Abstract
Diabetes is a chronic, progressive disease that calls for longitudinal data and analysis. We introduce a longitudinal mathematical model that is capable of representing the metabolic state of an individual at any point in time during their progression from normal glucose tolerance to type 2 diabetes (T2D) over a period of years. As an application of the model, we account for the diversity of pathways typically followed, focusing on two extreme alternatives, one that goes through impaired fasting glucose (IFG) first, and one that goes through impaired glucose tolerance (IGT) first. These two pathways are widely recognized to stem from distinct metabolic abnormalities in hepatic glucose production and peripheral glucose uptake, respectively. We confirm this but go beyond to show that IFG and IGT lie on a continuum ranging from high hepatic insulin resistance and low peripheral insulin resistance to low hepatic resistance and high peripheral resistance. We show that IFG generally incurs IGT, and IGT generally incurs IFG on the way to T2D, highlighting the difference between innate and acquired defects and the need to assess patients early to determine their underlying primary impairment. We illustrate the relevance of this for patient stratification by simulating the effects of properly and improperly targeted therapies. The model also incorporates insulin granule exocytosis and accounts for both first and second phase secretion. Simulations suggest that the loss of first phase secretion in both the IGT-first and IFG-first pathways is only a marker of progression to diabetes, not a causative mechanism.
Footnotes
Additional figures have been included comparing the model outputs to published experimental data and additional commentary on features omitted from the model have been made in the Discussion.