Discovery and understanding of novel mechanisms to improve insulin resistance, obesity and type 2 diabetes mellitus (T2DM) by targeting branched chain amino acid metabolism

Obesity and type 2 diabetes (T2DM) are major health problems in the UK and globally. Yet interventions for obesity and T2DM are limited to exercise, dietary advice aimed at weight loss and control of blood sugar, and the prescription of glucose lowering drug(s). The aim of our research was to explore effects of a novel intervention, aimed at manipulating the blood levels of three specific amino acids called the branched-chain amino acids (BCAAs). The abundance of these BCAAs is higher in the bloodstream of people with obesity, pre-diabetes and T2DM. Recent controversies have emerged with studies speculating that higher levels of BCAAs are a cause, rather than a consequence of insulin resistance (which is the main pre-requisite in the development of T2DM). Therefore, we aim to provide further evidence in this regard by firstly evaluating the associations between elevated BCAAs and obesity and T2DM. We postulated that reducing blood levels of BCAAs could offer therapeutic value. We first attempted to manipulate plasma BCAAs through a BCAA restricted diet; we speculated that successful lowering of BCAA concentrations would result in improved tissue and whole-body insulin sensitivity in humans. In addition, we also attempted to reduce circulating plasma BCAA concentrations targeting BCAA catabolism using the drug Sodium Phenylbutyrate. Further, we aimed to clarify the impact of other inventions on circulating BCAA levels, namely, bariatric surgery and very low calorie diets. For the BCAA dietary intervention study, we designed and implemented a diet that was reduced in BCAAs but crucially met individual energy and protein requirements; and were iso-nitrogenous and iso-caloric. For the drug intervention study, participants received 4.8mg of the drug Sodium Phenylbutyrate for a total of 21 days. Fasting BCAA levels from venous blood samples was assessed by GC-mass spectrometry. In addition, we also used in vitro models to assess the impact of elevated BCAAs on insulin signalling in skeletal muscle cells. We discovered a significant positive association between elevated BCAAs and the development of T2DM and obesity regardless of the follow-up time suggesting the utilisation of BCAAs as prognostic biomarkers. Subsequently, our attempt to manipulate circulating BCAAs through a novel dietary intervention was not only successful at reducing plasma BCAA concentrations by up to 50% but also showed improvements in insulin sensitivity. We also established a significant association between bariatric surgery and reduced concentrations of plasma BCAAs. Our second drug intervention study similarly reduced circulating plasma BCAA concentrations and this was augmented with improvements in glucose metabolism. We also showed that defects in BCAA catabolism could lead to insulin impairment in skeletal muscle cells. This work has provided further insights and offered proposals to some of the controversies that existed regarding elevated plasma BCAAs, most importantly it has provided the foundations for interventions targeting BCAA metabolism to offer benefits for obesity, insulin resistance and T2DM