Endothelial and Metabolic Effects of Glucagon-like Peptide-1 (GLP-1) in Coronary Circulation in Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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GLP-1 is an incretin hormone which is discharged from the intestines after food intake. The hormone is known for its powerful insulinotropic and trophic effects on the beta cells in the pancreas and is currently used as an anti-diabetic agent in patients with type 2 diabetes (T2DM). GLP-1 receptors are widely distributed including on the endothelial cells in both coronary and skeletal muscle circulation and on the myocardium. GLP-1-receptor studies on knock-out mice have shown that they exhibit a reduced myocardial contractility and reduced diastolic heart function. GLP-1 also shows beneficial cardiovascular effects in patients with acute myocardial infarctions and dogs with dilated cardiomyopathy in that the left ventricle function and endothelial dysfunction improves after GLP-1 treatment via insulin-independent mechanisms. Preclinical studies indicate that exogenous administrated GLP-1 in physiological concentrations can improve perfusion but this has never been tested in humans. It is also unknown whether GLP-1 can directly increase the glucose/metabolite uptake across both cardiac and skeletal muscle in an insulin independent manner. Unpublished studies do however indicate that the improvement in the cardiovascular system is largely dependent upon a high blood glucose level and only partially dependent upon the antiglycemic effects of GLP-1. In the proposed studies the investigators wish to examine the physiological role of GLP-1 receptor stimulation both with regard to perfusion, metabolic improvement as well as cardiac inotropic. These studies will be conducted in both healthy and in T2DM patients.

Official Title
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Endothelial and Metabolic Effects of GLP-1 in Coronary Circulation in Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Glucagon like peptide-1
* Drug: Adenosine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasians over 18 Emitted for non-acute coronary arteriography (CAG) in Gentofte hospital BMI 23-35 kg/m2 Normal hemoglobin Who gives informed consent Those with type 2 diabetes: HbA1c 6-10% Those without type 2 diabetes: Normal oral glucose tolerance test (OGTT) according to WHO criteria Exclusion Criteria: Liver disease (ALAT > 2x normal) Diabetic nefropati (Creatinine > 130 µM or albuminuria) Treatment with medicine that cannot be paused 12 hours before intervention Pregnancy or breastfeeding Insulin- or glitazone treatment Healthy controls: close family history with diabetes Unstable angina pectoris Non-STEMI Atrial fibrillation Valvular disease LVEF < 50% Severe systemic disease Type 1 diabetes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Type 2 Diabetes patients<br> | Drug: Glucagon like peptide-1<br>* 0,1 pmol/kg/min<br>Drug: Adenosine<br>* 20-40 microgram/minute<br>|
| Active Comparator: Healthy<br> | Drug: Glucagon like peptide-1<br>* 0,1 pmol/kg/min<br>Drug: Adenosine<br>* 20-40 microgram/minute<br>|
| Active Comparator: Artherosclerosis<br> | Drug: Glucagon like peptide-1<br>* 0,1 pmol/kg/min<br>Drug: Adenosine<br>* 20-40 microgram/minute<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary blood flow |  | 10 minutes after I.A. GLP-1 | 
| Coronary metabolite uptake |  | 10 minutes after I.A. GLP-1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Basic science, Type 2 Diabetes mellitus, Glucagon like peptid-1, Coronary Bloodflow, Metabolite uptake