A physiology based model for the glucose-insulin regulation in healthy volunteers and diabetic patients following intravenous glucose provocations.

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Objectives: The aim of this project was to develop a physiology based model to simultaneously describe the glucose and insulin regulation following different intravenous glucose provocations in healthy volunteers and type II diabetic patients.

Methods: The model was developed based on mechanistic knowledge of the insulin-glucose regulation. Data without drug effect from 30 volunteers and 42 patients and four different trials were used. All individuals received an intravenous glucose provocation, with or without insulin infusion. The administered glucose was enriched with stable-labeled glucose. Blood samples were drawn pre-dose and until 240 minutes post-dose for the determination of plasma glucose, labeled glucose and insulin concentrations. Six individuals received a euglycemic and hyperinsulinemic clamp experiment from which only labeled glucose concentrations were available. Simultaneous analysis of all data by non-linear mixed effect modeling was done in NONMEM version 6.

Results: The glucose submodel contained a two-compartment disposition model with endogenous production and insulin dependent and independent elimination. The insulin submodel contained a one-compartment disposition model with endogenous production and release, distinguishing between the early and late phase of insulin secretion. Labeled glucose was assumed to have the same disposition properties as total glucose with the exception of endogenous production. Control mechanisms were incorporated into the model to account for the regulation of glucose and insulin production, dependent on glucose concentration, and glucose elimination, dependent on insulin concentration. Differences between volunteers and patients were identified and quantified. Goodness-of-fit graphs show that the model was able to describe the data well. Simulations from the model well mimicked concentration-time profiles of insulin and total glucose from the experiments. With design-specific estimates for insulin dependent glucose elimination clearance (mechanistically plausible as different tests give rise to different hepatic-to-peripheral insulin ratios) also labeled glucose was well simulated.

Conclusion: The model presented here allows the simultaneous prediction and simulation of glucose, labeled glucose and insulin in volunteers and patients following three different intravenous glucose provocation tests.