Effect of Reduced Intake of Branched-Chain Amino Acids (BCAA) on Insulin Secretion and Sensitivity in Type 2 Diabetes

Circulating BCAA (valine, leucine, isoleucine) are increased in insulin resistant states and predict type 2 diabetes (T2D) suggesting a role of BCAA in the development of insulin resistance. Thus, we hypothesized that a dietary decrease of BCAA improves insulin sensitivity (IS) and oxidative phosphorylation in T2D and increases the levels of the hepatic metabolic regulator fibroblast-growth factor (FGF-21). In a randomized, placebo-controlled, double-blinded study, 12 patients (8 male, 4 female; age 54±4 years, body mass index 30.8±2.8 kg/m², HbA1c 6.6±0.9%, 49±10 mmol/mol) with known T2D duration of <5 years, received a 4-week isocaloric diet with constant protein intake of 1 g/kg body weight. In a cross-over design, their diet comprised either the complete amino acid set (BCAA⁺) or a 60% reduction in BCAA (BCAA^-) for 1 week. Whole body IS was assessed by hyperinsulinemic-euglycemic clamps and beta-cell function by mixed-meal tolerance tests (MMT). Mitochondrial efficiency was assessed from the respiratory control ratio (RCR) measured by high-resolution respirometry in muscle and adipose tissue. FGF-21 serum levels were quantified by ELISA. IS was lower after BCAA^- diet (3.1±1.7 mg*kg^-1*min^-1) compared to BCAA⁺ diet (3.5±1.8 mg*kg^-1*min^-1, p<0.01). However, this difference disappeared after normalization for prevalent insulin levels. MMT showed lower increases in insulin and C-peptide after BCAA^- than BCCA⁺ diet (incremental insulin area under the curve: 21±11 vs. 29±19 mU*ml^-1*4 h^-1, p<0.01). RCR in adipose tissue was 1.7-fold higher after BCAA^- diet (p<0.05), but unchanged in skeletal muscle. The BCAA^- diet also increased FGF-21 levels (from 323±189 to 405±233 pg/ml, p<0.05) which likely contributes to the effect on energy metabolism.

In conclusion, short-term dietary reduction of BCAA decreases meal-induced insulin and C-peptide secretion, increases FGF-21 levels and stimulates mitochondrial efficiency in adipose tissue, but fails to improve IS in T2D.