Short-term dietary reduction of branched-chain amino acids reduces meal-induced insulin secretion and modifies microbiome composition in type 2 diabetes: a randomized controlled crossover trial

The American Journal of Clinical Nutrition

Aug 2019

DOI: 10.1093/ajcn/nqz191

Citations:142

Influential Citations:4

Interventional (Human) Studies

Enhanced Details

Methods

Randomized, placebo-controlled, double-blind, crossover trial in 12 adults with type 2 diabetes. Participants: 12 individuals (8 men, 4 women), aged 54 ± 4 years, BMI 30.8 ± 2.8 kg/m2; disease duration ≤5 years; on lifestyle modification or metformin; well-controlled HbA1c ~6.6%. Design: each participant underwent two 4-week dietary periods with different AA mixes. Outcomes included MMT, hyperinsulinemic-euglycemic clamps (HECs), skeletal muscle and white adipose tissue biopsies, and fecal microbiome analysis.

Intervention

4-week isocaloric dietary intervention: 55% carbohydrate, 30% fat, 15% protein; protein kept at 1 g/kg body weight. Weeks 1 and 3 protein comes from regular foods; Weeks 2 and 4 ~60% of protein provided by an amino acid powder (supplement) either containing all amino acids (K-AM) or lacking branched-chain amino acids (ILV-AM3) dissolved in ~200 mL water; the remainder of protein from regular foods; powders packaged/blinded to participants and staff; total BCAA intake adjusted to maintain supply above minimum daily intake while manipulating BCAAs.

Results

Short-term BCAA reduction decreased meal-induced insulin secretion and improved postprandial insulin sensitivity and adipose tissue metabolism, with a gut microbiome shift toward Bacteroidetes. Specific findings: fasting BCAAs fell 17%; BCAAs fell 62% during MMT. During MMT, postprandial insulin secretion (iAUC) decreased by 28%; oral glucose sensitivity index (OGIS) increased by 24% and PREDIM by 27%. FGF21 rose ~21%. Adipose tissue showed lower AKT signaling and mTOR signaling and higher respiratory control ratio (RCR) by ~67% (improved mitochondrial efficiency). Whole-body and hepatic insulin sensitivity measured by clamp did not differ between diets. Authors conclude that short-term dietary BCAA reduction acutely decreases meal-induced insulin secretion and improves white adipose tissue metabolism and gut microbiome composition; longer-term safety and metabolic efficacy in diabetes require further study.

Limitations

Small sample size (n=12); short-term intervention (4 weeks per period); cannot determine long-term safety or chronic metabolic effects; depletion of BCAAs limited by essential amino acids; results may not generalize to all individuals with type 2 diabetes.

Abstract

ABSTRACT Background Epidemiological studies have shown that increased circulating branched-chain amino acids (BCAAs) are associated with insulin resistance and type 2 diabetes (T2D). This may result from altered energy metabolism or dietary habits. Objective We hypothesized that a lower intake of BCAAs improves tissue-specific insulin sensitivity. Methods This randomized, placebo-controlled, double-blinded, crossover trial examined well-controlled T2D patients receiving isocaloric diets (protein: 1 g/kg body weight) for 4 wk. Protein requirements were covered by commercially available food supplemented ≤60% by an AA mixture either containing all AAs or lacking BCAAs. The dietary intervention ensured sufficient BCAA supply above the recommended minimum daily intake. The patients underwent the mixed meal tolerance test (MMT), hyperinsulinemic-euglycemic clamps (HECs), and skeletal muscle and white adipose tissue biopsies to assess insulin signaling. Results After the BCAA− diet, BCAAs were reduced by 17% during fasting (P < 0.001), by 13% during HEC (P < 0.01), and by 62% during the MMT (P < 0.001). Under clamp conditions, whole-body and hepatic insulin sensitivity did not differ between diets. After the BCAA− diet, however, the oral glucose sensitivity index was 24% (P < 0.01) and circulating fibroblast-growth factor 21 was 21% higher (P < 0.05), whereas meal-derived insulin secretion was 28% lower (P < 0.05). Adipose tissue expression of the mechanistic target of rapamycin was 13% lower, whereas the mitochondrial respiratory control ratio was 1.7-fold higher (both P < 0.05). The fecal microbiome was enriched in Bacteroidetes but depleted of Firmicutes. Conclusions Short-term dietary reduction of BCAAs decreases postprandial insulin secretion and improves white adipose tissue metabolism and gut microbiome composition. Longer-term studies will be needed to evaluate the safety and metabolic efficacy in diabetes patients. This trial was registered at clinicaltrials.gov as NCT03261362. show less