The Impact of Gall Bladder Emptying and Bile Acids on the Human GLP-1-secretion

Study Overview
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Brief Summary
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The last couple of years it has been shown that bile acids not only acts as simple emulsifiers of fat, but constitutes a complex metabolic integrator which not only have an influence on fat digestion and lipid metabolism, but also modulates the energy expenditure in (brown) adipose tissue and muscle tissue. This action is due to stimulation of the receptor TGR5 by bile acids. Recently scientists have discovered that this receptor in rodents is also expressed on the surface of intestinal L-cells (which normally secrets Glucagon-Like Peptide-1 (GLP-1) in response to nutrient stimulation). The stimulation of this receptor has shown a GLP-1 secretion from the intestinal cells which is interesting since GLP-1 has a central role in maintaining normal glucose tolerance and thus blood sugar. Given the above, bile acids has an important impact on intestinal GLP-1 secretion. Whether these scientific findings can be proven in human beings is uncertain. The primary hypothesis is that stimulating gall bladder emptying via Cholecystokinin (CCK) in healthy subjects will result in a significant GLP-1 response. We also hypothesize that adding orally Metformin or a sequestrant (a bile acid binder) will further enhance this GLP-1 response.

Official Title
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The Impact of Gall Bladder Emptying and Bile Acids on the Human GLP-1-secretion

Conditions
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To Assess the Impact of Bile Acids on Human Glukagon-like-peptide-1 Secretion

Intervention / Treatment
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* Drug: Acetaminophen
* Drug: Metformin
* Drug: Colesevelam
* Other: Cholecystokinin-8
* Other: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HbA1c < 6,0% Not anaemic Written informed consent Exclusion Criteria: Liver disease Nephropathy fasting plasma glucose > 5,6mM Diabetes running in the family (parents or grandparents) Any medical treatment A former medical history of liver- or bile disease any surgical procedure conducted in the abdomen Body mass index < 18,5 kg/m2 or > 25 kg/m2

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acetaminophen+saline<br>Acetaminophen tablet 1500 mg via nasogastric tube + i.v. saline | Drug: Acetaminophen<br>* Acetaminophen dissolved in 50 ml of water<br>* Other names: Paracetamol;Other: Saline<br>* iv. saline infusion 40 ml/hour for the first 60 minutes<br>|
| Experimental: Acetaminophen+CCK<br>Acetaminophen tablet 1500 mg via nasogastric tube + iv. CCK-8, 24 pmol/kg/hour | Drug: Acetaminophen<br>* Acetaminophen dissolved in 50 ml of water<br>* Other names: Paracetamol;Other: Cholecystokinin-8<br>* iv. infusion of CCK-8, 24 pmol/kg/hour for the first 60 minutes<br>* Other names: CCK-8;|
| Experimental: Metformin+saline<br>Metformin tablet 1500 mg + Acetaminophen tablet 1500 mg via nasogastric tube + i.v. saline | Drug: Acetaminophen<br>* Acetaminophen dissolved in 50 ml of water<br>* Other names: Paracetamol;Drug: Metformin<br>* Metformin + acetaminophen dissolved in 50 ml of water<br>Other: Saline<br>* iv. saline infusion 40 ml/hour for the first 60 minutes<br>|
| Experimental: Metformin+CCK<br>Metformin tablet 1500 mg + Acetaminophen tablet 1500 mg via nasogastric tube + iv. CCK-8, 24 pmol/kg/hour | Drug: Acetaminophen<br>* Acetaminophen dissolved in 50 ml of water<br>* Other names: Paracetamol;Drug: Metformin<br>* Metformin + acetaminophen dissolved in 50 ml of water<br>Other: Cholecystokinin-8<br>* iv. infusion of CCK-8, 24 pmol/kg/hour for the first 60 minutes<br>* Other names: CCK-8;|
| Experimental: Colesevelam+saline<br>Colesevelam tablet 3750 mg + Acetaminophen tablet 1500 mg via nasogastric tube + iv. saline | Drug: Acetaminophen<br>* Acetaminophen dissolved in 50 ml of water<br>* Other names: Paracetamol;Drug: Colesevelam<br>* Colesevelam + acetaminophen dissolved in 50 ml of water<br>Other: Saline<br>* iv. saline infusion 40 ml/hour for the first 60 minutes<br>|
| Experimental: Colesevelam+CCK<br>Colesevelam tablet 3750 mg + Acetaminophen tablet 1500 mg via nasogastric tube + iv. CCK-8, 24 pmol/kg/hour | Drug: Acetaminophen<br>* Acetaminophen dissolved in 50 ml of water<br>* Other names: Paracetamol;Drug: Colesevelam<br>* Colesevelam + acetaminophen dissolved in 50 ml of water<br>Other: Cholecystokinin-8<br>* iv. infusion of CCK-8, 24 pmol/kg/hour for the first 60 minutes<br>* Other names: CCK-8;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GLP-1 response as incremental area under curve (iAUC) |  | -30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin |  | -30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bile acids, Gall bladder emptying, Human, Glucagon like peptide 1, GLP-1