Glucagon-like peptide-1 and interleukin-6 interaction in response to physical exercise: An in-silico model in the framework of immunometabolism

Background and objective: Glucagon-like peptide 1 (GLP-1) is classically identified as an incretin hormone, secreted in response to nutrient ingestion and able to enhance glucose-stimulated insulin secretion. However, other stimuli, such as physical exercise, may enhance GLP-1 plasma levels, and this exercise-induced GLP-1 secretion is mediated by interleukin-6 (IL-6), a cytokine secreted by contracting skeletal muscle. The aim of the study is to propose a mathematical model of IL-6-induced GLP-1 secretion and kinetics in response to physical exercise of moderate intensity. Methods: The model includes the GLP-1 subsystem (with two pools: gut and plasma) and the IL-6 subsystem (again with two pools: skeletal muscle and plasma); it provides a parameter of possible clinical relevance representing the sensitivity of GLP-1 to IL-6 (k0). The model was validated on mean IL-6 and GLP-1 data derived from the scientific literature and on a total of 100 virtual subjects. Results: Model validation provided mean residuals between 0.0051 and 0.5493 pg⋅mL-1 for IL-6 (in view of concentration values ranging from 0.8405 to 3.9718 pg⋅mL-1) and between 0.0133 and 4.1540 pmol⋅L-1 for GLP-1 (in view of concentration values ranging from 0.9387 to 17.9714 pmol⋅L-1); a positive significant linear correlation (r = 0.85, p<0.001) was found between k0 and the ratio between areas under GLP-1 and IL-6 curve, over the virtual subjects. Conclusions: The model accurately captures IL-6-induced GLP-1 kinetics in response to physical exercise.