	FG	FI	AUC_INS/GLU	WBISI	HOMA-IR^{^a}
			mg/dl	ng/ml	10⁻⁵
0	6		209 ± 12	1.43 ± 0.37	3.93 ± 0.50	1.94 ± 0.24	16.2 ± 4.0
25	4	Placebo	168 ± 18	1.49 ± 0.56	5.03 ± 1.41	1.37 ± 0.49	13.6 ± 5.7
	3	Low dose	146 ± 6^*	1.17 ± 0.28	3.98 ± 0.74	1.73 ± 0.34	9.8 ± 2.1
	4	High dose	142 ± 8^*	1.33 ± 0.36	5.00 ± 1.87	1.72 ± 0.59	10.2 ± 2.7
42	4	Placebo	162 ± 28	1.46 ± 0.50	4.28 ± 1.10	1.49 ± 0.62	13.0 ± 5.3
	4	Low dose	177 ± 11	1.47 ± 0.40	4.85 ± 1.35	1.27 ± 0.46	14.2 ± 4.3
	4	High dose	145 ± 15^*	1.05 ± 0.32	3.98 ± 0.70	2.04 ± 0.42^*	8.2 ± 2.7^*

↵a For HOMA-IR calculations, the glucose unit is mmol/l, and the insulin unit is μIU/ml.
↵* P < 0.05 vs. placebo.

TABLE 2

Hematology in GK rats

Results shown are mean ± S.D.

Day	Number of Rats	Group	Measurement
Day	Number of Rats	Group	RBC	Hb	Hct	HbA1c
			× 10⁶ cell	g/dl	%	%
0	7	Placebo	7.8 ± 0.4	15.8 ± 0.9	50.0 ± 2.8	4.94 ± 0.24
	6	Low dose	6.6 ± 1.4	13.1 ± 2.9	42.3 ± 9.3	4.75 ± 0.14
	7	High dose	7.2 ± 0.8	14.4 ± 1.6	46.0 ± 5.3	4.80 ± 0.19
25	7	Placebo	8.6 ± 0.9	16.1 ± 1.7	51.1 ± 7.4	5.19 ± 0.14
	6	Low dose	8.9 ± 0.2	16.6 ± 0.5	53.8 ± 1.6	4.95 ± 0.15^**
	7	High dose	8.3 ± 0.6	15.4 ± 1.2	49.8 ± 3.7	4.86 ± 0.27^**
42	7	Placebo	9.0 ± 0.7	16.2 ± 1.2	53.4 ± 3.8	5.41 ± 0.22
	5	Low dose	9.0 ± 0.5	16.3 ± 1.2	53.4 ± 2.8	5.20 ± 0.22
	7	High dose	9.4 ± 0.2	17.0 ± 0.5	54.1 ± 2.2	5.19 ± 0.20^*
84	7	Placebo	9.8 ± 0.8	17.9 ± 0.4	58.1 ± 1.6	6.89 ± 1.61
	5	Low dose	9.3 ± 0.8	16.7 ± 1.6	54.8 ± 4.9	5.86 ± 0.64
	7	High dose	9.8 ± 0.1	17.8 ± 0.2	57.7 ± 0.6	5.61 ± 0.32^*

TABLE 3

Pharmacodynamic parameter estimates for glucose-insulin and body weights

Parameter	Definition	Estimate (CV%)
k_outI, day⁻¹	Insulin output rate constant	408^{^a}
k_outG, day⁻¹	Glucose output rate constant	66^{^a}
I₀, ng/ml	Basal insulin (placebo, 5 and 10 mg/kg)	4.02, 2.83, 3.28^{^b}
G₀, mg/dl	Basal glucose (placebo, 5 and 10 mg/kg)	271, 260, 238^{^b}
S_G, dl/mg	Glucose sensitivity	0.03426 (75)
k_dis	Disease factor on insulin sensitivity	0.720 (7)
k_{el_p}, day⁻¹	Placebo elimination rate constant	2.68 (64)
k_pl, kg/mg·day	Placebo effect constant	0.388 (62)
k_eo, day⁻¹	Biophase rate constant	0.996 (69)
S_R, kg/mg	Protection factor on insulin sensitivity	0.0796 (20)
IC₅₀, μg/ml	Concentration for 50% of glucose inhibitory effect	1.97 (93)
I_max	Inhibition factor on glucose production	0.296 (39)
k_d^w, day⁻¹	Body weight output rate constant	0.0213 (5)
WT_ss, g	Steady-state body weight	398^{^a}
ID_50p, mg/kg	Placebo effect constant on body weight	10.20 (3)
ID_50w, mg/kg	Dose for 50% body weight loss inhibition	96.8 (16)