Role of BCAA in Glucose Homeostasis

Study Overview
=================
Brief Summary
-----------------
This clinical trial study aims to evaluate the effects of prolonged NaPB treatment in a maximum of 20 patients with T2D. The primary objective is: to investigate if prolonged boosting of ing BCAA oxidation will substantially lower plasma glucose levels in patients with T2D. Participants will undergo a Clinical randomized controlled trial (RCT) with a double-blinded, placebo-controlled, cross-over design, including a wash-out period of 12 weeks. The trial will contain 2 treatment arms, with each a duration of 12 weeks. Participants will have a 12-week oral administration of 4.8 g/m2/day NaPB (in the form of Pheburane) or placebo per day. Although depending on body surface area,  21 g Pheburane needs to be administered spread over the day 3 times taken with a meal.

Detailed Description
-----------------
Several studies identified branched-chain amino acids (BCAA; leucine, isoleucine, and valine) to be substantially elevated in people with T2D, possibly caused by lower BCAA oxidation rates. Plasma BCAA levels are strongly associated with insulin resistance and other key metabolic disarrangements as seen in T2D, including mitochondrial function, liver fat content, and metabolic flexibility. We, recently, showed that stimulating BCAA oxidation for 2 weeks with sodium-phenylbutyrate (NaPB) treatment -a drug known to accelerate BCAA oxidation- decreased BCAA plasma levels in patients with T2D. This reduction in plasma BCAA levels was paralleled with a robust improvement in peripheral insulin sensitivity and muscle mitochondrial oxidative capacity. Interestingly, a strong tendency was found for lower fasting glucose levels, an indication of better glucose control. These findings form lead to further evaluating this treatment strategy to improve glucose homeostasis and lower hyperglycaemic conditions in patients with T2D. So far, this strategy has been tested only in several rodent models reporting promising, beneficial outcomes on glucose homeostasis and heart function. The aim of the present study is to evaluate the effects of prolonged treatment: patients with T2D will undergo a 12-week NaPB intervention with the aim of substantially lower fasting plasma glucose levels. The outcomes of this project evaluate a novel strategy to treat patients with T2D.

Official Title
-----------------
Targeting Branched-chain Amino Acid Oxidation to Improve Glycaemic Control in Patients With Type 2 Diabetes

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: 4.8 g/m^2/day NaPB
* Drug: 4.8 g/m^2/day placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients are able to provide signed and dated written informed consent prior to any study specific procedures Women are post-menopausal (defined as at least 1 year post cessation of menses) and aged ≥ 45 and ≤ 76 years. Males are aged ≥ 40 years and ≤ 76 years Patients should have suitable veins for cannulation or repeated venipuncture Caucasians BMI: 25-38 kg/m2 Diagnosed with T2D at least 1.5 years before the start of the study Relatively well-controlled T2D: HbA1c < 8.5% Oral glucose lowering medication: metformin only or in combination with sulfonylurea agents and/or on stable dose of a DPPIV inhibitor treatment for at least the last 3 months No signs of active diabetes-related co-morbidities like active cardiovascular diseases, active diabetic foot, polyneuropathy or retinopathy No signs of active liver or kidney malfunction Exclusion Criteria: Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the Investigator Participate in physical activity more than 3 times a week Unstable body weight (weight gain or loss > 5 kg in the last three months) Insulin dependent T2D Patients with congestive heart failure and and/or severe renal and or liver insufficiency or known sodium retention with oedema Patients using Probalan (probenecid), Haldol (haloperidol), Depakene (valproate) or medical products containing corticosteroids Men: Hb <8.4 mmol/L, Women: Hb <7.8 mmol/l Any contra-indication MRI scanning. These contra-indications include patients with e.g. the following: Central nervous system aneurysm clip Implanted neural stimulator Implanted cardiac pacemaker of defibrillator Cochlear implant Metal containing corpora aliena in the eye or brains

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 76 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Clinical randomized controlled trial (RCT) with a double-blinded, placebo-controlled, cross-over design, including a wash-out period of 12 weeks. The trial will contain 2 treatment arms, with each a duration of 12 weeks.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 4.8 g/m^2/day NaPB<br>12-week oral administration of 4.8 g/m^2/day Sodium-phenylbutyrate (NaPB) (in the form of Pheburane) | Drug: 4.8 g/m^2/day NaPB<br>* 12-week oral administration of 4.8 g/m^2/day NaPB (in the form of Pheburane) per day. Although depending on body surface area,  21 g Pheburane needs to be administered spread over the day in 3 times taken with a meal.<br>* Other names: NaPB;|
| Placebo Comparator: 4.8 g/m^2/day Placebo<br>12-week oral administration of 4.8 g/m2/day identical placebo granules. | Drug: 4.8 g/m^2/day placebo<br>* 12-week oral administration of 4.8 g/m^2/day NaPB (in the form of Pheburane) or placebo per day. Although depending on body surface area,  21 g Pheburane needs to be administered spread over the day in 3 times taken with a meal.<br>* Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fasting plasma glucose levels | Glucose levels will be measured after an overnight fast expressed in mmol/l. | at week 12 of each intervention period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| whole-body insulin sensitivity | glucose clearance in ml/kg determined during an OGTT at 6 weeks glucose disposal rate (delta Rd) in umol/kg/min measured with the clamp at 12 weeks | at week 6 and week 12 of each intervention period | 
| muscle mitochondrial function | O2-flux will be measured with high-resolution respirometry | at week 6 and week 12 of each intervention period | 
| whole-body metabolic flexibility | insulin-stimulated change in respiratory exchange ratio will be determined with use of indirect calorimetry during the clamp | at week 12 of each intervention period | 
| energy status of the heart | PCr/ATP-ratio will be determined with phosphorus magnetic resonance spectroscopy | at week 12 of each arm | 
| cardiac function: ejection fraction | The cardiac function will be measured via ejection fraction (microL) with the use of cine-MRI | at week 12 of each arm | 
| cardiac function: left atrial maximum volume | The cardiac function will be measured via diastolic cardiac function with the use of ultrasound (transthoracic echocardiography) with the following parameter: Left atrial maximum volume (ml) | at week 12 of each arm | 
| cardiac function: peak A-wave velocity (cm/sec) | The cardiac function will be measured via diastolic cardiac function with the use of ultrasound (transthoracic echocardiography) with the following parameter: Peak A-wave velocity (cm/sec) | at week 12 of each arm | 
| cardiac function: pulsed wave TDI velocity (cm/sec) at lateral and septal basal regions | The cardiac function will be measured via diastolic cardiac function with the use of ultrasound (transthoracic echocardiography) with the following parameter: Pulsed wave TDI velocity (cm/sec) at lateral and septal basal regions | at week 12 of each arm | 
| cardiac function: peak E-wave velocity | The cardiac function will be measured via diastolic cardiac function with the use of of ultrasound (transthoracic echocardiography) will be assessed with the following parameters: Peak E-wave velocity (cm/sec) | at week 12 of each arm | 
| cardiac function: tricuspid regurgitation systolic jet velocity | The cardiac function will be measured via diastolic cardiac function with the use of ultrasound (transthoracic echocardiography) with the following parameter: Tricuspid regurgitation systolic jet velocity (m/sec) | at week 12 of each arm | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
type 2 Diabetes, branched-chain amino acid metabolism, glucose homeostasis, sodium-phenylbutyrate, insulin resistance