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

Sponsor

Filip Krag Knop (Other)

Overall Status

Completed

CT.gov ID

NCT01656057

Collaborator

University of Copenhagen (Other)

Enrollment

Location

Arms

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
To Assess the Impact of Bile Acids on Human Glukagon-like-peptide-1 Secretion	Drug: Acetaminophen Drug: Metformin Drug: Colesevelam Other: Cholecystokinin-8 Other: Saline	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

10 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

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

Study Start Date :

Jul 1, 2012

Actual Primary Completion Date :

Oct 1, 2013

Actual Study Completion Date :

Apr 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

Insulin [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]

Other Outcome Measures

c-peptide [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
glucagon [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
Glucagon-Like Peptide-2 [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
Peptide YY [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
Oxyntomodulin [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
Glucose-Dependent Insulinotropic Peptide [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
Bile acids [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
Gastrin [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
CCK [-30, -15, 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240]
Gall bladder emptying assessed ultrasonically [-30, -15, 20, 40, 60, 90, 120, 150, 180]
Resting energy expenditure [-10, 50, 210]
Estimation of satiety via visual analogue scale [0, 30, 60, 90, 120, 150, 180, 240]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital of Copenhagen, Gentofte Hospital, Diabetic Research Division	Copenhagen, Hellerup		Denmark	2900

Sponsors and Collaborators

Filip Krag Knop
University of Copenhagen

Investigators

Principal Investigator: Ulrich Rohde, MD, Diabetic Research Division, Department of Internal Medicine, University Hospital of Copenhagen, Gentofte Hospital