The Effects of Sodium Phenylbutyrate on Circulating Branched Chain Amino Acid Concentrations in Obese and Prediabetics.

A total of twenty proteinogenic amino acids are present in the human body1. Due to their chemical structure, three of the amino acids - isoleucine, leucine and valine, are termed branched chain amino acids (BCAAs). Humans consume BCAAs through protein containing foods such as meat, eggs and milk2,3. However, recent studies, have revealed links between elevated plasma levels of BCAAs and type 2 diabetes (T2D), insulin resistance (IR) and obesity4-6. Such is the strength of these links that elevated blood concentration of BCAAs are considered biomarkers and prognostic factors for obesity, insulin resistance and type 2 diabetes7-9. Collectively, these data suggest that targeting dysregulation of BCAAs by reducing BCAA levels could offer important therapeutic value. Various methods can be implemented in order to reduce circulating fasting BCAA concentrations one method that our department has successfully implemented includes the restriction of BCAAs in 6 healthy volunteer participants through diet control. By restricting BCAA in the diets of healthy individuals, we successfully reduced fasting circulating BCAAs by 50% in just seven days. However, the construction of the diet was very time consuming, tedious, and longer studies would be plagued with compliance issues. This has led us to try an alternative method, which is to lower BCAA levels using Sodium Phenylbutyrate (NaPB). NaPB is a commonly used medication to treat patients with urea cycle disorders (UCD). However, it seems a secondary effect of the drug is to reduce circulating BCAA levels in volunteers. Lindsey Burrage et al 2014, reported significantly lower circulating BCAAs in volunteers receiving NaPB when compared to subjects not receiving NaPB10. Although the mechanisms are not fully understood it has been suggested that NaPB causes depletion of glutamine in the blood which may activate BCAA catabolism and thus cause a reduction in circulating plasma BCAAs11. It is our aim to use NaPB to lower BCAAs in prediabetic and obese participants.

Screening Visit Volunteers will sign a consent form, A health assessment, including an ECG to monitor your heart, a blood pressure check, height and weight measurement and a medical history check A fasted blood sample to measure health parameters, including glucose, HbA1c, liver and kidney function, lipid profiles, thyroid function and full blood count.

Once we received the details and results (within 1 week) from your screening session, we will contact you regarding your suitability. If you are suitable, we (you and the research team together) will decide on the dates to start the programme.

Instruct you in the completion of a food diary. STUDY DAY 0 For this day, we will ask volunteers to attend after an overnight fast (except water). We will take small samples of your blood (fasting sample).

After the blood samples participants will receive a 'heavy water' drink called Deuterium Oxide (D2O). This is almost the same as normal water, but a small and harmless chemical change allows us to calculate how much new muscle your body is making. The amount of D2O you are given will be calculated based on your body weight. Participants will provide saliva samples before and after receiving D2O. Before they go home they will receive small daily top-ups of D2O and asked to collect your saliva 3 hours after taking your daily top-ups for the first week, and twice weekly thereafter and keep the saliva samples in a fridge/freezer.