Serum Branched-chain Amino Acids Research Articles

Association between serum branched chain amino acids, mammalian target of rapamycin levels and the risk of gestational diabetes mellitus: a 1:1 matched case control study

BackgroundTo investigate the association between serum branched chain amino acids (BCAAs), mammalian target of rapamycin (mTOR) levels and the risk of gestational diabetes mellitus (GDM) in pregnant women.Methods1:1 matched case–control study was conducted including 66 GDM patients and 66 matched healthy pregnant women (± 3 years) in 2019, in China. Fasting bloods of pregnant women were collected in pregnancy at 24 ~ 28 weeks gestation. And the serum levels of valine (Val), leucine (Leu), isoleucine (Ile) and mTOR were determined. Conditional logistic regressions models were used to estimate the associations of BCAAs and mTOR concentrations with the risk of GDM.ResultsConcentrations of serum Val and mTOR in cases were significantly higher than that in controls (P < 0.05). After adjusted for the confounded factors, both the second tertile and the third tertile of mTOR increased the risk of GDM (OR = 11.771, 95%CI: 3.949–35.083; OR = 4.869 95%CI: 1.742–13.611, respectively) compared to the first tertile of mTOR. However, the second tertile of serum Val (OR = 0.377, 95%CI:0.149–0.954) and the second tertile of serum Leu (OR = 0.322, 95%CI: 0.129–0.811) decreased the risk of GDM compared to the first tertile of serum Val and Leu, respectively. The restricted cubic spline indicated a significant nonlinear association between the serum levels of mTOR and the risk of GDM (P values for non-linearity = 0.0058).ConclusionWe confirmed the association of higher mTOR with the increased risk of GDM in pregnant women. Pregnant women who were in the certain range level of Val and Leu were at lower risk of GDM. Our findings provided epidemiological evidence for the relation of serum BCAAs and mTOR with risk of GDM.

Associations of serum branched-chain amino acid and marine omega-3 fatty acid levels with exercise intolerance in heart failure patients

Associations of serum branched-chain amino acid and marine omega-3 fatty acid levels with exercise intolerance in heart failure patients

Lipid Nanoparticle mRNA Therapy Improves Survival and Reduces Serum Branched-Chain Amino Acids in Mouse Models of Maple Syrup Urine Disease.

Maple syrup urine disease (MSUD) is a rare, inherited, metabolic disorder characterized by dysfunction of the multi-subunit, mitochondrial enzyme complex branched-chain alpha-keto acid dehydrogenase (BCKDH). BCKDH catalyzes the oxidative decarboxylation of branched-chain amino acids (BCAAs). BCAAs and their neurotoxic alpha-keto intermediates can accumulate in the blood and tissues in the absence of functional BCKDH. We evaluated a lipid nanoparticle (LNP)-based treatment approach to address all possible genetic mutations that can cause MSUD (BCKDHA, BCKDHB, and DBT). In the intermediate MSUD mouse model, which harbors a mutation in the dihydrolipoamide branched-chain transacylase E2 (DBT) subunit of BCKDH, repeated administration of LNP-encapsulated mRNA therapy significantly extended survival and reduced serum leucine levels. We also evaluated our LNP approach in several models of classic MSUD, namely DBT knockout (KO) mice and the new BCKDHA KO and BCKDHB KO mice. The latter two were generated by CRISPR/Cas9 gene editing and contain the highly prevalent classic MSUD-causing mutations seen in the Mennonite and Costa Rican populations. Intravenous LNP-encapsulated mRNA administration extended survival and increased body weight in the DBT KO and BCKDHA KO models of classic MSUD but was not effective in BCKDHB KO mice. Our data provide a promising proof-of-concept that a universal, mutation-independent approach to treating MSUD is possible and viable.

Serum Branched-Chain Amino Acids and Long-Term Complications of Liver Cirrhosis: Evidence from a Population-Based Prospective Study.

