769-P: Short-Term Dietary Reduction of Branched-Chain Amino Acids Reduces Meal-Induced Insulin Secretion and Modifies Microbiome Composition in Overweight Patients with Type 2 Diabetes

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<0.05). After the BCAA^- diet, MMT-derived insulin sensitivity (PREDIM, the validated predicted HEC-derived M-value from meal data), turned 23% higher (p<0.01), whereas HEC-derived insulin sensitivity (M-value) remained unchanged. Respiratory control ratio was 1.7-fold higher in adipose tissue (p<0.05), but unchanged in skeletal muscle. Mechanistic target of rapamycin (mTOR) was downregulated by 13% in adipose tissue (p<0.05). BCAA^- diet was associated with a 40% increase of fecal Bacteroidetes and a 11% decrease of Firmicutes (both p<0.05).

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.