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

Abstract

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.

Protein restriction and branched‐chain amino acid restriction promote geroprotective shifts in metabolism

“…Over the course of a week, the intentional reduction in dietary BCAAs resulted in reduced circulating BCAAs by 50%. Additionally, the intervention slightly reduced insulin resistance as measured by Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR) (Ramzan et al, 2020 ). Presumably, a longer intervention would yield significant improvements in insulin resistance and overall glucose homeostasis, but more clinical trials are needed, especially in populations with underlying metabolic conditions.…”

Insight Into the Metabolomic Characteristics of Post-Transplant Diabetes Mellitus by the Integrated LC-MS and GC-MS Approach- Preliminary Study

“…Since BCAAs and AAAs (expect tyrosine) are essential amino acid which must be obtained from the diet, their elevated circulating levels might be the result of excess intake and/or disruption of their catabolic process. However, epidemiological results are controversial, with some indicating that a diet high in BCAAs were positively associated with circulating levels ( 38 ), while others not ( 35 ). Since then, we inferred that the elevated circulating levels of BCAAs might arise from the hindrances to their downstream catabolism.…”

“…Prevotella copri and Bacteroides vulgatus were proven to be the main species associated with the biosynthesis of BCAAs and insulin resistance ( 40 ). Gavage with Prevotella copri would induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs ( 38 ), while Gavage with Bacteroides vulgatus exerted the opposite effect ( 41 ). Similar to previous studies, the levels of L-leucine and L-phenylalanine were significantly higher in PTDM recipients than in non-PTDM ones, which might be due to BCAAs catabolism hindrance and/or host intestinal microbiota dysbiosis.…”

Longitudinal Branched-Chain Amino Acids, Lifestyle Intervention, and Type 2 Diabetes in the Finnish Diabetes Prevention Study

“…In adolescents (n = 33) the BCAA concentration was associated with insulin resistance after a 6-month lifestyle intervention ( 14 ), but the change in BCAA concentration during the intervention was not significant and no association between the changes in BCAAs and changes in glycemia measures from baseline was seen. A 7-day BCAA-restricted diet ( 16 ) decreased BCAA concentration and reduced insulin resistance in healthy volunteers (n = 12). These studies suggest that there might be an interaction between BCAA and lifestyle intervention for the T2D risk or insulin resistance.…”