The role of serum branched-chain amino acids (BCAAs) in long-term liver cirrhosis complication events remains unclear. We aimed to evaluate the associations between serum BCAAs and the risk of liver-related events. We included a total of 64,005 participants without liver cirrhosis complication events at baseline from the UK Biobank. Cox proportional hazards regression models were utilized to estimate multivariable hazard ratios (HRs) and 95% CIs for the incidence of liver cirrhosis complication events, adjusting for potential confounders, including sociodemographic and lifestyle factors. Relationships between serum BCAAs and liver cirrhosis complications were examined using nonparametrically restricted cubic spline regression. During a median follow-up of 12.7 years, 583 participants developed liver cirrhosis complication events. The multivariable Cox regression model suggested that total BCAAs (HR = 0.88, 95% CI 0.82-0.95), serum leucine (HR = 0.88, 95% CI 0.81-0.95), serum isoleucine (HR = 0.88, 95% CI 0.82-0.96), and serum valine (HR = 0.87, 95% CI 0.82-0.96) were all independent protective factors for liver cirrhosis complications after adjustment for sociodemographic and lifestyle factors. Cox models with restricted cubic splines showed U-shaped associations between serum valine and liver cirrhosis complication incidence. Serum total BCAA and isoleucine concentrations might reduce the risk of liver cirrhosis complications by raising the risk of (type 2 diabetes mellitus) T2DM. Lower serum BCAA levels exacerbate the long-term risk of liver cirrhosis complications. Future studies should confirm these findings and identify the biological pathways of these associations.

Dietary and circulating branched chain amino acids are unfavorably associated with body fat measures among Chinese adults

Animal studies showed a detrimental effect of dietary branched chain amino acids (BCAAs) on metabolic health, while epidemiological evidence on dietary BCAAs and obesity is limited and inconclusive. We hypothesized that high dietary and circulating BCAAs are unfavorably associated with obesity in community-dwelling adults. We evaluated the 1-year longitudinal associations of dietary BCAA intake and circulating BCAAs with body fat measures. Body weight, height, and circumferences of the waist (WC) and hip (HC) were measured at baseline and again after 1-year. Body composition and liver fat [indicated by controlled attenuation parameter (CAP)] were also assessed after 1-year. Serum BCAA concentrations at baseline were quantified by liquid chromatography mass spectrometry. Diet was collected using 4 quarterly 3-day recalls during the 1-year. The correlation coefficients between dietary and serum BCAAs were 0.12 (P = .035) for total dietary BCAAs, and ranged from -0.02 (soy foods, P = .749) to 0.18 (poultry, P = .001). Total dietary BCAA intake was associated with increase in body weight (β = 0.044, P = .022) and body mass index (BMI, β = 0.047, P = .043). BCAAs from animal foods were associated with increase in HC, while BCAAs from soy foods were associated with weight gain and higher CAP (all P < .05). Serum BCAAs were associated with higher WC, HC, BMI, body fat mass, visceral fat level, and CAP (all P < .05). These results support that dietary and circulating BCAAs are positively associated with the risk of obesity. More cohort studies with validated dietary assessment tools and long-term follow-up among diverse populations are needed to confirm our findings.

LC-MS/MS-based bioanalysis of branched-chain and aromatic amino acids in human serum.

Aim: Branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) were suggested as potential biomarkers in liver disease. This study aimed to develop and validate a simple and rapid LC-MS/MS method to simultaneously measure serum BCAAs and AAAs levels in patients with liver injury, and further establish reference intervals of Chinese healthy adult populations.Patients & methods: Samples were prepared by a one-step protein precipitation and analysis time was 4min per run.Results: The validation results showed good linearity (r2>0.9969), satisfactory accuracy (94.44%-107.75%) and precision (0.10%-5.90%).Conclusion: This method proved to be suitable for high-throughput routine clinical use and could be a valuable adjunct diagnosis tool for liver injury and other clinical applications.

Acute kidney injury development is associated with mortality in Japanese patients with cirrhosis: impact of amino acid imbalance

BackgroundAcute kidney injury (AKI) is a serious complication of cirrhosis. This study analyzed the prognostic effect of AKI in patients with cirrhosis and its risk factors, particularly in relation to amino acid imbalance.MethodsThis retrospective study reviewed 808 inpatients with cirrhosis at two institutes in Gifu, Japan. AKI was diagnosed according to the recommendations of the International Club of Ascites. Amino acid imbalance was assessed by measuring serum branched-chain amino acid (BCAA) levels, tyrosine levels, and the BCAA-to-tyrosine ratio (BTR). Factors associated with mortality and AKI development were assessed using the Cox proportional hazards regression model with AKI as a time-dependent covariate and the Fine–Gray competing risk regression model, respectively.ResultsOf the 567 eligible patients without AKI at baseline, 27% developed AKI and 25% died during a median follow-up period of 4.7 years. Using a time-dependent covariate, AKI development (hazard ratio [HR], 6.25; 95% confidence interval [CI], 3.98–9.80; p < 0.001) was associated with mortality in patients with cirrhosis independent of potential covariates. In addition, alcohol-associated/-related liver disease, metabolic dysfunction-associated steatohepatitis, Child–Pugh score, and BTR (subdistribution HR 0.78; 95% CI 0.63–0.96; p = 0.022) were independently associated with AKI development in patients with cirrhosis. Similar results were obtained in the multivariate model that included BCAA and tyrosine levels instead of BTR.ConclusionsAKI is common and associated with mortality in Japanese patients with cirrhosis. An amino acid imbalance is strongly associated with the development of AKI in patients with cirrhosis.

