The Role of GLP-1 Receptor Signalling in the Glucose-lowering Effect of Metformin in Patients With T2D

The Role of GLP-1 Receptor Signalling in the Glucose-lowering Effect of Metformin During Meal Ingestion in Patients With T2D

Delineation of the role of glucagon-like peptide-1 receptor signalling in the glucose-lowering effect of metformin during meal ingestion in patients with type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Metformin; Drug: Saline; Drug: Exendin (9-39)

Detailed Description

Aim: To evaluate the contribution of metformin-induced GLP-1 secretion on the glucose-lowering effect of metformin in patients with type 2 diabetes treated with metformin for 14 days. Furthermore, the investigators aim to elucidate the mechanisms by which metformin-induced GLP-1 secretion may affect glucose levels in patients with type 2 diabetes.

Fifteen patients with type 2 diabetes treated with lifestyle intervention and/or metformin as the only glucose-lowering drug will be enrolled in the study. The effect of a 14-day metformin treatment course on postprandial glucose tolerance will be examined with and without infusion of the GLP-1 receptor antagonist exendin9-39 in 15 patients with type 2 diabetes.

The double-blinded, placebo-controlled, randomised, cross-over study consists of four study days with concomitant infusions of A) placebo + placebo, B) placebo + exendin9-39, C) metformin + placebo and D) metformin + exendin9-39.

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

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen
    • Gentofte, Copenhagen, Denmark, 2900
      • Center for diabetes research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 diabetes for at least three months (diagnosed according to the criteria of the World Health Organization (WHO)), with a HbA1c <58 mmol/mol.
• Caucasian ethnicity
• Lifestyle intervention and/or metformin monotherapy
• Normal haemoglobin
• Age >18 years
• BMI >23 kg/m2 and <35 kg/m2
• Informed and written consent

Exclusion Criteria:

• Liver disease
• Gastrointestinal disease, previous intestinal resection, cholecystectomy or any major intra-abdominal surgery
• Hypo- or hyperphosphataemia
• Reduced kidney function or nephropathy
• Treatment with medicine that cannot be paused for 12 hours
• Intake of antibiotics two 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
• Pregnancy
• Women who are breastfeeding
• Any condition considered incompatible with participation by the investigators
• If the subjects receive any antibiotic treatment while included in the study they will be excluded

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo, oral tablet in 14 days and in liquid meal.	Drug: Placebo Oral Tablet; 2-4 tablets in 14 days
Experimental: Metformin; Metformin, oral tablet 2-4 x 500 mg in 14 days and in liquid meal.	Drug: Metformin; 1000-2000 mg in 14 days
Experimental: Saline; Saline infusion (9mg/mL) on experimental days	Drug: Saline; 9 mg/ml saline infusion during experimental days
Experimental: Exendin(9-39); Exendin(9-39) infusion. GLP-1 receptor antagonist used as a study tool on experimental days.	Drug: Exendin (9-39); Infusion of GLP-1 receptor antagonist used as a tool during experimental days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma glucose	The difference between the effect of metformin on postprandial glucose tolerance (as assessed by area under curve (AUC) for plasma glucose during a standardised liquid mixed meal test) with and without blockade of GLP-1 signalling by exendin 9-39.	Minutes 240

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2017
• Primary Completion (Actual): December 10, 2017
• Study Completion (Actual): December 10, 2017

Study Registration Dates

• First Submitted: August 1, 2017
• First Submitted That Met QC Criteria: August 7, 2017
• First Posted (Actual): August 11, 2017

Study Record Updates

• Last Update Posted (Actual): July 9, 2018
• Last Update Submitted That Met QC Criteria: July 6, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: GLP-1; Metformin; glucagon-like peptide-1; Exendin(9-39)
• Additional Relevant MeSH Terms: Metabolic Diseases; Glucose Metabolism Disorders; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: UHG-CFD-METEX

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No