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Increased levels of branched-chain amino acids (BCAA) associate with insulin resistance and type 2 diabetes (T2D), which could result from dietary habits, gut microbiome composition or direct effects on cellular energy metabolism. We hypothesized that reduced dietary intake of BCAA improves whole body insulin sensitivity and hyperinsulinemia in patients with T2D. In a randomized, placebo-controlled, double-blinded, cross over trial, 12 metabolically well-controlled patients with T2D received an isocaloric diet (protein: 1 g/kg body weight), containing either the complete amino acid set (BCAA+) or a 60% reduction in BCAA (BCAA-) for 1 week each. Effects on glucose homeostasis were assessed from mixed meal tolerance tests (MMT) and hyperinsulinemic-euglycemic clamps (HEC, M-value), and pathways affecting insulin signaling were analyzed in muscle and adipose tissue biopsies. Microbiome composition was assessed by next generation sequencing. After the BCAA- diet, MMT-derived insulin secretion was 28% lower compared to the BCAA+ diet (p In conclusion, a short-term dietary reduction of BCAA decreases insulin secretion, increases postprandial insulin sensitivity, which may relate to adipocyte mitochondrial efficiency and altered gut microbiome composition in patients with T2D. Disclosure Y. Karusheva: None. T. van Gemert: None. K. Strassburger: None. D.F. Markgraf: Research Support; Self; Sanofi. T. Jelenik: None. L. Mastrototaro: None. M. Simon: None. O.P. Zaharia: None. K. Bodis: None. F. Bärenz: None. D. Schmoll: Employee; Self; Sanofi-Aventis Deutschland GmbH. V. Burkart: None. K. Muessig: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding Sanofi Aventis Deutschland GmbH

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 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. Disclosure Y. Karusheva: None. T. van Gemert: None. M. Simon: None. D.F. Markgraf: None. K. Strassburger: None. D. Schmoll: Employee; Self; Sanofi-Aventis Deutschland GmbH. V. Burkart: None. K. Müssig: None. J. Szendroedi: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.