Dietary intake of branched-chain amino acids (BCAAs), serum BCAAs, and cardiometabolic risk markers among community-dwelling adults.

To investigate the associations between dietary/serum branched-chain amino acids (BCAAs) and cardiometabolic risk markers. In a cohort of 2791 participants, diet and cardiometabolic risk markers were measured twice at baseline in overall participants and after 1-year in a subset of 423 participants. We assessed serum BCAAs at baseline and arterial stiffness after 1-year. The cross-sectional associations between dietary/serum BCAAs and cardiometabolic risk markers were analyzed using baseline measurements by linear regression, while the 1-year longitudinal association were analyzed using repeated measurements by linear mixed-effects regression. Higher BCAA intake from poultry was associated with lower triglycerides (β=-0.028, P = 0.027) and higher high-density lipoprotein cholesterol (HDL-C, β = 0.013, P = 0.006), while BCAAs in red and processed meat or fish were inversely associated with low-density lipoprotein cholesterol (β = 0.025, P = 0.001) and total cholesterol (β = 0.012, P = 0.033), respectively. BCAAs in whole grains and nuts were associated with higher HDL-C (β = 0.011, P = 0.016), and lower TG (β=-0.021, P = 0.041) and diastolic blood pressure (β=-0.003, P = 0.027). Also, BCAAs from soy or vegetables and fruits were inversely associated with arterial stiffness (β=-0.018, P = 0.047) and systolic blood pressure (β=-0.011, P = 0.003), respectively. However, BCAAs in refined grains were positively associated with triglycerides (β = 0.037, P = 0.014). Total serum BCAAs were unfavorably associated with multiple cardiometabolic risk markers (all P < 0.05). Dietary BCAAs in poultry, whole grains and nuts, soy, and vegetables and fruits may be favorably, while BCAAs in red and processed meat, fish, and refined grains were unfavorably associated with cardiometabolic health. Serum BCAAs showed a detrimental association with cardiometabolic risk markers.

Serum branched-chain amino acid levels are associated with fracture risk in Japanese women.

Branched-chain amino acids (BCAAs) have been shown to exert beneficial effects on muscle and bone metabolism; however, no studies to date have investigated whether BCAAs have beneficial effects on bone fractures. Herein, we aim to prospectively investigate the relationship between serum BCAA concentrations and the occurrence of vertebral fractures (VFs) in Japanese women. During the observation period (7.5 ± 6.1 years), 188 of 983 participants experienced VF. Kaplan-Meier analyses were conducted to examine time-dependent variations in the vertebral compression fracture occurrence rate. Patients were stratified into quartiles based on serum BCAA concentration for this analysis. The analysis results indicated that the group with the lowest BCAA level developed VFs significantly earlier and with a higher frequency than the other groups (P < 0.001). A Cox proportional hazards model showed that BCAA concentration was a significant risk factor for incident fracture, even after adjusting for possible confounding factors. A series of multiple regression analyses were performed to identify factors related to serum BCAA concentration, with the results identifying levels of glycated hemoglobin (P < 0.001), adiponectin (P < 0.001), and NOx (P = 0.011) as significant factors associated with serum BCAA. Overall, the present study revealed that a lower serum BCAA level was an independent risk factor for incident VF in postmenopausal women. Geriatr Gerontol Int 2024; 24: 603-608.

