Resveratrol and First-degree Relatives of Type 2 Diabetic Patients

Study Overview
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Brief Summary
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The main objective of the study is to investigate if resveratrol supplementation can improve overall and muscle-specific insulin sensitivity in first-degree relatives of type 2 diabetic patients. As a secondary objective the investigators want to investigate whether the improved insulin sensitivity can be attributed to improved muscle mitochondrial oxidative capacity and a reduced intrahepatic and cardiac lipid content. Furthermore, in a subset of the participants the investigators want to investigate the effect of resveratrol on glucose uptake in brown adipose tissue.

Official Title
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Effects of Resveratrol on Insulin Sensitivity, Brown Adipose Tissue and Metabolic Profile in First-degree Relatives of Type 2 Diabetic Patients

Conditions
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Pre-diabetes

Intervention / Treatment
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* Dietary Supplement: placebo
* Dietary Supplement: resveratrol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male sex Age: 40-70 years BMI 27-35 kg/m2 Has first-degree relative(s) diagnosed with type 2 diabetes Sedentary Not more than 2 hours of sports a week No active job that requires strenuous physical activity Stable dietary habits: no weight gain or loss > 5kg in the last three months Insulin resistant: glucose clearance rate below < 350 ml/kg/min, as determined using OGIS120 Willingness to abstain from resveratrol-containing food products Subjects will only be included when the dependent medical doctor of this study approves participation after evaluating data obtained during screening Exclusion Criteria: Use of anticoagulants Uncontrolled hypertension Haemoglobin <7.8 mmol/l In case of an abnormal ECG in rest: this will be discussed with the responsible medical doctor HBA1C > 6.5% Diagnosed with type 2 diabetes Medication use known to interfere with glucose homeostasis/metabolism Current alcohol consumption > 20 grams/day Subjects who don't want to be informed about unexpected medical findings during the screening /study, or do not wish that their physician is informed, cannot participate in the study. Subjects who intend to donate blood during the intervention or subjects who have donated blood less than three months before the start of the intervention. Participation in another biomedical study within 1 month before the first screening visit Any condition, disease or abnormal laboratory test result that, in the opinion of the Investigator, would interfere with the study outcome, affect trial participation or put the subject at undue risk Any contra-indication to MRI scanning. These contra-indications include patients with following devices: Central nervous system aneurysm clip Implanted neural stimulator Implanted cardiac pacemaker of defibrillator Cochlear implant Insulin pump Metal containing corpora aliena in the eye or brains

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: resveratrol<br>resveratrol will be given for 30 or 34 days (if included in brown adipose tissue measurement), twice daily. One pill, which contains 75 mg of resveratrol, will be provided with lunch, and the other pill of 75 mg will be provided with dinner. So in total 150 mg/day of resveratrol will be given. | Dietary Supplement: resveratrol<br>* resveratrol will be given for 30 days or 34 days (if included in brown adipose tissue measurement), twice daily. One pill, which contains 75 mg of resveratrol, will be provided with lunch, and the other pill, also containing 75 mg will be given with dinner. So in total a dose of 150 mg/day will be given.<br>* Other names: resVida (99% pure trans-resveratrol);|
| Placebo Comparator: placebo<br>A placebo will be given for 30 or 34 days (if included in brown adipose tissue measurement), twice daily. One pill will be provided with lunch and the other pill will be provided with dinner. | Dietary Supplement: placebo<br>* A placebo will given for 30 days or 34 days (if included in brown adipose tissue measurement), twice daily. One pill will be provided with lunch, and the other pill will be provided with dinner.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| insulin sensitivity: overall, muscle- and liver specific | Hyperinsulinemic euglycemic clamp combined with indirect calorimetry: Glucose infusion rate (GIR), rate of appearance and disappearance of glucose (Ra, Rd), endogenous glucose production (EGP), oxidative and non-oxidative glucose disposal, carbohydrate and lipid oxidation, energy expenditure. | 30 days after supplementation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| muscle mitochondrial oxidative capacity (in vivo and ex vivo) | In vivo: Phosphocreatine levels will be measured by P-MRS (before, during, and after exercise) as a marker for in vivo mitochondrial function in the vastus lateralis muscle. Ex vivo mitochondrial function in skeletal muscle will be measured by oxygen consumption in muscle fibres (muscle biopsy) on lipid-derived and carbohydrate-derived substrates. | 30 days after supplementation | 
| intramyocellular lipid content | Skeletal muscle lipid accumulation measured by immunohistochemistry in muscle biopsy from vastus lateralis muscle | 30 days after supplementation | 
| intrahepatic lipid content | Intrahepatic lipid content measured with H-MRS | 30 days after supplementation | 
| intracardiac lipid content | Intracardiac lipid content measured with H-MRS | 30 days after supplementation | 
| heart function | Cardiac function: diastolic and systolic heart function will be measured with ultrasound | 30 days after supplementation | 
| brown adipose tissue activity | subjects will be exposed to an individualized cooling protocol, after which an 18F-FDG PET/CT scan is made | 34 days after supplementation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Analgesics, Non-Narcotic, Analgesics, Sensory System Agents, Peripheral Nervous System Agents, Physiological Effects of Drugs, Pharmacologic Actions, Anti-Inflammatory Agents, Therapeutic Uses, Antirheumatic Agents, Antineoplastic Agents, Phytogenic, Antineoplastic Agents, Antioxidants, Molecular Mechanisms of Pharmacological Action, Protective Agents, Enzyme Inhibitors, Platelet Aggregation Inhibitors, Hematologic Agents, Resveratrol, Diabetes Mellitus, Type 2, Insulin Resistance, Glucose Metabolism Disorders, Metabolic Diseases, Endocrine System Diseases, Hyperinsulinism, Anti-Inflammatory Agents, Non-Steroidal, Antimutagenic Agents, Anticarcinogenic Agents, Central Nervous System Agents, Brown Adipose Tissue