Effect of Bile Acids on GLP-1 Secretion

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Effect of Bile Acids in the Gut on GLP-1 Secretion in Healthy Subjects and Patients With Type 2 Diabetes

Conditions
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Obesity, Type 2 Diabetes

Intervention / Treatment
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* Drug: Colesevelam
* Drug: Chenodeoxycholic Acid
* Other: saline
* Drug: Colesevelam 3750 mg + chenodeoxycholic acid 1250 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colesevelam<br> | Drug: Colesevelam<br>* Colesevelam 3750 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.<br>|
| Experimental: Chenodeoxycholic acid<br> | Drug: Chenodeoxycholic Acid<br>* 1.250 mg dissolved in 100 ml saline, administered in a feeding tube at time = 0.<br>|
| Experimental: Colesevelam + chenodeoxycholic acid<br> | Drug: Colesevelam 3750 mg + chenodeoxycholic acid 1250 mg<br>* Colesevelam and chenodeoxycholic acid dissolved in 100 ml saline, administered in a duodenal tube at time = 0.<br>|
| Experimental: Placebo<br> | Other: saline<br>* 100 ml saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Evaluated by Visual Analog Scale (VAS) | At baseline, and 30, 60, 90, 120 and 180 minutes | 
| Change in gallbladder volume | Evaluated by ultrasound | -30, 0 (baseline), 30, 60, 120 og 180 minutes | 
| Change in basal metabolic rate | Evaluated by indirect calorimetry | At -30, 60 og 150 minutes | 
| Change in bile acid composition | Evaluated by duodenal aspiration | At -30, 0, 30, 60, 120 og 180 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, Bile acid, TGR-5, GLP-1