Transcriptomics and UHPLC-QQQ-MS analyses reveal the dysregulation of branched chain amino acids metabolism in renal fibrotic rats

The dysregulated levels of branched chain amino acids (BCAA) contribute to renal fibrosis in chronic kidney disease (CKD), yet specific analysis of BCAA contents and how they are regulated still remain unclear. It is therefore of great scientific interest to understand BCAA catabolism in CKD and develop a sensitive method for simultaneous determination of individual BCAA and their metabolites branched chain α-ketoacids (BCKA). In this work, the important role of BCAA metabolism that drives renal fibrosis in the process of CKD was first revealed by using transcriptomics. The key target genes controlling BCAA metabolism were then validated, that is, mRNA levels of BCKDHA and BCKDHB, the regulating rate-limiting enzymes during BCAA metabolism were abnormally reduced by quantitative PCR (qPCR), and a similar drop-off trend of protein expression of BCKDH, HIBCH and MCCC2 that are closely related to BCAA metabolism was also confirmed by western blotting. Furthermore, we established a novel strategy that simultaneously determines 6 individual BCAA and BCKA in serum and tissue. The method based on dansylhydrazine derivatization and ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-QQQ-MS) achieved to simultaneously determine the contents of BCAA and BCKA, which is efficient and stable. Compared with normal rats, levels of BCAA including leucine, isoleucine and valine in serum and kidney of CKD rats was decreased, while BCKA including α-ketoisocaproic acid, α-ketomethylvaleric acid and α-ketoisovaleric acid was increased. Together, these findings revealed the abnormality of BCAA metabolism in driving the course of kidney fibrosis and CKD. Our current study sheds new light on changes in BCAA metabolism during CKD, and may facilitate development of drugs to treat CKD and renal fibrosis.

Association of Elevated Serum Branched-chain Amino Acid Levels With Longitudinal Skeletal Muscle Loss.

Branched-chain amino acids (BCAA) are substrates for protein synthesis. Although their intake may contribute to an increase in skeletal muscle mass, elevated serum BCAA levels have been reported to be associated with insulin resistance, potentially resulting in decreased skeletal muscle mass. This study aimed to explore the association between elevated serum BCAA levels and longitudinal skeletal muscle loss. A cohort analysis was conducted, in which serum amino acids were analyzed in healthy individuals who underwent a medical health checkup at Kameoka Municipal Hospital (HOZUGAWA study), Japan. Seventy-one participants (37 men and 34 women) underwent follow-up checkups after the baseline visit. The follow-up duration was 1.2 ± .4 years. The relationship between fasting baseline serum BCAA levels and lifestyle factors, body composition, blood test results, dietary history, and changes in skeletal muscle mass was evaluated. In both men and women, serum BCAA levels were positively correlated with body weight, body mass index, skeletal muscle mass index (SMI), and serum triglycerides but inversely correlated with serum high-density lipoprotein cholesterol. In men, fasting serum BCAA levels were inversely associated with the rate of change in SMI (adjusted β = -.529, P = .006), and elevated BCAA levels were independently associated with a longitudinal decrease in skeletal muscle mass (odds ratio: 1.740; 95% confidence interval: 1.023-2.960 per 50 nmol/mL serum BCAAs increase). Increased circulating BCAAs could be an indicator of skeletal muscle loss in men.

Skeletal Muscle Mass, Serum Branched Chain Amino Acid Levels, And Dietary Protein Intake In Patients With Advanced Heart Failure

Skeletal Muscle Mass, Serum Branched Chain Amino Acid Levels, And Dietary Protein Intake In Patients With Advanced Heart Failure

Chronic triclosan exposure induce impaired glucose tolerance by altering the gut microbiota

Triclosan (TCS) is an antimicrobial compound incorporated into more than 2000 consumer products. This compound is frequently detected in the human body and causes ubiquitous contamination in the environment, thereby raising concerns about its impact on human health and environmental pollution. Here, we demonstrated that 20 weeks’ exposure of TCS drove the development of glucose intolerance by inducing compositional and functional alterations in intestinal microbiota in rats. Fecal-transplantation experiments corroborated the involvement of gut microbiota in TCS-induced glucose-tolerance impairment. 16S rRNA gene-sequencing analysis of cecal contents showed that TCS disrupted the gut microbiota composition in rats and increased the ratio of Firmicutes to Bacteroidetes. Cecal metabolomic analyses detected that TCS altered host metabolic pathways that are linked to host glucose and amino acid metabolism, particularly branched-chain amino acid (BCAA) biosynthesis. BCAA measurement confirmed the increase in serum BCAAs in rats exposed to TCS. Western blot and immunostaining results further confirmed that elevated BCAAs stimulated mTOR, a nutrient-sensing complex, and following IRS-1 serine phosphorylation, resulted in insulin resistance and glucose intolerance. These results suggested that TCS may induce glucose metabolism imbalance by regulating BCAA concentration by remodeling the gut microbiota.

