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

Helga Ellingsgaard; 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

doi:10.1007/s00125-019-05045-y

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

Helga Ellingsgaard, 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

58 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	63
Udgave nummer	2
Sider (fra-til)	362-373
Antal sider	12
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-019-05045-y
Status	Udgivet - feb. 2020

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10.1007/s00125-019-05045-y

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Ellingsgaard, H., Seelig, E., Timper, K., Coslovsky, M., Soederlund, L., Lyngbaek, M. P., Wewer Albrechtsen, N. J., Schmidt-Trucksäss, A., Hanssen, H., Frey, W. O., Karstoft, K., Pedersen, B. K., Böni-Schnetzler, M., & Donath, M. Y. (2020). GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study. Diabetologia, 63(2), 362-373. https://doi.org/10.1007/s00125-019-05045-y

Ellingsgaard, H, Seelig, E, Timper, K, Coslovsky, M, Soederlund, L, Lyngbaek, MP , Wewer Albrechtsen, NJ, Schmidt-Trucksäss, A, Hanssen, H, Frey, WO, Karstoft, K , Pedersen, BK, Böni-Schnetzler, M & Donath, MY 2020, 'GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study', Diabetologia, bind 63, nr. 2, s. 362-373. https://doi.org/10.1007/s00125-019-05045-y

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

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",

author = "Helga Ellingsgaard and Eleonora Seelig and Katharina Timper and Michael Coslovsky and Line Soederlund and Lyngbaek, {Mark P} and {Wewer Albrechtsen}, {Nicolai J} and Arno Schmidt-Trucks{\"a}ss and Henner Hanssen and Frey, {Walter O} and Kristian Karstoft and Pedersen, {Bente K} and Marianne B{\"o}ni-Schnetzler and Donath, {Marc Y}",

year = "2020",

month = feb,

doi = "10.1007/s00125-019-05045-y",

language = "English",

volume = "63",

pages = "362--373",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "2",

}

TY - JOUR

T1 - GLP-1 secretion is regulated by IL-6 signalling

T2 - a randomised, placebo-controlled study

AU - Ellingsgaard, Helga

AU - Seelig, Eleonora

AU - Timper, Katharina

AU - Coslovsky, Michael

AU - Soederlund, Line

AU - Lyngbaek, Mark P

AU - Wewer Albrechtsen, Nicolai J

AU - Schmidt-Trucksäss, Arno

AU - Hanssen, Henner

AU - Frey, Walter O

AU - Karstoft, Kristian

AU - Pedersen, Bente K

AU - Böni-Schnetzler, Marianne

AU - Donath, Marc Y

PY - 2020/2

Y1 - 2020/2

N2 - 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.

AB - 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.

KW - Diabetes

KW - Exercise

KW - Glucagon-like peptide-1

KW - Interleukin-6

KW - Obesity

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U2 - 10.1007/s00125-019-05045-y

DO - 10.1007/s00125-019-05045-y

M3 - Journal article

C2 - 31796986

SN - 0012-186X

VL - 63

SP - 362

EP - 373

JO - Diabetologia

JF - Diabetologia

IS - 2

ER -

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

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