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Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study

  • Natasha C. Bergmann
  • Asger Lund
  • Lærke S. Gasbjerg
  • Emma C. E. Meessen
  • Maria M. Andersen
  • Sigrid Bergmann
  • Bolette Hartmann
  • Jens J. Holst
  • Lene Jessen
  • Mikkel B. Christensen
  • Tina Vilsbøll
  • Filip K. KnopEmail author



Glucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans.


We examined 17 overweight/obese men in a crossover design with 5 study days. On day 1, a 50 g OGTT was performed; on the following 4 study days, the men received an isoglycaemic i.v. glucose infusion (IIGI) plus saline (154 mmol/l NaCl; placebo), GIP (4 pmol kg−1 min−1), GLP-1 (1 pmol kg−1 min−1) or GIP+GLP-1 (4 and 1 pmol kg−1 min−1, respectively). All IIGIs were performed in a randomised order blinded for the participant and the investigators. The primary endpoint was energy intake as measured by an ad libitum meal after 240 min. Secondary endpoints included appetite ratings and resting energy expenditure, as well as insulin, C-peptide and glucagon responses.


Energy intake was significantly reduced during IIGI+GLP-1 compared with IIGI+saline infusion (2715 ± 409 vs 4483 ± 568 kJ [mean ± SEM, n = 17], p = 0.014), whereas there were no significant differences in energy intake during IIGI+GIP (4062 ± 520 kJ) or IIGI+GIP+GLP-1 (3875 ± 451 kJ) infusion compared with IIGI+saline (p = 0.590 and p = 0.364, respectively). Energy intake was higher during IIGI+GIP+GLP-1 compared with IIGI+GLP-1 infusion (p = 0.039).


While GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect.

Trial registration NCT02598791


This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.


Appetite Dual receptor agonism Energy expenditure Energy intake Glucagon-like peptide 1 Glucose-dependent insulinotropic polypeptide Obesity Overweight 



Glucose-dependent insulinotropic polypeptide


Glucagon-like peptide 1


Isoglycaemic i.v. glucose infusion


Insulin secretion rate


Resting energy expenditure


Repeated measures ANOVA



The authors would like to thank all study participants and acknowledge invaluable laboratory assistance from A. Rasmussen-Lanng, S. M. Schmidt and I. al Nachar, all from Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Denmark. Part of this work has been presented at the annual meeting of the European Association for the Study of Diabetes, 11–15 September 2017, Lisbon, Portugal, and published as an abstract in Diabetologia 2017;60(Suppl 1):5.

Contribution statement

NCB was involved in planning the study, conducting clinical experiments and statistical analyses, and writing the manuscript. AL was involved in planning the study. LSG was involved in planning the study, conducting clinical experiments, analysing the plasma samples for GIP, GLP-1 and glucagon, and statistical analyses. ECEM, MMA and SB were involved in conducting clinical experiments. BH and JJH analysed plasma samples for GIP, GLP-1 and glucagon. LJ, MC and TV were involved in planning the study. FKK conceptualised the study and was involved in planning the study and writing the manuscript. All authors critically reviewed the manuscript and approved the version to be published. NCB and FKK are the guarantors of the work.


This study was supported by grants from the Innovation Fund Denmark (grant no. 4135-00091B) and the Vissing Foundation. The funders were not involved in the design of the study, collection, analysis or interpretation of data, preparation of the manuscript; or the decision to publish.

Duality of interest

NCB holds an unrestricted grant from the Innovation Fund Denmark and is employed as a PhD student at Zealand Pharma in collaboration with Steno Diabetes Center Copenhagen, Gentofte Hospital. LSG is a minority shareholder in Antag Therapeutics. LJ is employee of Zealand Pharma. JJH has served on advisory panels for GlaxoSmithKline, Novo Nordisk, Zealand Pharma, AstraZeneca, MSD, Intarcia and Hanmi and as a consultant for Novo Nordisk, and has received research support from Merck, Sharp & Dome. FKK has received lecture fees from, participated in advisory boards of, consulted for and/or received research grants from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD/Merck, Novo Nordisk, Sanofi and Zealand Pharma, and is a minority shareholder in Antag Therapeutics. AL, ECEM, MMA, SB, BH, MC and TV declare no duality of interest associated with their contribution to this manuscript.

Supplementary material

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Copyright information

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

Authors and Affiliations

  • Natasha C. Bergmann
    • 1
    • 2
    • 3
  • Asger Lund
    • 1
    • 4
  • Lærke S. Gasbjerg
    • 1
    • 3
    • 5
  • Emma C. E. Meessen
    • 6
  • Maria M. Andersen
    • 1
  • Sigrid Bergmann
    • 1
  • Bolette Hartmann
    • 3
    • 5
  • Jens J. Holst
    • 3
    • 5
  • Lene Jessen
    • 2
  • Mikkel B. Christensen
    • 1
    • 7
    • 8
  • Tina Vilsbøll
    • 1
    • 8
  • Filip K. Knop
    • 1
    • 5
    • 8
    Email author
  1. 1.Clinical Metabolic PhysiologySteno Diabetes Center Copenhagen, Gentofte HospitalHellerupDenmark
  2. 2.Department of In Vivo PharmacologyZealand Pharma A/SGlostrupDenmark
  3. 3.Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  4. 4.Department of Medicine, Gentofte HospitalUniversity of CopenhagenHellerupDenmark
  5. 5.Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  6. 6.Department of Endocrinology and Metabolism, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamthe Netherlands
  7. 7.Department of Clinical PharmacologyBispebjerg Hospital, University of CopenhagenCopenhagenDenmark
  8. 8.Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

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