BCAT proteins: A metabolic link between Type II Diabetes and Alzheimer’s Disease

AbstractBackgroundAberrant energy pathways compounded by dysregulated cellular redox plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD) but the underlying mechanisms are not clear. Clinical and epidemiological data show that those with Type II Diabetes Mellitus (T2DM) have a 65% increased risk of developing AD (Arvanitakis et al., 2004). Our group and others have shown that serum branched chain amino acids and the branched chain aminotransferase proteins (BCAT) are increased in subjects with AD and T2DM, which has been linked with dysregulated autophagy and metabolic reprogramming. Here, we explore how changes in cellular redox regulate and influence metabolic‐related pathology changes associated with AD.MethodsSHSY‐5Y cells were used as a neuronal model to observe the effects of BCATc dysregulation in neuronal metabolism. Cells were transfected with our BCATc overexpression constructs and metabolite load assessed using LC‐MS/MS. Activity of glycolytic enzymes GAPDH and enolase were assessed, and overall glycolytic rate characterised using a Seahorse XF analyser. Oxidative stress was measured using the HyPer‐7 molecular probe (Bousolov et al, 2004) and cells were visualised using confocal microscopy. Finally, Western blot analysis was performed to assess levels of BCATc in the presence of increasing glucose (+/‐ 100 nM insulin) and hydrogen peroxide treatments and to demonstrate changes in levels of β‐amyloid and hyperphosphorylated tau.ResultsHere we show that BCATc overexpression increases the level of glucose and fructose, whilst decreasing GAPDH, enolase activity and glycolytic rate (p &lt; 0.05). There was an observable increase in hydrogen peroxide generation (p&lt;0.001), while levels of amyloid precursor protein (P&lt;0.01), β‐amyloid (p&gt;0.05) and hyperphosphorylated tau (p&lt;0.05) were significantly increased. In addition, levels of BCATc increased dose‐dependently following hydrogen peroxide treatments (p &lt; 0.001) and decreased in the presence of excess glucose (+ 100 nM insulin) (p&lt;0.05).ConclusionOur results demonstrate that the reprogramming of BCAT as a result of hallmarks of T2DM such as excess dietary‐derived nutrient signals and a concurrent increase in oxidative stress, are associated with aberrant processing and aggregation of β‐amyloid and tau protein and are likely to contribute to the pathophysiology of AD.

Serum branched chain amino acids: an effective indicator of diabetic kidney disease.

In recent years, there has been a growing association between elevated circulating levels of branched-chain amino acids (BCAA) and diabetes mellitus. However, the relationship between serum BCAA levels and diabetic kidney disease (DKD) remains ambiguous. This study aims to investigate serum BCAA levels in DKD patients at various stages and assess the correlation between BCAA and clinical characteristics. We enrolled patients with type 2 diabetes mellitus (T2DM) who were admitted to our hospital and categorized them into three groups based on different DKD stages: normal proteinuria, microproteinuria, and macroalbuminuria groups. Forty healthy volunteers were included as the control group, and we measured serum BCAA concentrations using liquid chromatography-mass spectrometry (LC-MS). Subsequently, we conducted correlation and regression analyses to assess the associations between BCAA and clinical indicators. Serum BCAA levels were significantly elevated in T2DM patients compared to healthy controls. However, these levels exhibited a gradual decline with the progression of DKD. Furthermore, after adjusting for age, gender, and disease duration, we observed an independent association between serum albumin, urinary transferrin, and urinary microalbumin with BCAA. Our findings suggest a noteworthy decline in serum BCAA levels alongside the advancement of DKD. Additionally, serum BCAA exhibits an independent correlation with renal function indicators. These observations point to the possibility that serum BCAA concentrations in individuals with T2DM hold promise as a crucial predictor for both the initiation and progression of DKD.

