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Diabetologia

pp 1–12 | Cite as

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

  • Helga EllingsgaardEmail author
  • Eleonora Seelig
  • Katharina Timper
  • Michael Coslovsky
  • Line Soederlund
  • Mark P. Lyngbaek
  • Nicolai J. Wewer Albrechtsen
  • Arno Schmidt-Trucksäss
  • Henner Hanssen
  • Walter O. Frey
  • Kristian Karstoft
  • Bente K. Pedersen
  • Marianne Böni-Schnetzler
  • Marc Y. Donath
Article

Abstract

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.

Keywords

Diabetes Exercise Glucagon-like peptide-1 Interleukin-6 Obesity 

Abbreviations

CIM

Centre of Inflammation and Metabolism

CFAS

Centre for Physical Activity Research

DPP-4

Dipeptidyl peptidase-4

GIP

Glucose-dependent insulinotropic peptide

GLP-1

Glucagon-like peptide-1

MMTT

Mixed meal tolerance test

PYY

Peptide YY

Notes

Acknowledgements

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.

Contribution statement

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.

Funding

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.

Supplementary material

125_2019_5045_MOESM1_ESM.pdf (1.1 mb)
ESM (PDF 1170 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Helga Ellingsgaard
    • 1
    Email author
  • Eleonora Seelig
    • 2
    • 3
  • Katharina Timper
    • 2
    • 4
  • Michael Coslovsky
    • 5
  • Line Soederlund
    • 1
  • Mark P. Lyngbaek
    • 1
  • Nicolai J. Wewer Albrechtsen
    • 6
  • Arno Schmidt-Trucksäss
    • 7
  • Henner Hanssen
    • 7
  • Walter O. Frey
    • 8
  • Kristian Karstoft
    • 1
  • Bente K. Pedersen
    • 1
  • Marianne Böni-Schnetzler
    • 9
  • Marc Y. Donath
    • 2
    • 9
  1. 1.Centre of Inflammation and Metabolism (CIM)/ Centre for Physical Activity Research (CFAS)CopenhagenDenmark
  2. 2.Clinic of EndocrinologyDiabetes and Metabolism University Hospital BaselBaselSwitzerland
  3. 3.University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic ScienceAddenbrooke’s HospitalCambridgeUK
  4. 4.Max Planck Institute for Metabolism Research Cologne, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP)University Hospital CologneCologneGermany
  5. 5.Department of Clinical Research, CTUUniversity of Basel, University Hospital BaselBaselSwitzerland
  6. 6.Department of Clinical BiochemistryRigshospitalet University of CopenhagenCopenhagenDenmark
  7. 7.Sports and Exercise Medicine, Department of Sport, Exercise and HealthUniversity of BaselBaselSwitzerland
  8. 8.Balgrist MoveMed, Swiss Olympic Medical CenterUniversity Hospital BalgristZurichSwitzerland
  9. 9.Department BiomedicineUniversity of BaselBaselSwitzerland

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