Effect of Metformin and Cholecystokinin-mediated Gallbladder Emptying on GLP-1 Secretion in Type 2 Diabetes

May 2, 2017 updated by: Andreas Brønden, University Hospital, Gentofte, Copenhagen

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. Metformin will be applied as a tool to reduce bile acid reuptake in the small intestine; thereby increasing bile acid concentration in the more distal parts of the gut where GLP-1-secreting L cell are abundant. Interestingly, metformin has been shown to reduce the active reabsorption of bile acids in the ileum and cause increased faecal elimination of bile acids. Clinical data has suggested that metformin causes an increase in the postprandial secretion of GLP-1 in humans including patients with type 2 diabetes. Intravenous infusion of cholecystokinin will be used to elicit gallbladder contraction and emptying. The aim is to examine how (and if) modification of bile acid reabsorption 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

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Hellerup, Denmark, 2900
        • Center for Diabetes Research, Herlev-Gentofte Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

36 years to 71 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
  • 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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

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

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
Time Frame: -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4
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
Time Frame: -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4
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
Time Frame: -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4
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
Time Frame: -30 min to 240 min
Basal metabolic rate
-30 min to 240 min
Gallbladder volume as assessed by Ultrasound measurements
Time Frame: -30 min to 240 min
Gallbladder volume
-30 min to 240 min
Appetite as assessed by Visual analog scale score
Time Frame: -30 min to 240 min
Appetite
-30 min to 240 min

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Gentofte, Copenhagen

Investigators

  • Principal Investigator: Andreas Brønden, MD, PhD student

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2015

Primary Completion (Actual)

July 1, 2016

Study Completion (Actual)

July 1, 2016

Study Registration Dates

First Submitted

July 9, 2015

First Submitted That Met QC Criteria

July 9, 2015

First Posted (Estimate)

July 14, 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

Other Study ID Numbers

  • H-15007280

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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