FRI071 Changes In Branched-chain Amino Acids One-year After Sleeve Gastrectomy In Youth With Obesity And Its Association With Changes In Insulin Resistance

Abstract Disclosure: I. Becetti: None. M. Lauze: None. H. Lee: None. M. Bredella: None. M. Misra: None. V. Singhal: None. Introduction: Branched-chain amino acids (BCAAs), isoleucine, leucine and valine, have been linked to obesity, insulin resistance (IR) and risk for type 2 diabetes. Adults with obesity have a reduction in BCAA levels following metabolic and bariatric surgery (MBS), which may contribute to the modulation of metabolic advantages of MBS. We examine for the first time this relationship in youth with moderate-to-severe obesity who underwent sleeve gastrectomy (SG). Objective: To examine changes in dietary intake and serum BCAAs in youth with obesity one-year after SG, and their associations with changes in markers of IR. Methods: 53 youth 13-25 years old with severe obesity (41 females) were followed for a year; 25 had SG and 28 were non-surgical controls (NS). Subjects had fasting glucose and insulin levels and a 24-hour food recall. We assessed baseline and 12-month change within (Wilcoxon signed-rank test) and between (Student’s t-test/Wilcoxon Rank Sum test) groups, and associations between BCAAs and markers of IR (Spearman’s correlation). Results: SG and NS groups were similar for age, sex and race. SG had higher median body mass index (BMI) vs. NS at baseline [45.3 (42.1, 53.7) vs. 41.9 (38.4, 47.1) kg/m2; p=0.02]. At baseline, SG and NS did not differ for intake or serum levels of isoleucine, leucine, valine or total BCAAs. SG and NS groups also did not differ at baseline for glycated hemoglobin (HbA1C) or Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, marker of IR). Over a year, SG vs. NS had greater reductions in BMI, serum isoleucine, leucine, valine and BCAAs (p≤0.02), and SG had significant within group reductions in intake of isoleucine, leucine, valine and BCAAs (p≤0.048). Further, SG vs. NS groups had greater reductions in HbA1c and HOMA-IR (p≤0.007). Serum BCAA levels were not associated with their dietary intake. Baseline HOMA-IR was positively associated with baseline serum levels of leucine (ρ=0.56, p=0.01). Over one year, decreases in HOMA-IR and HbA1c were positively associated with decreases in serum valine (ρ=0.60 and ρ=0.63, p=0.01 and p=0.007, respectively). Associations between changes in HOMA-IR and serum valine held after controlling for BMI (baseline and change) and dietary intake of valine. Conclusion: We demonstrate decreases in BCAA intake and serum levels one-year post-SG in youth with obesity. Associations between BCAAs and IR markers, even after controlling for BMI, suggest a potential role of BCAA in regulating metabolic health. Reducing serum levels of BCAAs may reduce IR. Presentation: Friday, June 16, 2023

Serum branched amino acids and the risk of all-cause mortality: a meta-analysis and systematic review.

Recently, the serum levels of branched-chain amino acids (BCAAs) have been considered as an indicator to evaluate health status and predict chronic diseases risk. This systematic review and meta-analysis aimed to assess the relationship between Serum BCAAs and the risk of all-cause mortality. We carried out a comprehensive and systematic search in various important databases, including PubMed, Scopus, and Web of Science databases to find the relevant studies published up to October 2022 with no language, design, or time limitation. We extracted the reported hazard ratio (HR) with 95% confidence interval (CI) and odds ratio (OR) with 95%CI in cohorts and case-control studies, respectively, and computed the log HR or OR and its standard error. Then, we used the random-effects model with inverse variance weighting method for the present meta-analysis, to calculate the pooled effect size. Ten observational studies, including nine cohort studies and one case-control study, were included in the present meta-analysis. The number of participants ranges from 53 to 26,711, with an age range of 18-99years. During 6months to 24years of follow-up, 3599 deaths were ascertained. The pooled results indicated that there was no significant association between serum BCAAs (RR: 1.17; 95% CI 0.85-1.60), isoleucine (RR: 1.41; 95%CI 0.92-2.17), leucine (RR: 1.13; 95% CI 0.94-1.36), and valine (RR: 1.02; 95%CI 0.86-1.22) and all-cause mortality. Also, there was significant heterogeneity between studies for serum BCAAs (I2 = 74.1% and P-heterogeneity = 0.021), isoleucine (I2 = 89.4% and P-heterogeneity < 0.001), leucine (I2 = 87.8% and P-heterogeneity < 0.001), and valine (I2 = 86.6% and P-heterogeneity < 0.001). Our results suggested that the serum BCAAs and its components, including isoleucine, leucine, and valine, were not associated with the risk of all-cause mortality.

