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Abstract
Published compact and extended models of the glucose-insulin physiologic control system are compared, in order to understand why a specific functional form of the compact model proved to be necessary for a satisfactory representation of acute perturbation experiments such as the Intra Venous Glucose Tolerance Test (IVGTT). A spectrum of IVGTT’s of virtual subjects ranging from normal to IFG to IGT to frank T2DM were simulated using an extended model incorporating the population-of-controllers paradigm originally hypothesized by Grodsky, and proven to be able to capture a wide array of experimental results from heterogeneous perturbation procedures. The simulated IVGTT’s were then fitted with the Single-Delay Model (SDM), a compact model with only six free parameters, previously shown to be very effective in delivering precise estimates of insulin sensitivity and secretion during an IVGTT. Comparison of the generating, extended-model parameter values with the obtained compact model estimates shows that the functional form of the nonlinear insulin-secretion term, empirically found to be necessary for the compact model to satisfactorily fit clinical observations, captures the pancreatic reserve level of the simulated virtual patients. This result supports the validity of the compact model as a meaningful analysis tool for the clinical assessment of insulin sensitivity.
Highlights
Mathematical models for representing and simulating insulin/glucose metabolism, both in normal conditions and under perturbation tests, have been developed and used since the 1960’s [1]. Their importance resides in the possibility to better understand the pathophysiology and development of Type 2 Diabetes Mellitus (T2DM) and of its pre-conditions, such as Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG)
In a previous work [24] we obtained very good fits of the Compact Model on the Extended Model using directly parameters reported in [17] for generating virtual patients with profiles ranging from Normal Glucose Regulation (NGR) to T2DM; we introduce here some modifications of the Extended Model in order to better reproduce observed Intra-Venous Glucose Tolerance Test (IVGTT) from a larger sample of clinical tests
Since the insulin-sensitivity parameter is present in both models, we reported in the same plot (Fig 7) the relation between the generating k2 parameter values and the corresponding estimated kXGI values: as it is clear from the figure, the cloud of points lies mostly along the line kXGI = k2, showing that the Compact Model [10] and the Extended Model are very consistent in particular for what concerns insulin sensitivity
Summary
Mathematical models for representing and simulating insulin/glucose metabolism, both in normal conditions and under perturbation tests, have been developed and used since the 1960’s [1]. Their importance resides in the possibility to better understand the pathophysiology and development of Type 2 Diabetes Mellitus (T2DM) and of its pre-conditions, such as Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG). More extended models are used to simulate virtual patients in order to test control algorithms, Comprehensive models of the glucose-insulin system [7, 8] allow to simulate healthy subjects and T2DM patients for clinical research purposes, e.g. for testing control algorithms in silico
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