Integrating a Model for Weight Change into the Mechanism-Based Model for Type 2 Diabetes
W. de Winter(1), S. Rossenu (1), A. Dunne (1), A. Vermeulen (1)
(1) Advanced Modeling & Simulation, Divison of Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
Background: Obesity and weight gain, caused by an imbalance between energy intake and energy expenditure, play a primary role in the development of type 2 diabetes mellitus. Excessive fat storage, especially intra-abdominally, causes loss of insulin sensitivity in liver, fat and muscle tissues. Initially, this reduced insulin sensitivity is compensated by increased insulin secretion, but in many patients the beta-cells cannot keep this up indefinitely, leading to elevated blood glucose and overt diabetes. Because of this close interplay between body weight regulation and the disease processes underlying type 2 diabetes, most antidiabetic agents also affect body weight and fat storage, either by increasing or reducing it. This may have important consequences for the long-term effects of a compound on disease progression and cardiovascular clinical outcomes.
Objectives: To develop a mechanism-based, integrated model of type 2 diabetes disease progression and body weight change that allows the estimation of the direct effects of antidiabetic treatment on glucose homeostasis and disease progression, as well as its indirect effects via body weight change.
Methods: The mechanism-based disease progression model for type diabetes [1] is integrated with an in-house developed turn-over model for body weight change based on the energy flux balance equation [2]. The models are implemented in NONMEM VI on phase III data comparing topiramate 96 and 192 mg to placebo in obese diabetic patients.
Results: The models provide adequate descriptions of the data. Because the patient population was typically early in the disease, the differential equation for HbA1c in original diabetes disease progression model [1] is modified to take account of the relatively larger contribution to HbA1c formation of post-prandial glucose excursions. An issue to be resolved were the different time-scales of the physiological processes represented in the model: changes in the glucose-insulin homeostasis take place in a matter of minutes, whereas changes in HbA1c and body weight occur over weeks or months. Therefore, in the original diabetes model [1], the differential equations for fasting plasma glucose and insulin are reduced to their steady-state solutions. The added value of integrating the weight change model into diabetes disease progression model is evaluated.
Conclusions: Type 2 diabetes mellitus is disorder not only of glucose homeostasis, but also of lipid metabolism and storage and as such tightly linked to body weight regulation. This is highlighted by the fact that cardiovascular disease is the primary cause of death among type 2 diabetics. In this light, the model presented here can be seen as a further step towards a full, comprehensive disease model of type 2 diabetes and its long-term clinical outcomes.
References:
[1] De Winter et al. (2006) A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying Type 2 Diabetes Mellitus. J. Pharmacokin Pharmacodyn, Vol. 33-3, pp. 313-343.
[2] E.g. Chow CC, Hall KD (2008) The Dynamics of Human Body Weight Change. PLoS Comput Biol 4(3): e1000045. doi:10.1371/journal.pcbi.1000045