Effects of Exercise Training and IL-6 Receptor Blockade on Gastric Emptying and GLP-1 Secretion in Obese Humans: Secondary Analyses From a Double Blind Randomized Clinical Trial

Abstract

BackgroundInterleukin-6 (IL-6) is released from skeletal muscle during exercise and systemic IL-6 levels therefore increase acutely in response to a single bout of exercise. We recently showed that an acute increase in IL-6 delayed gastric emptying rate and improved postprandial glycemia. Here we investigate whether repeated increases in IL-6, induced by exercise training, influence gastric emptying rate and moreover if IL-6 is required for exercise-induced adaptations in glycemic control including secretion of glucagon and glucagon-like peptide-1 (GLP-1).MethodsA total of 52 abdominally obese non-diabetic men and women were randomly assigned into four groups performing 12 weeks of endurance exercise or no exercise with or without IL-6 receptor blockade (tocilizumab). The primary endpoint was change in gastric emptying rate in response to the intervention and other endpoints included changes in glycemic control, glucagon, and GLP-1 secretion.ResultsThere was no change in gastric emptying rate in any of the four groups following the intervention and comparing differences in change between groups also revealed no difference. Postprandial glucose remained unchanged in all groups but the exercise + tocilizumab group, which improved postprandial glucose in response to the intervention. The area under the curve for meal-stimulated glucagon, active and total GLP-1 increased in response to IL-6 receptor blockade, this effect was independent of exercise.ConclusionExercise training and long-term IL-6 receptor blockade did not change gastric emptying rates in obese humans. IL-6 receptor blockade increased glucagon and GLP-1 secretion and implicate IL-6 in the regulation of the human alpha and L cells.

Exercise and Adipose Tissue Immunity: Outrunning Inflammation

“…Interestingly, in humans, the exercise‐induced reduction in fat mass was recently shown to be dependent on intact IL‐6 signaling. Indeed, IL‐6 receptor blockade with tocilizumab prevented the reduction in visceral AT mass caused by exercise training (52), supporting prior literature that muscle‐derived IL‐6 is an important signaling mediator during exercise that may contribute to long‐term exercise adaptations (summarized in Pedersen and Febbraio) (53).…”

Effect of 6 weeks of very low‐volume high‐intensity interval training on oral glucose‐stimulated incretin hormone response

“…Three intervention studies in similar cohorts also found no effect of less strenuous but more time‐consuming interval training (3–6 sessions per week: 6–10 × 2–3 min intervals at ∼80% VO 2 max or ∼90% HRmax, total time consumption 45–60 min) on overall GLP‐1 (Heiston et al, 2019; Lehrskov et al, 2019; Malin et al, 2018) and GIP (Malin et al, 2018) responses to OGTTs or mixed meal tests. This is in line with results from most moderate‐intensity, continuous endurance training intervention studies.…”

“…Adaptively decreased fasting (Kullman et al, 2016; Martins, Kulseng, Rehfeld, King, & Blundell, 2013) and oral glucose‐stimulated (Kullman et al, 2016) incretin hormone concentrations have also been reported following moderate‐intensity, continuous endurance training interventions. However, results are conflicting, and most studies find no effect of high‐volume, moderate‐intensity, continuous endurance (Chanoine et al, 2008; Ellingsgaard et al, 2020; Gibbons et al, 2017; Malin et al, 2018; Malkova et al, 2020; Martins, Kulseng, King, Holst, & Blundell, 2010; Ueda et al, 2013; Weiss et al, 2015) or interval training (Heiston et al, 2019; Lehrskov et al, 2019; Malin et al, 2018; Shakiba, Sheikholeslami‐Vatani, Rostamzadeh, & Karim, 2019) on fasting and postprandial incretin hormone levels. The effect of more strenuous but time‐efficient, very low‐volume HIT on incretin hormone concentrations has never been reported.…”

Unravelling the broader complexity of IL-6 involvement in health and disease

“…Interestingly, IL-6 activities are often enhanced by exercise or as a consequence of an active lifestyle [162][163][164] . Systemic changes in IL-6 following physical exercise affects glucose disposal and insulin sensitivity [165][166][167] .…”