Effect of Bile Acids on GLP-1 Secretion - Full Text View

Purpose

The purpose of this study is to describe the physiological, pathophysiological and potentially therapeutic implications of bile-induced glucagon-like peptide-1 (GLP-1) secretion in human glucose homeostasis.

Condition	Intervention
Type 2 Diabetes Obesity	Drug: Ursodeoxycholic Acid Drug: Chenodeoxycholic Acid Other: saline

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Basic Science
Official Title:	Effect of Bile Acids in the Gut on GLP-1 Secretion in Healthy Subjects and Patients With Type 2 Diabetes

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Diabetes Medicines Diabetes Type 2 Obesity

Drug Information available for: Ursodiol Chenodiol

U.S. FDA Resources

Further study details as provided by University Hospital, Gentofte, Copenhagen:

Primary Outcome Measures:

Change in GLP-1 [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change in insulin [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in C-peptide [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in glucagon [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in glucagon-like-peptide 2 (GLP-2) [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in glucose-dependent insulinotropic polypeptide (GIP) [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in peptide YY (PYY) [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in oxyntomodulin [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in bile acids [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in gastrin [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in CCK [ Time Frame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes ] [ Designated as safety issue: No ]
Change in appetite, satiety and prospective food consumption [ Time Frame: At baseline, and 30, 60, 90, 120 and 180 minutes ] [ Designated as safety issue: No ]
Evaluated by Visual Analog Scale (VAS)
Change in gallbladder volume [ Time Frame: -30, 0 (baseline), 30, 60, 120 og 180 minutes ] [ Designated as safety issue: No ]
Evaluated by ultrasound
Change in basal metabolic rate [ Time Frame: At -30, 60 og 150 minutes ] [ Designated as safety issue: No ]
Evaluated by indirect calorimetry
Change in bile acid composition [ Time Frame: At -30, 0, 30, 60, 120 og 180 minutes ] [ Designated as safety issue: No ]
Evaluated by duodenal aspiration

Estimated Enrollment:	20
Study Start Date:	August 2012
Estimated Study Completion Date:	July 2013
Estimated Primary Completion Date:	January 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Ursodeoxycholic acid	Drug: Ursodeoxycholic Acid 1.500 mg dissolved in 100 ml saline, administered in a duodenal tube at time = 0.
Experimental: Chenodeoxycholic acid	Drug: Chenodeoxycholic Acid 1.250 mg dissolved in 100 ml saline, administered in a duodenal tube at time = 0.
Placebo Comparator: saline	Other: saline 110 ml saline

Detailed Description:

The investigators hypothesize that even modest increments in endogenous GLP-1 secretion will elicit important antidiabetic effects of GLP-1. To evaluate whether bile acids have such effects, the investigators plan to perform intraduodenal infusion of two different bile acids and placebo.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Patients with type 2 diabetes

Inclusion Criteria:

danish caucasian ethnicity
normal haemoglobin
BMI > 25 kg/m2
HbA1c < 9%
informed consent

Exclusion Criteria:

liver disease(ALT and AST > upper reference limit)
gastrointestinal disease
liver and biliary tract disease
nephropathy (serum creatinine > 150 μM, and/or albuminuria)
treatment with insulin, glp-1 analogues and/ or DPP-4 inhibitors
treatment with medicine that can not be paused for 12 hours
previous abdominal surgery eg. cholecystectomy
BMI < 18,5 kg/m2 or > 35 kg/m2

Healthy Volunteers

Inclusion Criteria:

danish caucasian ethnicity
normal haemoglobin
HbA1c < 6,0 (American Diabetes Association guidelines)
informed consent

Exclusion Criteria:

liver disease(ALT and AST > upper reference limit)
gastrointestinal disease
liver and biliary tract disease
nephropathy (serum creatinine > 150 μM, and/or albuminuria)
treatment with medicine that can not be paused for 12 hours
previous abdominal surgery eg. cholecystectomy
BMI < 18,5 kg/m2 or > 35 kg/m2
first degree relatives diagnosed with diabetes
previously diagnosed with diabetes, or treated with antidiabetic agents

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01666223

Contacts

Contact: Morten Hansen, MD

+45 39772691

mortenhansen.privat@gmail.com

Locations

Denmark
Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen	Not yet recruiting
Hellerup, Copenhagen, Denmark
Contact: Morten Hansen, MD

Sponsors and Collaborators

University Hospital, Gentofte, Copenhagen

Investigators

Principal Investigator:

Morten Hansen, MD

Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen

More Information

Publications:

Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002 Nov 15;298(5):714-9.

Adrian TE, Ballantyne GH, Longo WE, Bilchik AJ, Graham S, Basson MD, Tierney RP, Modlin IM. Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon. Gut. 1993 Sep;34(9):1219-24.

Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005 Apr 1;329(1):386-90.

Rafferty EP, Wylie AR, Hand KH, Elliott CE, Grieve DJ, Green BD. Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R(-/-) mice. Biol Chem. 2011 Apr;392(6):539-46. Epub 2011 Apr 27.

Responsible Party:	Morten Hansen, MD, PhD Student, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier:	NCT01666223 History of Changes
Other Study ID Numbers:	H-1-2012-049
Study First Received:	July 11, 2012
Last Updated:	August 15, 2012
Health Authority:	Denmark: The Danish National Committee on Biomedical Research Ethics

Keywords provided by University Hospital, Gentofte, Copenhagen:

Type 2 diabetes
GLP-1
Bile acid
TGR-5

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 2
Obesity
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight

Signs and Symptoms
Bile Acids and Salts
Chenodeoxycholic Acid
Ursodeoxycholic Acid
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Cathartics
Cholagogues and Choleretics

ClinicalTrials.gov processed this record on May 22, 2013