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.

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.

Background: The mechanisms of diabetes remission following bariatric surgery independent of calorie restriction and weight loss remain unclear. Objectives: To undertake a systematic review and meta-analysis to investigate mechanisms underpinning diabetes remission. Methods: We included individuals with type 2 diabetes who have undergone RYGB, SG, and a very low-calorie diet (VLCD). In total, 234 studies were identified (N = 52 for qualitative; N = 40 for quantitative synthesis). Review Manager v5.4 and IBM SPSS for Windows (v28.0.1.1) were used for analysis. Results: Crude annualised diabetes relapse rates for RYGB and SG are as follows: −6.98 ± 16.19 (p = 0.046) and −2.75 ± 4.94 (p = 0.08); crude remission rates for RYGB and SG, respectively, are as follows: 39.59 ± 45.93 (p = 0.000) and 33.36 ± 33.87 SG (p = 0.006). Differences in other metabolic outcomes (standardised mean difference and 95% confidence intervals (CIs)) are BMI: ([RYGB: −2.73, 95%CI: −3.14 to −2.32, p < 0.000001) (SG: −2.82, 95%CI: −5.04 to −0.60, p = 0.01)]; HbA1c: [(RYGB: −1.58, 95%CI: −2.16 to −1.00, p < 0.00001) (SG: −1.42, 95%CI: −1.69 to −1.15, p < 0.00001)]; insulin: [(RYGB: 0.16, 95%CI: −0.19 to −0.50, p = 0.37) (SG: −3.00, 95%CI: −3.17 to −2.82, p = 0.75)]; and fat mass [(RYGB: −2.56, 95%CI: −4.49 to −0.64, p = 0.009) (SG: −1.69, 95%CI: −4.58 to 1.21, p = 0.25)]. RYGB and SG produced a significant improvement in HOMA-B measurements. Adiponectin and the Matsuda index were significantly increased with RYGB. No difference was observed for other metabolic markers (RYGB: GLP-1, GIP, leptin, ghrelin, PYY) (SG: GLP-1 and FGF19) (VLCD: leptin, GLP-1, GIP, and ghrelin). Conclusions: Diabetes remission following RYGB and SG was primarily driven by improvement in beta-cell function, with improvement in insulin resistance markers also observed for RYGB, driven by reductions in fat mass. No other metabolic mechanism explaining diabetes remission was observed based on clinical studies.