Effect of Bile Acid Secretion and Sequestration on GLP-1 Secretion

Accumulating evidence suggests that bile acids in our intestines may constitute essential components in the complex mechanisms regulating gut hormone secretion and glucose homeostasis. Thus, it is likely that modification of the enterohepatic circulation of bile acids can lead to changes in gut hormone secretion and consequently affect glucose homeostasis.

The current study is a human interventional randomized controlled cross-over study including four study days for each participant. 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 has been shown to improve glycaemic control in patients with chronic kidney disease and type 2 diabetes. Intravenous infusion of cholecystokinin will be used to elicit gallbladder contraction and emptying. The aim is to examine how (and if) bile acid sequestration can influence postprandial glucagon-like peptide-1 (GLP-1) secretion and glucose homeostasis in patients with type 2 diabetes.

The investigators hypothesize that higher luminal concentrations of bile acids in the distal gut will elicit changes in gut hormone secretion. 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 and glucose metabolism.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Sevelamer placebo; Drug: Isotonic saline; Drug: Cholecystokinin; Drug: Sevelamer

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Center for diabetes research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization (WHO))
• Men and postmenopausal women
• Metformin applied as the only anti-diabetic drug
• Caucasian ethnicity
• Normal haemoglobin
• Age above 40 years and below 70 years
• BMI >23 kg/m2 and <35 kg/m2
• Informed and written consent

Exclusion Criteria:

• 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
• Nephropathy (serum creatinine >150 µM and/or albuminuria)
• Hypo- and hyperthyroidism
• Hypo- and hypercalcaemia
• Hypo- and hyperphosphataemia
• Active or recent malignant disease
• Treatment with medicine that cannot be paused for 12 hours
• Treatment with oral anticoagulants
• Any treatment or condition requiring acute or sub-acute medical or surgical intervention
• Any condition considered incompatible with participation by the investigators

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo+Placebo; Oral ingestion of sevelamer placebo powder combined with intravenous infusion of isotonic saline.	Drug: Sevelamer placebo; Drug: Isotonic saline
Active Comparator: Placebo+Cholecystokinin; Oral ingestion of sevelamer placebo powder combined with intravenous infusion of cholecystokinin.	Drug: Sevelamer placebo; Drug: Cholecystokinin
Active Comparator: Sevelamer+Placebo; Oral ingestion of sevelamer powder combined with intravenous infusion of isotonic saline.	Drug: Isotonic saline; Drug: Sevelamer
Active Comparator: Sevelamer+Cholecystokinin; Oral ingestion of sevelamer powder combined with intravenous infusion of cholecystokinin.	Drug: Cholecystokinin; Drug: Sevelamer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucagon-like peptide-1 (GLP-1): Incremental and total area under the Concentration-Time Curve	Incremental and total area under the Concentration-Time Curve (AUC 0-240 min)	-30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responses of various other gut hormones: Incremental and total area under the Concentration-Time Curve	Incremental and total area under the Concentration-Time Curve (AUC 0-240 min)	-30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4
Blood analysis of paracetamol as an assessment of gastric emptying	Assessment of gastric emptying	-30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4
Indirect calorimetry: Basal metabolic rate	Basal metabolic rate	-30 min to 240 min
Gallbladder volume as assessed by Ultrasound measurements	Gallbladder volume	-30 min to 240 min
Appetite as assessed by Visual analog scale score	Appetite	-30 min to 240 min

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: May 8, 2015
• First Submitted That Met QC Criteria: May 14, 2015
• First Posted (Estimate): May 15, 2015

Study Record Updates

• Last Update Posted (Actual): May 3, 2017
• Last Update Submitted That Met QC Criteria: May 2, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Chelating Agents; Sequestering Agents; Cholagogues and Choleretics; Sevelamer; Cholecystokinin
• Other Study ID Numbers: NCT02445508