Research Article: A system model of the effects of exercise on plasma Interleukin-6 dynamics in healthy individuals: Role of skeletal muscle and adipose tissue

Date Published: July 12, 2017

Publisher: Public Library of Science

Author(s): Micaela Morettini, Maria Concetta Palumbo, Massimo Sacchetti, Filippo Castiglione, Claudia Mazzà, Marta Letizia Hribal.


Interleukin-6 (IL-6) has been recently shown to play a central role in glucose homeostasis, since it stimulates the production and secretion of Glucagon-like Peptide-1 (GLP-1) from intestinal L-cells and pancreas, leading to an enhanced insulin response. In resting conditions, IL-6 is mainly produced by the adipose tissue whereas, during exercise, skeletal muscle contractions stimulate a marked IL-6 secretion as well. Available mathematical models describing the effects of exercise on glucose homeostasis, however, do not account for this IL-6 contribution. This study aimed at developing and validating a system model of exercise’s effects on plasma IL-6 dynamics in healthy humans, combining the contributions of both adipose tissue and skeletal muscle. A two-compartment description was adopted to model plasma IL-6 changes in response to oxygen uptake’s variation during an exercise bout. The free parameters of the model were estimated by means of a cross-validation procedure performed on four different datasets. A low coefficient of variation (<10%) was found for each parameter and the physiologically meaningful parameters were all consistent with literature data. Moreover, plasma IL-6 dynamics during exercise and post-exercise were consistent with literature data from exercise protocols differing in intensity, duration and modality. The model successfully emulated the physiological effects of exercise on plasma IL-6 levels and provided a reliable description of the role of skeletal muscle and adipose tissue on the dynamics of plasma IL-6. The system model here proposed is suitable to simulate IL-6 response to different exercise modalities. Its future integration with existing models of GLP-1-induced insulin secretion might provide a more reliable description of exercise’s effects on glucose homeostasis and hence support the definition of more tailored interventions for the treatment of type 2 diabetes.

Partial Text

The cytokine Interleukin-6 (IL-6) has a central role in glucose homeostasis; however, the evidence of its dual nature of as an adipokine (i.e., adipose tissue-derived cytokine) and as a myokine (i.e., muscle-derived cytokine) has been a matter of scientific debate [1]. Experimental and clinical evidences suggest that an altered secretion of adipokines by the adipose tissue determines a condition of “chronic low-grade inflammation”, correlated to insulin resistance and IL-6 as one of the adipokines involved in this process [2–5]. It has also been shown that IL-6 is secreted by skeletal muscles during exercise [6], in an amount that has proven to be considerable and depending on the intensity and duration of the exercise [7–9]. IL-6 has been shown to trigger the secretion of anti-inflammatory cytokines [10,11] and to contribute to an improvement of insulin-stimulated glucose disposal [12].

Results of the cross-validation are reported in Table 2. In all four stages, the value of V (IL-6 distribution volume) was set to 14 l according to reported experimental data [28]. The half-life duration corresponding to the turnover rate ke was 13 min for D1, 56 min for D2, 147 min for D3 and 51 min for D4.

This study aimed at proposing and validating a system model describing the IL-6 dynamics during an exercise bout. A preliminary single-compartment description has been proposed in [33], however the novel two-compartment formulation here reported provides a more detailed and physiologically sound description of the IL-6 dynamics within the skeletal muscle.




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