GIP/GLP-1 Co-Activity in Subjects With Obesity: Lowering of Food Intake

Study Overview
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Brief Summary
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We aim to delineate the effects of separate and combined infusion of GIP and GLP-1 on food intake, appetite, bone health and fat metabolism in overweight/obese subjects.

Detailed Description
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The gut-derived incretin glucagon-like peptide-1 (GLP-1) is a potent regulator of gastric emptying, appetite and food intake in humans whereas its sister incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), does not seem to have independent effects on these variables in humans. Interestingly, recent data from rodents have shown that concomitant activation of the GIP and the GLP-1 receptor may potentiate the satiety-promoting and body weight-reducing effects of GLP-1. Also, evidence suggests that GIP may be an important mediator of bone remodelling and lipid deposition. The effect of simultaneous activation of the GIP and GLP-1 receptors on appetite, food intake, fat metabolism and bone health has not been thoroughly examined in humans. The aim of this study is to delineate the effects of GIP/GLP-1 receptor co-activation on food intake, mechanisms regulating food intake, fat and bone metabolism in obese subjects. Material and methods: The investigators plan to include 18 obese/overweight men without diabetes. The primary endpoint of the study is food intake during continuous intravenous infusions of saline (placebo), GIP, GLP-1 and GIP+GLP-1, respectively. Secondary endpoints includes resting energy expenditure (measured by indirect calorimetry), appetite, satiety and hunger assessments (measured by visual analogue scales), plasma insulin, C-peptide and glucagon secretion, plasma triglycerides, cholesterols, and free fatty acid responses and changes in plasma bone turnover markers.

Official Title
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GIP/GLP-1 Co-Activity in Subjects With Obesity: Lowering of Food Intake

Conditions
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Obesity, Adiposity, Type 2 Diabetes

Intervention / Treatment
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* Other: IIGI+GIP
* Other: IIGI+GLP-1
* Other: IIGI+NaCl (placebo)
* Other: OGTT
* Other: IIGI+GIP+GLP-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian men Age between 25 and 70 years Body mass index (BMI) between 25 and 40 kg/m2 Exclusion Criteria: Diabetes or prediabetes (defined as glycated haemoglobin (HbA1c) ≥ 43 mmol/mol) Anaemia (defined as haemoglobin < 8.3 mmol/l) Any gastrointestinal disease that may interfere with the endpoint variables Anorexia, bulimia or binge eating disorder Allergy or intolerance to ingredients included in the standardised meals Tobacco smoking Any regular drug treatment that cannot be discontinued for minimum 18 hours Any physical or psychological condition that the investigator feels would interfere with trial participation

