GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study
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.
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.
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).
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.
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.
KeywordsDiabetes Exercise Glucagon-like peptide-1 Interleukin-6 Obesity
Centre of Inflammation and Metabolism
Centre for Physical Activity Research
Glucose-dependent insulinotropic peptide
Mixed meal tolerance test
P. Zala (Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel), S Ruesch (Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel), R. Rovsing (Centre for Physical Activity Research, Rigshospitalet) and H. Villumsen (Centre for Physical Activity Research, Rigshospitalet) are acknowledged for their technical assistance.
HE and MYD conceived and designed the study. HE, ES, KT, LS, MPL, HH, AS-T, WOF, KK, NJWA, BKP and MBS acquired the data. MC analysed the data. HE, ES, MYD interpreted the data.
HE, ES and MYD drafted the article. AS-T, WOF, BKP, MBS and NJWA provided resources. All co-authors critically revised the article. All co-authors approved the final version to be published. MYD is the guarantor of this work.
The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). HE was further supported by grants from the Danish Council for Independent Research (grant no. 12-132429) and the Novo Nordisk Foundation (project no. 959532028), and CIM/CFAS is a member of DD2 – the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant nos 09-067009 and 09-075724). This study was also supported by grants from the European Foundation for the Study of Diabetes and by the Swiss National Research Foundation.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
- 10.Nauck MA, Heimesaat MM, Behle K et al (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87(3):1239–1246. https://doi.org/10.1210/jcem.87.3.8355 CrossRefPubMedGoogle Scholar
- 15.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419. https://doi.org/10.1007/bf00280883 CrossRefPubMedGoogle Scholar
- 16.Phillips DI, Clark PM, Hales CN, Osmond C (1994) Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion. Diabet Med 11(3):286–292. https://doi.org/10.1111/j.1464-5491.1994.tb00273.x CrossRefPubMedGoogle Scholar
- 18.Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70Google Scholar
- 19.Pinheiro JB, DebRoy S, Sarkar D, R Core Team (2017) Linear and nonlinear mixed effects models. R package version 3.1–131Google Scholar
- 26.Herman GA, Stevens C, Van Dyck K et al (2005) Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 78(6):675–688. https://doi.org/10.1016/j.clpt.2005.09.002 CrossRefPubMedGoogle Scholar
- 27.Bergman AJ, Stevens C, Zhou Y et al (2006) Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther 28(1):55–72. https://doi.org/10.1016/j.clinthera.2006.01.015 CrossRefPubMedGoogle Scholar
- 29.Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ, Porte D Jr (1987) Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 30(9):698–702. https://doi.org/10.1007/bf00296991 CrossRefPubMedGoogle Scholar
- 33.DeFronzo RA, Buse JB, Kim T et al (2016) Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia 59(8):1645–1654. https://doi.org/10.1007/s00125-016-3992-6 CrossRefPubMedPubMedCentralGoogle Scholar