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.