Effect of Apelin on Insulin Sensitivity in Type 2 Diabetic Volunteers

Study Overview
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Brief Summary
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Preclinical studies have demonstrated in mouse models that (PYR1)-apelin-13 exerts a glucose-regulating action in vivo. The (PYR1)-apelin-13 effect on insulin sensitivity in healthy overweighed volunteers has been previously assessed in a phase I clinical trial (APELINS study; NCT02033473). The APELINS-2 clinical trial aims to expand the initial proof of concept to the population targeted by future innovative insulin-sensitizing therapies: patients living with type 2 diabetes.

Detailed Description
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Insulin sensitivity is measured using the hyperinsulinemic euglycemic glucose clamp method. The hypothesis of the investigators is that a continuous (pyr1)-apelin-13 infusion improves insulin sensitivity of type 2 diabetic patients compared to placebo infusion. This study could bring new elements for understanding the pathophysiology of insulin resistance and type 2 diabetes mellitus in humans and could lead to the development of innovative therapies in type 2 diabetes mellitus.

Official Title
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Influence of Apelin on Insulin Sensitivity in Type 2 Diabetic Volunteers

Conditions
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Diabetes

Intervention / Treatment
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* Drug: apelin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of type2 diabetes Body Mass Index between 27 and 33 kg / cm ² HbA1c < 8.5% Non-pathological Electrocardiogram Heart rate between 50 and 80 beats per minute at rest. Complete Blood Count (CBC) with no significant anomaly in terms of the investigator.. Serum electrolytes without clinically significant abnormalities in terms of the investigator. Liver function tests without clinically significant abnormalities in terms of the investigator Renal function tests without clinically significant abnormalities in terms of the investigator Good peripheral vein (forearm and back of the hand). Agreement to participate in the establishment of a serum bank. Ability to sign informed consent. Affiliation to a social security scheme Exclusion Criteria: Secondary prevention of cardio-vascular disease Insulin therapy or Glucagon Like Peptid 1 (GLP-1) analogs therapy in the 6 months before inclusion. Risk factor, treatment or electrocardiogram as recommended by International Conference on Harmonization (ICH) E14 Clinical Evaluation of QT / QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Repeated a QTc interval> 450 ms measurement Risk factor for torsade de pointes: myocardial infarction, hypokalemia, family history of long QT syndrome Personal history of cancer. Positive HIV serology. Hepatitis B serology positive. Positive hepatitis C serology. Cognitive impairment or mental illness (at the discretion of the investigator). Chronic excessive alcohol consumption (consumption > 30g/day or 210g/week). Person under judicial protection, guardianship. Subject with a resting systolic blood pressure greater than 140 mm Hg and diastolic blood pressure greater than 90 mmHg Smoking more than 10 cigaret per day and can not be interrupted for 24 hours.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Apelin then Placebo<br>First clamp during which an apelin infusion will be administered followed by a wash-out period and then, a second clamp in which a placebo infusion will be administered | Drug: apelin<br>* Assessing the difference between the insulin sensitivity measured during hyperinsulinemic euglycemic clamps in the presence of a 2 hours continuous infusion of (PYR1)-apelin-13 (30nmol/kg) versus a 2 hours continuous infusion of placebo (vehicle alone).<br>* Other names: [pyr1]-apelin-13 infusion;Drug: placebo<br>* 2 hours continuous infusion of placebo (vehicle alone) to compare with 2 hours infusion of apelin<br>|
| Other: Placebo then Apelin<br>First clamp during which a placebo infusion will be administered followed by a wash-out period and then, a second clamp in which an apelin infusion will be administered | Drug: apelin<br>* Assessing the difference between the insulin sensitivity measured during hyperinsulinemic euglycemic clamps in the presence of a 2 hours continuous infusion of (PYR1)-apelin-13 (30nmol/kg) versus a 2 hours continuous infusion of placebo (vehicle alone).<br>* Other names: [pyr1]-apelin-13 infusion;Drug: placebo<br>* 2 hours continuous infusion of placebo (vehicle alone) to compare with 2 hours infusion of apelin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta between Glucose Infusion Rate | Difference between glucose infusion rate measured during investigational product infusion (mean of values measured at 210, 215, 220, 225, 230, 235 and 240 minutes) and basal glucose infusion rate (mean of values measured at 90, 95, 100, 105, 110, 115 and 120 minutes). | 240 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of M-value (a glucose physiological parameter) | Difference between value of product time (mean of values measured at 210, 215, 220, 225, 230, 235 and 240 minutes) and value of basal (mean of values measured at 90, 95, 100, 105, 110, 115 and 120 minutes). | 240 minutes | 
| systolic blood pressure and diastolic blood pressure |  | 240 minutes | 
| heart rate |  | 240 minutes | 
| Measure of QTc interval with electrocardiogram examination |  | 240 minutes | 
| Clinic sign of apelin intolerance |  | 240 minutes | 
| Dosage of plasma proteins | A kinetic is realized with samples at 0, 15, 30, 45, 60, 75, 90, 100, 110, 120, 135, 150, 165, 180, 195, 200, 220, 230 and 240 minutes | 240 minutes | 
| Clinic sign of apelin allergy | Modification in physiological parameters | 240 minutes | 
| Clinic sign of apelin toxicity | Modification in physiological parameters | 240 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetic volunteers