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Mathematical modeling of the glucagon challenge test
Saeed Masroor1, Marloes G J van Dongen2, Ricardo Alvarez-Jimenez3
1Maastricht University, Maastricht, The Netherlands.
Journal of Pharmacokinetics and Pharmacodynamics
|October 2, 2019
Summary
This study models glucose homeostasis, incorporating glucagon receptor internalization. The model explains how this process leads to reduced blood glucose response to glucagon challenges, particularly in patients treated with anti-sense drugs.
Area of Science:
- Biochemistry
- Physiology
- Pharmacology
Background:
- Glucose homeostasis is regulated by insulin and glucagon.
- Glucagon receptor internalization is a key cell signaling mechanism.
- Anti-sense drugs targeting glucagon receptors are being developed.
Purpose of the Study:
- To develop a mathematical model of glucose homeostasis including glucagon receptor internalization.
- To interpret data from glucagon challenge tests in patients treated with a novel glucagon receptor anti-sense drug.
- To quantify the effect of receptor internalization on glucagon's action.
Main Methods:
- Mathematical modeling of glucose homeostasis and receptor dynamics.
- Simulation of glucagon challenge tests.
- Analysis of patient data before and after anti-sense drug treatment.
Main Results:
- The model successfully simulates glucose homeostasis and receptor internalization.
- Receptor internalization leads to tolerance in blood glucose concentration to glucagon-induced hyperglycemia.
- The study quantifies the reduction in liver glucagon receptors post-treatment.
Conclusions:
- Glucagon receptor internalization is a critical factor in glucose regulation.
- This mechanism explains the observed tolerance to glucagon in treated subjects.
- The developed model provides a quantitative framework for understanding anti-sense drug efficacy.
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