Effect of Bile Acids on GLP-1 Secretion
Study Details
Study Description
Brief Summary
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 or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Colesevelam
|
Drug: Colesevelam
Colesevelam 3750 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.
|
| Experimental: Chenodeoxycholic acid
|
Drug: Chenodeoxycholic Acid
1.250 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.
|
| Experimental: Colesevelam + chenodeoxycholic acid
|
Drug: Colesevelam 3750 mg + chenodeoxycholic acid 1250 mg
Colesevelam and chenodeoxycholic acid dissolved in 100 ml saline, administered in a duodenal tube at time = 0.
|
| Experimental: Placebo
|
Other: saline
100 ml saline
|
Outcome Measures
Primary Outcome Measures
- Change in GLP-1 [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
Secondary Outcome Measures
- Change in insulin [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in C-peptide [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in glucagon [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in glucagon-like-peptide 2 (GLP-2) [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in glucose-dependent insulinotropic polypeptide (GIP) [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in peptide YY (PYY) [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in oxyntomodulin [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in bile acids [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in gastrin [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in CCK [At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes]
- Change in appetite, satiety and prospective food consumption [At baseline, and 30, 60, 90, 120 and 180 minutes]
Evaluated by Visual Analog Scale (VAS)
- Change in gallbladder volume [-30, 0 (baseline), 30, 60, 120 og 180 minutes]
Evaluated by ultrasound
- Change in basal metabolic rate [At -30, 60 og 150 minutes]
Evaluated by indirect calorimetry
- Change in bile acid composition [At -30, 0, 30, 60, 120 og 180 minutes]
Evaluated by duodenal aspiration
Eligibility Criteria
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen | Hellerup | Copenhagen | Denmark |
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
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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. doi: 10.1515/BC.2011.050. Epub 2011 Apr 27.
- H-1-2012-049