Mathematical diabetes disease progression modeling in the integrated glucose-insulin model among individuals with impaired glucose tolerance from the Finnish Diabetes Prevention Study

The integrated glucose-insulin (IGI) model describes glucose and insulin after glucose administration in healthy individuals and patients with type 2 diabetes. The model, however, does not include disease progression (DP) from prediabetes to overt diabetes, which is driven by decreased insulin sensitivity and relative beta-cell failure. The objective of this study was to develop the IGI model to include the DP model for glucose and insulin in individuals with impaired glucose tolerance (IGT), with and without lifestyle intervention. Data of frequently sampled intravenous glucose tolerance test and oral glucose tolerance test (OGTT) were obtained from a sub study of the Finnish Diabetes Prevention Study (FDPS) in 101 individuals with IGT, randomly assigned to control and lifestyle intervention groups. A combination of intravenous and oral IGI model was used to fit the baseline until the fourth-year data using NONMEM, with prior information. The first-phase insulin secretion (FPS) and insulin-dependent glucose clearance (CLGI) decreased by 3.0% year and 8.1%/year, due to DP. Baseline insulin concentration (ISS) was increased by 68% from baseline to Year 1, and remained unchanged thereafter. With intervention, a net reduction of 0.1%/year for FPS and reduction of 2.1%/year for CLGI was quantified, translated to a much slower deterioration of the first-phase insulin secretion and insulin sensitivity. The ISS was affected by a net increase of 153% from baseline to Year 1 and remained constant after that, possibly reflecting beta-cell function improvement. The DP was successfully included in the IGI model to describe differences in IGT population, with and without lifestyle intervention.