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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Glucose Metabolism Disorders

Intervention / Treatment
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* Drug: Placebo Oral Tablet
* Drug: Metformin
* Drug: Saline
* Drug: Exendin (9-39)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-1, glucagon-like peptide-1, Metformin, Exendin(9-39)