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IIGI+GIP<br>4 hour i.v. infusion of glucose-dependent insulinotropic polypeptide (4 pmol/kg/min) during isoglycemic conditions | Other: IIGI+GIP<br>* Glucose-dependent insulinotropic polypeptide (4 pmol/kg/min) during isoglycemia<br>Other: IIGI+GLP-1<br>* glucagon-like peptide-1 (1 pmol/kg/min) during isoglycemia<br>Other: IIGI+NaCl (placebo)<br>* i.v. NaCl during isoglycemia<br>Other: OGTT<br>* 50 g oral glucose tolerance test<br>Other: IIGI+GIP+GLP-1<br>* i.v infusion of GIP and GLP-1 (4 + 1 pmol/kg/min) during isoglycemia<br>|
| Active Comparator: IIGI+GLP-1<br>4 hour i.v. infusion of glucagon-like peptide-1 (1 pmol/kg/min) during isoglycemic conditions | Other: IIGI+GIP<br>* Glucose-dependent insulinotropic polypeptide (4 pmol/kg/min) during isoglycemia<br>Other: IIGI+GLP-1<br>* glucagon-like peptide-1 (1 pmol/kg/min) during isoglycemia<br>Other: IIGI+NaCl (placebo)<br>* i.v. NaCl during isoglycemia<br>Other: OGTT<br>* 50 g oral glucose tolerance test<br>Other: IIGI+GIP+GLP-1<br>* i.v infusion of GIP and GLP-1 (4 + 1 pmol/kg/min) during isoglycemia<br>|
| Placebo Comparator: IIGI+NaCl (placebo)<br>4 hour i.v. NaCl (placebo) during isoglycemic conditions | Other: IIGI+GIP<br>* Glucose-dependent insulinotropic polypeptide (4 pmol/kg/min) during isoglycemia<br>Other: IIGI+GLP-1<br>* glucagon-like peptide-1 (1 pmol/kg/min) during isoglycemia<br>Other: IIGI+NaCl (placebo)<br>* i.v. NaCl during isoglycemia<br>Other: OGTT<br>* 50 g oral glucose tolerance test<br>Other: IIGI+GIP+GLP-1<br>* i.v infusion of GIP and GLP-1 (4 + 1 pmol/kg/min) during isoglycemia<br>|
| Active Comparator: IIGI+GIP+GLP-1<br>4 hour co-infusion of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 | Other: IIGI+GIP<br>* Glucose-dependent insulinotropic polypeptide (4 pmol/kg/min) during isoglycemia<br>Other: IIGI+GLP-1<br>* glucagon-like peptide-1 (1 pmol/kg/min) during isoglycemia<br>Other: IIGI+NaCl (placebo)<br>* i.v. NaCl during isoglycemia<br>Other: OGTT<br>* 50 g oral glucose tolerance test<br>Other: IIGI+GIP+GLP-1<br>* i.v infusion of GIP and GLP-1 (4 + 1 pmol/kg/min) during isoglycemia<br>|
| Other: 50 g OGTT<br>50 g oral glucose tolerance test (OGTT) | Other: IIGI+GIP<br>* Glucose-dependent insulinotropic polypeptide (4 pmol/kg/min) during isoglycemia<br>Other: IIGI+GLP-1<br>* glucagon-like peptide-1 (1 pmol/kg/min) during isoglycemia<br>Other: IIGI+NaCl (placebo)<br>* i.v. NaCl during isoglycemia<br>Other: OGTT<br>* 50 g oral glucose tolerance test<br>Other: IIGI+GIP+GLP-1<br>* i.v infusion of GIP and GLP-1 (4 + 1 pmol/kg/min) during isoglycemia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| food intake | How much does the participant eat of from the ad libitum meal, measured in gram | 250-280 min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hunger | feeling of hunger measured on a visual analogue scale | measured at time 0, 30, 60, 90, 120, 180, 210, 240 min | 
| satiety | feeling of satiety measured on a visual analogue scale | measured at time 0, 30, 60, 90, 120, 180, 210, 240 min | 
| Fullness | feeling of fullness measured on a visual analogue scale | measured at time 0, 30, 60, 90, 120, 180, 210, 240 min | 
| Prospective food consumption | Prospective food consumption measured on a visual analogue scale | measured at time 0, 30, 60, 90, 120, 180, 210, 240 min | 
| resting energy expenditure (REE) | changes in REE measured by a ventilated hood 15 minutes at baseline and 15 minutes at time point 210 min. | -15 to 0 min. and 210 to 225 min. | 
| Insulin | changes in insulin measured in serum | -30, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min | 
| C-peptide level | changes in C-peptide level measured in serum | -30, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min | 
| glucagon levels | changes in glucagon levels measured in plasma | -30, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min | 
| Cholesterol and FFA | changes in cholesterol (TAG, Total cholesterol and free fatty acid measured in plasma) | -30, 0, 30, 60, 90, 120, 180, 240 min | 
| C-terminal cross-linked telopeptide of bone collagen (CTX) | changes in level of CTX measured in plasma | -30, 0, 30, 60, 90, 120, 180, 240 min | 
| procollagen type 1 N-terminal propeptide (P1NP) | changes in level of P1NP measured in plasma | -30, 0, 30, 60, 90, 120, 180, 240 min | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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incretin hormones, GIP, GLP-1