GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study

• Published in: Diabetologia Vol. 63; no. 2; pp. 362 - 373
• Main Authors: Ellingsgaard, Helga, Seelig, Eleonora, Timper, Katharina, Coslovsky, Michael, Soederlund, Line, Lyngbaek, Mark P., Wewer Albrechtsen, Nicolai J., Schmidt-Trucksäss, Arno, Hanssen, Henner, Frey, Walter O., Karstoft, Kristian, Pedersen, Bente K., Böni-Schnetzler, Marianne, Donath, Marc Y.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2020; Springer Nature B.V
• Subjects: Antibodies, Monoclonal, Humanized - therapeutic use; Beta cells; Clinical trials; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dipeptidyl-peptidase IV; Double-Blind Method; Exercise; Exercise - physiology; Female; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; Homeostasis; Human Physiology; Humans; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - metabolism; Internal Medicine; Intravenous administration; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Monoclonal antibodies; Obesity; Obesity - drug therapy; Obesity - metabolism; Peptidase; Receptors, Interleukin-6 - metabolism; Sitagliptin Phosphate - therapeutic use; Obesity; Glucagon-like peptide-1; Exercise; Diabetes; Interleukin-6
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-019-05045-y

Aims/hypothesis IL-6 is a cytokine with various effects on metabolism. In mice, IL-6 improved beta cell function and glucose homeostasis via upregulation of glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise potentiated this beneficial increase in GLP-1. This study aimed to identify whether exercise-induced IL-6 has a similar effect in humans. Methods In a multicentre, double-blind clinical trial, we randomly assigned patients with type 2 diabetes or obesity to intravenous tocilizumab (an IL-6 receptor antagonist) 8 mg/kg every 4 weeks, oral sitagliptin (a dipeptidyl peptidase-4 inhibitor) 100 mg daily or double placebos (a placebo saline infusion every 4 weeks and a placebo pill once daily) during a 12 week training intervention. The primary endpoints were the difference in change of active GLP-1 response to an acute exercise bout and change in the AUC for the concentration–time curve of active GLP-1 during mixed meal tolerance tests at baseline and after the training intervention. Results Nineteen patients were allocated to tocilizumab, 17 to sitagliptin and 16 to placebos. During the acute exercise bout active GLP-1 levels were 26% lower with tocilizumab (multiplicative effect: 0.74 [95% CI 0.56, 0.98], p  = 0.034) and 53% higher with sitagliptin (1.53 [1.15, 2.03], p  = 0.004) compared with placebo. After the 12 week training intervention, the active GLP-1 AUC with sitagliptin was about twofold that with placebo (2.03 [1.56, 2.62]; p  < 0.001), while GLP-1 AUC values showed a small non-significant decrease of 13% at 4 weeks after the last tocilizumab infusion (0.87 [0.67, 1.12]; p  = 0.261). Conclusions/interpretation IL-6 is implicated in the regulation of GLP-1 in humans. IL-6 receptor blockade lowered active GLP-1 levels in response to a meal and an acute exercise bout in a reversible manner, without lasting effects beyond IL-6 receptor blockade. Trial registration Clinicaltrials.gov NCT01073826. Funding Danish National Research Foundation. Danish Council for Independent Research. Novo Nordisk Foundation. Danish Centre for Strategic Research in Type 2 Diabetes. European Foundation for the Study of Diabetes. Swiss National Research Foundation.