Dynamics of disease progression and drug effects in type 2 diabetic rats
Type 2 Diabetes (T2D) is a prevailing chronic progressive metabolic disorder with disturbance of the glucose-insulin feedback system. The disease progression of T2D involves insulin resistance and decreased β-cell function. Multiple factors, such as genetic disposition, and drug interventions, influence the development of T2D. Numerous studies have been done in human and animals about the time-course of T2D progression under different interventions. Disease progression modeling (DPM) is a powerful tool to study degenerative disease progression under these factors. However, the applications of DPM to T2D are limited. This thesis investigated the time course of T2D in the model animal, Goto-Kakizaki (GK) rats, under natural conditions and drug treatment. The basic structural model for the glucose and insulin system, the feedback model, was selected based on the analysis of glucose tolerance tests conducted in monkeys. With the basic model, by including disease components on insulin sensitivity and β-cell function, the mechanism-based disease progression model successfully characterized T2D development in GK rats. After chronic treatment with the insulin sensitizer: rosiglitazone, GK rats presented with improved insulin sensitivity. A PK/PD/Disease model adequately described the effect of rosiglitazone on glucose and insulin turnover, as well as disease progression. Another relatively new drug: exendin-4, which has promising β-cell protection, was also investigated. Exendin-4 showed target-mediated disposition in healthy and GK rats, monkeys and humans. This drug showed the direct stimulation effect on insulin release, but a more complicated effect on glucose. The proposed PK/PD model well characterized exendin-4 disposition and effects on glucose and insulin in vivo homeostasis. In summary, this thesis not only extends the understanding of disease progression of T2D, but also provides us with insights for dynamics of anti-diabetic drug treatment in acute and chronic time frame. The sophisticated PK/PD/Disease models, starting from the parsimonious feedback structure model, exemplify quantitative approaches which are feasible for investigating physiology system and drug effects.