Integrated model of insulin and glucose kinetics describing both hepatic glucose and pancreatic insulin regulation

BACKGROUND AND OBJECTIVES: Modeling of glucose kinetics has to a large extent been based on models with plasma insulin as a known forcing function. Furthermore, population-based statistical methods for parameter estimation in these models have mainly addressed random inter-individual variations and not intra-individual variations in the parameters. Here we present an integrated whole-body model of glucose and insulin kinetics which extends the well-known two-compartment glucose minimal model. The population-based estimation technique allow for quantification of both random inter- and intra-individual variation in selected parameters using simultaneous data series on glucose and insulin.

METHODS: We extend the two-compartment glucose model into a whole-body model for both glucose and insulin using a simple model for the pancreas compartment which includes feedback of glucose on both insulin secretion and formation of insulin in pancreas. The model has 15 unknown parameters of which 8 have been selected for both intra- and inter-individual variations. The statistical technique for parameter estimation is based on first order conditional estimation.

RESULTS: The model has been evaluated on two datasets: Study group 1 includes 13 healthy subjects with 3-5 repeated IVGTT series of simultaneous plasma glucose and insulin measurements and Study group 2 includes 26 obese patients (3 subgroups: 10 type 2 diabetes (T2D), 7 impaired glucose tolerance (IGT) and 9 normal glucose tolerance (NGT)) with a single IVGTT series. In general the estimated population parameters compares well with reported values in similar studies. Overall the model fits the data series well and the random variation in the 8 selected parameters can account for both intra- and inter-individual variations in the data series. Simulation studies perform reasonable in response to either a slow glucose infusion or a staircase experiment with increasing glucose infusion. Furthermore, the parameters related to the pancreas compartment add useful interpretations in relation to discrimination between populations with varying degree of glucose intolerance.

CONCLUSIONS: We report a new and improved whole-body model of glucose and insulin kinetics which performs robustly under differing conditions and adds useful interpretations in relation to glucose intolerance.