The Association between Circulating Branched Chain Amino Acids and the Temporal Risk of Developing Type 2 Diabetes Mellitus: A Systematic Review & Meta-Analysis.

Introduction: Recent studies have concluded that elevated circulating branched chain amino acids (BCAA) are associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and obesity. However, the development of this association over time and the quantification of the strength of this association for individual BCAAs prior to T2DM diagnosis remains unexplored. Methods: A systematic search was conducted using the Healthcare Databases Advance Search (HDAS) via the National Institute for Health and Care Excellence (NICE) website. The data sources included EMBASE, MEDLINE and PubMed for all papers from inception until November 2021. Nine studies were identified in this systematic review and meta-analysis. Stratification was based on follow-up times (0−6, 6−12 and 12 or more years) and controlling of body mass index (BMI) through the specific assessment of overweight cohorts was also undertaken. Results: The meta-analysis revealed a statistically significant positive association between BCAA concentrations and the development of T2DM, with valine OR = 2.08 (95% CI = 2.04−2.12, p < 0.00001), leucine OR = 2.25 (95% CI = 1.76−2.87, p < 0.00001) and isoleucine OR = 2.12, 95% CI = 2.00−2.25, p < 0.00001. In addition, we demonstrated a positive consistent temporal association between circulating BCAA levels and the risk of developing T2DM with differentials in the respective follow-up times of 0−6 years, 6−12 years and ≥12 years follow-up for valine (OR = 2.08, 1.86 and 2.14, p < 0.05 each), leucine (OR = 2.10, 2.25 and 2.16, p < 0.05 each) and isoleucine (OR = 2.12, 1.90 and 2.16, p < 0.05 each) demonstrated. Conclusion: Plasma BCAA concentrations are associated with T2DM incidence across all temporal subgroups. We suggest the potential utility of BCAAs as an early biomarker for T2DM irrespective of follow-up time.

Indicators of response to exercise training: a systematic review and meta-analysis.

BACKGROUND: Means-based analysis of maximal rate of oxygen consumption (VO2max) has traditionally been used as the exercise response indicator to assess the efficacy of endurance (END), high intensity interval (HIIT) and resistance exercise training (RET) for improving cardiorespiratory fitness and whole-body health. However, considerable heterogeneity exists in the interindividual variability response to the same or different training modalities. OBJECTIVES: We performed a systematic review and meta-analysis to investigate exercise response rates in the context of VO2max: (1) in each training modality (END, HIIT and RET) versus controls, (2) in END versus either HIIT or RET and (3) exercise response rates as measured by VO2max versus other indicators of positive exercise response in each exercise modality. METHODS: Three databases (EMBASE, MEDLINE, CENTRAL) and additional sources were searched. Both individual response rate and population average data were incorporated through continuous data, respectively. Of 3268 identified manuscripts, a total of 29 studies were suitable for qualitative synthesis and a further 22 for quantitative. Stratification based on intervention duration (less than 12 weeks; more than or equal to 12 weeks) was undertaken. RESULTS: A total of 62 data points were procured. Both END and HIIT training exhibited differential improvements in VO2max based on intervention duration. VO2max did not adequately differentiate between END and HIIT, irrespective of intervention length. Although none of the other exercise response indicators achieved statistical significance, LT and HRrest demonstrated common trajectories in pooled and separate analyses between modalities. RET data were highly limited. Heterogeneity was ubiquitous across all analyses. CONCLUSIONS: The potential for LT and HRrest as indicators of exercise response requires further elucidation, in addition to the exploration of interventional and intrinsic sources of heterogeneity.

A Novel Dietary Intervention Reduces Circulatory Branched-Chain Amino Acids by 50%: A Pilot Study of Relevance for Obesity and Diabetes.

Elevated circulating branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) are associated with obesity and type 2 diabetes (T2D). Reducing circulatory BCAAs by dietary restriction was suggested to mitigate these risks in rodent models, but this is a challenging paradigm to deliver in humans. We aimed to design and assess the feasibility of a diet aimed at reducing circulating BCAA concentrations in humans, while maintaining energy balance and overall energy/protein intake. Twelve healthy individuals were assigned to either a 7-day BCAA-restricted diet or a 7-day control diet. Diets were iso-nitrogenous and iso-caloric, with only BCAA levels differing between the two. The BCAA-restricted diet significantly reduced circulating BCAA concentrations by ~50% i.e., baseline 437 ± 60 to 217 ± 40 µmol/L (p < 0.005). Individually, both valine (245 ± 33 to 105 ± 23 µmol/L; p < 0.0001), and leucine (130 ± 20 to 75 ± 13 µmol/L; p < 0.05), decreased significantly in response to the BCAA-restricted diet. The BCAA-restricted diet marginally lowered Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) levels: baseline 1.5 ± 0.2 to 1.0 ± 0.1; (p = 0.096). We successfully lowered circulating BCAAs by 50% while maintaining iso-nitrogenous, iso-caloric dietary intakes, and while meeting the recommended daily allowances (RDA) for protein requirements. The present pilot study represents a novel dietary means by which to reduce BCAA, and as such, provides a blueprint for a potential dietary therapeutic in obesity/diabetes.