To boost amino acid oxidation in diabetes

Rationale: Insulin resistance is the most important risk factor in Type 2 Diabetes (T2D). Several studies identified branched-chain amino acids (BCAA; leucine, isoleucine and valine) to be substantially elevated in people with T2D. Recently, I confirmed the finding of higher BCAA in people with T2D. Furthermore, I found strong associations between BCAA and key metabolic disarrangements seen in T2D at the level of mitochondrial function, liver fat, insulin resistance and metabolic flexibility. Importantly, data showed lower whole body leucine oxidation in patients with T2DM vs. control humans. Here, I want to administer the drug sodium phenylbutyrate (NaPB) -a drug known to lower plasma BCAA in humans via accelerated BCAA oxidation- in patients with T2DM as strategy to enhance BCAA metabolism. This project aims to investigate whether Na-PB-enhanced BCAA oxidation would be a potential strategy in people with T2D to improve metabolic health.

Objective: Primary objective is the delta change in whole body insulin sensitivity expressed as glucose disposal rate (µmol/kg/min) upon 2 weeks of Na-PB vs. placebo treatment.

Secondary objectives are muscle mitochondrial oxidative capacity (pmol/mg/s), muscle and liver fat content (%) and energy metabolism (respiratory exchange ratio and kJ/kg/min).

Study design: 2 week clinical randomized controlled trial (RCT) with a double blinded, placebo-controlled, cross-over design, including a wash-out period of 6 weeks.

Study population: 16 male and (post-menopausal) female participants (50% m/ 50% f) with T2D. Participants will be relatively well-controlled (HbA1C<8.5%), are on oral glucose-lowering medication, are overweight/obese (BMI 25-38 kg/m2) and between 40-75 years old.

Intervention: 2 weeks oral administration of 4.8 g/m2/day Pheburane or placebo per day, depending on body surface area. Pheburane needs to be administered spread over the day in 3 times taken with a meal.

Main study parameters/endpoints: insulin sensitivity expressed as delta change in µmol/kg/min upon Na-PB treatment versus placebo. The endpoint of study is the measurement of insulin sensitivity of the 15th participant after the second intervention period.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: No direct health benefits for the participants are expected. Burdens: time investment with study visits and administration of study drug. (Low) risks of measurements: hypoglycaemia during the clamp, hematomas and inflammation upon muscle biopsies. Risks with study drug: negative nitrogen balance, loss of appetite, changed body odour (described for 3-4% of all patients using Na-PB with long administration time).

Sodium phenylbutyrate administration in patients with T2D would improve whole body insulin sensitivity.

2 times 2 week intervention period with a washout of 6-8 weeks between the treatment arms. Total duration of the study is 10-12 weeks for each participant

2 weeks oral administration of 4.8 g/m2/day Pheburane or placebo per day, depending on body surface area. Pheburane needs to be administered spread over the day in 3 times taken with a meal.