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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Sevelamer 1600 mg TID for 7 days; Drug: Placebo 1600 mg TID for 7 days

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Diabetes Research Division, Gentofte Hospital, Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / 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

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood analysis	Lipids	Fasting status on study days 1 and 7
Blood analysis	Inflammatory and metabolic markers	Fasting status on study days 1 and 7
Faecal samples	Gut microbiota composition	Prior to study days 1 and 7
Blood analysis of paracetamol	Assessment of gastric emptying	-30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7
Bodyweight		Fasting state on study days 1 and 7
Indirect calorimetry	Basal metabolic rate	-30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7
Ultrasound measurements	Gall bladder volume	-30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7
Visual analog scale score	Appetite	-30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen
• Collaborators: Sanofi

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: February 6, 2014
• First Submitted That Met QC Criteria: February 10, 2014
• First Posted (Estimate): February 12, 2014

Study Record Updates

• Last Update Posted (Estimate): November 23, 2015
• Last Update Submitted That Met QC Criteria: November 20, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Sevelamer
• Other Study ID Numbers: H-2-2013-148