Natasha C Bergmann1,2,3, Asger Lund1,4, Lærke S Gasbjerg1,3,5, Emma C E Meessen6, Maria M Andersen1, Sigrid Bergmann1, Bolette Hartmann3,5, Jens J Holst3,5, Lene Jessen2, Mikkel B Christensen1,7,8, Tina Vilsbøll1,8, Filip K Knop9,10,11. 1. Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark. 2. Department of In Vivo Pharmacology, Zealand Pharma A/S, Glostrup, Denmark. 3. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. 5. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 6. Department of Endocrinology and Metabolism, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 7. Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark. 8. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 9. Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Kildegårdsvej 28, DK-2900, Hellerup, Denmark. filip.krag.knop.01@regionh.dk. 10. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. filip.krag.knop.01@regionh.dk. 11. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. filip.krag.knop.01@regionh.dk.
Abstract
AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: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). CONCLUSIONS/ INTERPRETATION: While GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT02598791 FUNDING: This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.
RCT Entities:
AIMS/HYPOTHESIS: 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. METHODS: We examined 17 overweight/obesemen 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. RESULTS: 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). CONCLUSIONS/ INTERPRETATION: While GLP-1 infusion lowered energy intake in overweight/obesemen, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT02598791 FUNDING: This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.
Entities:
Keywords:
Appetite; Dual receptor agonism; Energy expenditure; Energy intake; Glucagon-like peptide 1; Glucose-dependent insulinotropic polypeptide; Obesity; Overweight
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