Integrated Modeling of Glucose and Insulin Regulation Following Provocation Experiments

Abstract: Blood glucose is controlled by a complex system of insulin and other hormones to assure a constant supply of glucose to the tissues. Type 2 diabetes is a metabolic disorder which is characterized by progressively worsening glycemic control due to a relative deficiency of insulin secretion and a decreased response to insulin. Numerous mathematical models have been developed with the aim of describing glucose and insulin regulation. A drawback with most previously presented models is that they use an open-loop approach which simplifies the model development but at the same time limits the possible use for predictive purposes.The integrated glucose-insulin model presented in this thesis is a semi-mechanistic model which describes glucose and insulin simultaneously. The model has been used to analyze both intravenous and oral provocations and has been shown to describe and predict healthy and diabetic individuals well. Important differences between healthy and diabetic individuals were identified in insulin secretion and sensitivity. The model was used for design optimization of the intravenous glucose tolerance test and it was shown that the design could be improved and simplified by reduction of the number of samples and by change of glucose and insulin dose. Two methodological aspects which were of importance for model development were evaluated. These were (i) comparison of methods for incorporation of baseline data, and (ii) evaluation of the effects of model misspecification on hypothesis testing for covariate inclusion. Baseline information should be included in the model using either of three presented methods and normalization or subtraction of baseline should be avoided. The likelihood ratio test performed well in most cases except when serial correlation was present.In conclusion, a new model for glucose and insulin regulation has been proposed which is expected to play an important role in clinical development of anti-diabetic drugs.