Effect of Bile Acid Sequestration on Postprandial GLP-1 Secretion, Glucose Homeostasis and Gut Microbiota

Study Overview
=================
Brief Summary
-----------------
Accumulating evidence suggests that bile acids and bacteria in our intestines may constitute essential components in the complex mechanisms regulating gut hormone secretion and glucose homeostasis. At the same time, bile acids and gut bacteria are interdependent. Thus, it is likely that modification of the enterohepatic circulation of bile acids can lead to changes in gut hormone secretion or gut bacteria composition and consequently affect glucose homeostasis. The current study is a human interventional study with 7-day ingestion of a bile acid sequestrant or placebo, preceded and followed by meal tests and faecal sampling. The aim is to examine how (and if) bile acid sequestration can influence postprandial glucagon-like peptide-1 (GLP-1) secretion, gut microbiota and glucose homeostasis in patients with type 2 diabetes and healthy individuals. As a tool to sequester bile acids we will use sevelamer, a phosphate binding resin used in the treatment of hyperphosphataemia in adult patients with chronic kidney disease. Surprisingly, sevelamer was recently shown to improve glycaemic control in patients with chronic kidney disease and type 2 diabetes. The investigators hypothesize that higher luminal concentrations of bile acids in the distal gut will elicit changes in the postprandial gut hormone secretion and gut bacteria composition. The current study will help to clarify this hypothesis and improve our general understanding of the association between bile acid circulation and signalling, gut hormone secretion, gut bacteria and glucose metabolism.

Official Title
-----------------
Effect of Bile Acid Sequestration on Postprandial GLP-1 Secretion, Glucose Homeostasis and Gut Microbiota

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Sevelamer 1600 mg TID for 7 days
* Drug: Placebo 1600 mg TID for 7 days


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Both groups Caucasian ethnicity Normal haemoglobin Age above 35 years and below 80 years Informed and written consent BMI > 23 kg/m2 and <35 kg/m2 Patients with type 2 diabetes Type 2 diabetes for at least 3 months Diagnosed according to the criteria of the World Health Organization (WHO) Healthy Subjects Normal fasting plasma glucose (FPG) <6.5 mM and Normal glycated haemoglobin (HbA1c) <6.0 % Exclusion Criteria: Both groups Liver disease (alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2 times normal values) or history of hepatobiliary disorder Gastrointestinal disease, previous intestinal resection, cholecystectomy or any major intra-abdominal surgery Hypo- or hyperphosphataemia Nephropathy (serum creatinine >150 µM and/or albuminuria Treatment with medicine that cannot be paused for 12 hours Intake of antibiotics six months prior to study Hypo- or hypercalcaemia Hypo- and hyperthyroidism Treatment with oral anticoagulants Active or recent malignant disease Any treatment or condition requiring acute or sub-acute medical or surgical intervention Lack of effective birth control in premenopausal women Positive pregnancy test on study days in premenopausal women Tobacco smoking Any condition considered incompatible with participation by the investigators Patients with type 2 diabetes Treatment with insulin Treatment with incretin-based therapy Healthy Subjects Diabetes or prediabetes (fasting plasma glucose levels >6.5 mM or HbA1c >6.0%) First-degree relatives with diabetes

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: T2DM, sevelamer<br>Patients with type 2 diabetes treated with sevelamer | Drug: Sevelamer 1600 mg TID for 7 days<br> <br> |
| Placebo Comparator: T2DM, placebo<br>Patients with type 2 diabetes treated with placebo | Drug: Placebo 1600 mg TID for 7 days<br> <br> |
| Active Comparator: Healthy subjects, sevelamer<br>Healthy subjects treated with sevelamer | Drug: Sevelamer 1600 mg TID for 7 days<br> <br> |
| Placebo Comparator: Healthy subjects, placebo<br>Healthy subjects treated with placebo | Drug: Placebo 1600 mg TID for 7 days<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incremental and total area under the Concentration-Time Curve (AUC 0-240 min) | Postprandial responses of glucagon-like peptide-1 (GLP-1) | -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1 and 7 (meal tests start at 0 min) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incremental and total area under the Concentration-Time Curve (AUC 0-240 min) | Postprandial responses of various other gut hormones | -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1 and 7 (meal tests start at 0 min) |