Glucose Homeostasis Modeling: Improvement of the Insulin Action Component
Roberto Bizzotto (1), Andrea Natali (2), Ele Ferrannini (2), Andrea Mari (1)
(1) Institute of Biomedical Engineering, National Research Council, Padova, Italy; (2) Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy
Objectives: Glucose homeostasis models are important for predicting the effects of antidiabetic drugs. Some relevant models already exist [1]; however, the complexity of the system requires refinements of the model components to achieve better accuracy. In current models, glucose clearance is typically dependent on insulin but not on glucose concentration. This is not correct [2], but a quantitative analysis of the phenomenon is lacking, and the aim of this study was address this issue.
Methods: Data were obtained from a combined hyperglycemic/hyperinsulinemic clamp [3] in 8 healthy subjects, with glucose (5-18 mmol/L) and insulin (20-10000 pmol/L) spanning wide ranges. A glucose tracer was used to calculate glucose clearance. A model (A) was developed based on a circulatory model of glucose kinetics [4] and a model for insulin action that includes a simplified description of interstitial diffusion and insulin-controlled glucose transport across the cell membrane. Model parameters were estimated in each subject individually using Matlab/Simulink. A prototypal glucose homeostasis model (B) was then set up by adding a b-cell [5] and glucose appearance [6] submodel. Model B was used to simulate an oral glucose test (OGTT), including or excluding the glucose effect on clearance of model A.
Results: Estimation of model A parameters provided a good fit of the tracer data. The model was able to reproduce a characteristic feature of these data, i.e., the lack of glucose clearance increase in presence of hyperinsulinemia accompanied by hyperglycemia. The prediction of the dependence of glucose clearance on glucose concentration was qualitatively in agreement with what is known from the literature. In a representative subject, glucose clearance at an insulin concentration of 500 pmol/L was reduced from 81 to 42 ml min-1m-2 when glucose was raised from 5 to 10 mmol/L. The OGTT simulation with model B showed that the impact of the glucose effect on clearance was remarkable: including vs. excluding the effect produced an increase in 2-h glucose post OGTT from 6.7 to 7.6 mmol/L.
Conclusions: The new glucose clearance model can describe experimental characteristics that cannot be reproduced by more classical models; accounting for the dependence of glucose clearance on glucose concentration has a remarkable impact on glucose homeostasis. Thus, this model is expected to improve the representation of glucose homeostasis, with benefit for the prediction of drug effects.
References:
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[4] Natali A, Gastaldelli A, Camastra S, Sironi AM, Toschi E, Masoni A, Ferrannini E, Mari A: Dose-response characteristics of insulin action on glucose metabolism: a non-steady-state approach. Am J Physiol Endocrinol Metab 278:E794-801, 2000
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[6] Bonuccelli S, Muscelli E, Gastaldelli A, Barsotti E, Astiarraga BD, Holst JJ, Mari A, Ferrannini E: Improved tolerance to sequential glucose loading (Staub-Traugott effect): size and mechanisms. Am J Physiol Endocrinol Metab 297:E532-537, 2009
This study has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DDMoRe project is also financially supported by contributions from Academic and SME partners.
