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

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ClinicalTrials.gov Identifier: NCT02061124
Recruitment Status : Completed
First Posted : February 12, 2014
Last Update Posted : November 23, 2015
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Andreas Brønden, University Hospital, Gentofte, Copenhagen

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.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Sevelamer 1600 mg TID for 7 days Drug: Placebo 1600 mg TID for 7 days Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Effect of Bile Acid Sequestration on Postprandial GLP-1 Secretion, Glucose Homeostasis and Gut Microbiota
Study Start Date : February 2014
Actual Primary Completion Date : October 2015
Actual Study Completion Date : October 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Sevelamer

Arm Intervention/treatment
Active Comparator: T2DM, sevelamer
Patients with type 2 diabetes treated with sevelamer
Drug: Sevelamer 1600 mg TID for 7 days
Placebo Comparator: T2DM, placebo
Patients with type 2 diabetes treated with placebo
Drug: Placebo 1600 mg TID for 7 days
Active Comparator: Healthy subjects, sevelamer
Healthy subjects treated with sevelamer
Drug: Sevelamer 1600 mg TID for 7 days
Placebo Comparator: Healthy subjects, placebo
Healthy subjects treated with placebo
Drug: Placebo 1600 mg TID for 7 days



Primary Outcome Measures :
  1. Incremental and total area under the Concentration-Time Curve (AUC 0-240 min) [ Time Frame: -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) ]
    Postprandial responses of glucagon-like peptide-1 (GLP-1)


Secondary Outcome Measures :
  1. Incremental and total area under the Concentration-Time Curve (AUC 0-240 min) [ Time Frame: -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) ]
    Postprandial responses of various other gut hormones


Other Outcome Measures:
  1. Blood analysis [ Time Frame: Fasting status on study days 1 and 7 ]
    Lipids

  2. Blood analysis [ Time Frame: Fasting status on study days 1 and 7 ]
    Inflammatory and metabolic markers

  3. Faecal samples [ Time Frame: Prior to study days 1 and 7 ]
    Gut microbiota composition

  4. Blood analysis of paracetamol [ Time Frame: -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 ]
    Assessment of gastric emptying

  5. Bodyweight [ Time Frame: Fasting state on study days 1 and 7 ]
  6. Indirect calorimetry [ Time Frame: -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 ]
    Basal metabolic rate

  7. Ultrasound measurements [ Time Frame: -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 ]
    Gall bladder volume

  8. Visual analog scale score [ Time Frame: -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 ]
    Appetite



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Ages Eligible for Study:   35 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02061124


Locations
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Denmark
Diabetes Research Division, Gentofte Hospital, Copenhagen
Hellerup, Denmark, 2900
Sponsors and Collaborators
University Hospital, Gentofte, Copenhagen
Sanofi

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Responsible Party: Andreas Brønden, MD, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier: NCT02061124     History of Changes
Other Study ID Numbers: H-2-2013-148
First Posted: February 12, 2014    Key Record Dates
Last Update Posted: November 23, 2015
Last Verified: November 2015

Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Bile Acids and Salts
Sevelamer
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents