Background: A previously developed semi-mechanistic model [1] linked fasting serum insulin (FSI), fasting plasma glucose (FPG), and glycosylated haemoglobin (HbA1c) to characterise the disease progression of newly diagnosed type 2 diabetic (T2DM) patients. To build upon the model, weight change (DWT) as an effector to the FSI-FPG-HbA1c relationship was implemented in the present study.
Methods: Non-linear mixed effects modelling using NONMEM 7.2 was performed on placebo arm data collected from 181 newly diagnosed (treatment naive) T2DM Swedish obese patients (mean baseline weight = 104 kg) with a controlled diet. The subjects were given diet and exercise (D&E) counselling starting from screening 7 weeks before the start of the study, as well as placebo starting from randomisation. The study duration was 60 weeks. The effect of D&E is modelled as an inhibitory effect on the input to weight, and DWT is used as the predictor of treatment effect on insulin sensitivity (IS), which drives the FPG-FSI homeostasis.
Results: D&E had a weight loss effect on the patients (mean DWT = -1.8kg at 90 days; -4.1kg at end of study), which was reflected as an initial decrease in FPG (8.0 to 7.5 mmol/L) and HbA1c (6.8 to 6.5%) at 90 days. The estimated baseline values for beta-cell function and IS was 32.1% and 7.5% of normal, respectively. At the end of the study the mean gain in IS due to DWT was 45%. The disease progression of T2DM counters the FPG-lowering effect of D&E which at the end of the study period elevated the FPG and HbA1c back to near baseline levels.
Conclusions: The addition of weight change as an effector was successfully applied to the semi-mechanistic disease progression model for T2DM. As T2DM is intricately linked with obesity further application of this updated model could prove useful in understanding this disease.
