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

• Published in: Diabetologia 2020-02, Vol.63 (2), p.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: Article
• Language: English
• 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
• ISSN: 0012-186X; 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