Clinical trial NCT05836350: Role of BCAA in Glucose Homeostasis
Official title: Targeting Branched-chain Amino Acid Oxidation to Improve Glycaemic Control in Patients With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Type 2 Diabetes
Keywords: type 2 Diabetes
branched-chain amino acid metabolism
glucose homeostasis
sodium-phenylbutyrate
insulin resistance
Lead sponsor: Maastricht University
Sponsor class: OTHER
First posted: 2023-05-01
Enrollment: 20
Sex: ALL
Minimum age (years): 40
Maximum age (years): 76
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Patients are able to provide signed and dated written informed consent prior to any study specific procedures
2. 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
3. Patients should have suitable veins for cannulation or repeated venipuncture
4. Caucasians
5. BMI: 25-38 kg/m2
6. Diagnosed with T2D at least 1.5 years before the start of the study
7. Relatively well-controlled T2D: HbA1c \< 8.5%
8. 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
9. No signs of active diabetes-related co-morbidities like active cardiovascular diseases, active diabetic foot, polyneuropathy or retinopathy
10. No signs of active liver or kidney malfunction

Exclusion Criteria:

1. Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the Investigator
2. Participate in physical activity more than 3 times a week
3. Unstable body weight (weight gain or loss \> 5 kg in the last three months)
4. Insulin dependent T2D
5. Patients with congestive heart failure and and/or severe renal and or liver insufficiency or known sodium retention with oedema
6. Patients using Probalan (probenecid), Haldol (haloperidol), Depakene (valproate) or medical products containing corticosteroids
7. Men: Hb \<8.4 mmol/L, Women: Hb \<7.8 mmol/l
8. 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

Primary outcomes:
measure: fasting plasma glucose levels
timeFrame: at week 12 of each intervention period
Secondary outcomes:
measure: whole-body insulin sensitivity
timeFrame: at week 6 and week 12 of each intervention period
measure: muscle mitochondrial function
timeFrame: at week 6 and week 12 of each intervention period
measure: whole-body metabolic flexibility
timeFrame: at week 12 of each intervention period
measure: energy status of the heart
timeFrame: at week 12 of each arm
measure: cardiac function: ejection fraction
timeFrame: at week 12 of each arm
measure: cardiac function: left atrial maximum volume
timeFrame: at week 12 of each arm
measure: cardiac function: peak A-wave velocity (cm/sec)
timeFrame: at week 12 of each arm
measure: cardiac function: pulsed wave TDI velocity (cm/sec) at lateral and septal basal regions
timeFrame: at week 12 of each arm
measure: cardiac function: peak E-wave velocity
timeFrame: at week 12 of each arm
measure: cardiac function: tricuspid regurgitation systolic jet velocity
timeFrame: at week 12 of each arm
Other outcomes:
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