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.

Louise Lang Lehrskov,Sabrina Ravn Fagerlind,Monica Korsager Larsen,Emma Dorph,Rikke Krogh-Madsen,Sidsel Kofoed Seide,Nicole Vinum,Kristian Karstoft,Stine Nymand,Natja Launbo,Maria Ball,Bente Klarlund Pedersen,Regitse Højgaard Christensen,Grit Elster Legaard,Helga Ellingsgaard,Nicolai J Wewer Albrechtsen ,Jaya B Rosenmeier ,Camilla Noerfelt Dahl ,Mathias Ried‐Larsen ,Anne‐Sophie Wedell‐Neergaard ,Jens J Holst ,M Henneberg

doi:10.3389/fphys.2019.01249

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.

Highlights

Gastric emptying is a critical regulator of postprandial glucose contributing to as much as 35% of peak glucose following a meal (Horowitz et al, 1993)
This study was a randomized exercise training intervention study with the overall primary endpoint to investigate the role of IL-6 in exercise training-induced regulation of visceral adipose tissue mass (Wedell-Neergaard et al, 2018)
The remaining 52 participants were randomized to no exercise + placebo (n = 12), no exercise + tocilizumab (n = 13), exercise + placebo (n = 14), and exercise + tocilizumab (n = 13) and included in the per protocol analysis (Figure 1)

Summary

Introduction

Gastric emptying is a critical regulator of postprandial glucose contributing to as much as 35% of peak glucose following a meal (Horowitz et al, 1993). We recently showed that acutely increased IL-6, following an IL-6 infusion, delayed gastric emptying rate and improved postprandial glucose (Lehrskov et al, 2018). Consistent with these effects, IL-6 receptor blockade enhanced the rate of gastric emptying after an acute bout of exercise suggesting that IL-6 regulation of gastric emptying may be a physiological phenomenon (Lehrskov et al, 2018). Interleukin-6 (IL-6) is released from skeletal muscle during exercise and systemic IL-6 levels increase acutely in response to a single bout of exercise. We investigate whether repeated increases in IL-6, induced by exercise training, influence gastric emptying rate and if IL-6 is required for exercise-induced adaptations in glycemic control including secretion of glucagon and glucagon-like peptide-1 (GLP-1)

Methods

Results

Conclusion