Resistant starch decreases intrahepatic triglycerides in patients with NAFLD via gut microbiome alterations

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic dysfunction for which effective interventions are lacking. To investigate the effects of resistant starch (RS) as a microbiota-directed dietary supplement for NAFLD treatment, we coupled a 4-month randomized placebo-controlled clinical trial in individuals with NAFLD (ChiCTR-IOR-15007519) with metagenomics and metabolomics analysis. Relative to the control (n= 97), the RS intervention (n= 99) resulted in a 9.08% absolute reduction of intrahepatic triglyceride content (IHTC), which was 5.89% after adjusting for weight loss. Serum branched-chain amino acids (BCAAs) and gut microbial species, in particular Bacteroides stercoris, significantly correlated with IHTC and liver enzymes and were reduced by RS. Multi-omics integrative analyses revealed the interplay among gut microbiota changes, BCAA availability, and hepatic steatosis, with causality supported by fecal microbiota transplantation and monocolonization in mice. Thus, RS dietary supplementation might be a strategy for managing NAFLD by altering gut microbiota composition and functionality.

Changes in Branched-Chain Amino Acids One Year after Sleeve Gastrectomy in Youth with Obesity and Their Association with Changes in Insulin Resistance.

Adults with obesity have a reduction in branched-chain amino acid (BCAA) levels following metabolic and bariatric surgery (MBS), which is hypothesized to contribute to the metabolic advantages of MBS. We examined this relationship in 62 youth 13-24 years old with severe obesity (47 female) over 12 months. Thirty had sleeve gastrectomy (SG) and 32 were non-surgical controls (NS). We measured fasting insulin, glucose, glycated hemoglobin (HbA1c), isoleucine, leucine, and valine concentrations, and post-prandial insulin and glucose, following a mixed meal tolerance test. Twenty-four-hour food recalls were collected. At baseline, groups did not differ in the intake or the serum levels of BCAAs, HbA1C, HOMA-IR, Matsuda index, insulinogenic index, or oral Disposition index (oDI). Over 12 months, SG vs. NS had greater reductions in serum BCAAs, and SG had significant reductions in BCAA intake. SG vs. NS had greater reductions in HbA1c and HOMA-IR, with increases in the Matsuda index and oDI. In SG, baseline leucine and total BCAA concentrations were negatively correlated with the baseline Matsuda index. Reductions in serum leucine were positively associated with the reductions in HOMA-IR over 12 months. These associations suggest a potential role of BCAA in regulating metabolic health. Reducing dietary intake and serum BCAA concentrations may reduce insulin resistance.

Lower serum branched-chain amino acid catabolic intermediates are predictive signatures specific to patients with diabetic foot

Diabetic foot (DF) is one of the serious chronic complications of diabetes. Accurate prediction of the risk of DF may take timely intervention measures to prevent its occurrence. The understanding of metabolomic changes in the progression of diabetes to DF may reveal new targets for interventions. We hypothesized that changes in metabolic pathways during DF would lead to changes in the metabolic profile, which could be predictive signature specific to it. In the present study, 43 participants with type 2 diabetes mellitus (T2DM), 32 T2DM participants with DF (T2DM-F), and 36 healthy subjects were enrolled and their serum samples were used for targeted and nonpolar metabolic analysis with liquid chromatography-tandem mass spectrometry. Differential metabolites related to T2DM-F were discovered in metabolomic analysis. Lasso machine learning regression model, random forest algorithm, causal mediation analysis, disease risk assessment, and clinical decision model were carried out. T2DM and T2DM-F groups could be distinguished with the healthy control group. The differential metabolites were all enriched in alpha-linolenic acid and linoleic acid metabolic pathways including arachidonic acid, docosapentaenoic-acid 22N-6, and docosahexaenoic-acid, which were significantly lower in the T2DM and T2DM-F groups compared with the healthy control group. The differential metabolites in T2DM-F vs T2DM groups were enriched to branched-chain amino acid (BCAA) catabolic pathways involving in methylmalonic acid, succinic acid, 3-methyl-2-oxovaleric acid, and ketoleucine, which were the BCAA catabolic intermediates and significantly lower in the T2DM-F compared with the T2DM group except for succinic acid. We reveal a new set of predictive signatures and associate the lower BCAA catabolic intermediates with the progression from T2DM to T2DM-F.