The etiology and natural history of type 2 diabetes

Type 2 diabetes is a complex disorder characterized by progressive defects in nearly every aspect of metabolic regulation. Despite this complexity, traditional in vivo methodologies have limited experimental examination to a small number of metabolic indices at one or two points in time. As a result the etiology and natural history of this disease remain unclear and much debated. This thesis takes a two pronged approach to this problem. First, a mathematical model is developed to incorporate experimental data from different sources into an integrated representation of metabolic regulation. Bifurcation and simulation analysis of this model are used to investigate mechanisms of metabolic regulation as well as the pathogenesis of type 2 diabetes. Second, new experimental methodologies are developed that greatly improve the practicality of estimating several key metabolic indices in vivo. Applying these methodologies to animal models of type 2 diabetes allowed us to perform a fully dynamic and integrative analysis of the pathogenesis of type 2 diabetes in two commonly used animal models. Overall, data from this thesis suggests that the etiology of type 2 diabetes lies in two distinct abnormalities; rapid development of insulin resistance coupled to impaired P-cell mass adaptation.