Impact of lifestyle Intervention on branched‐chain amino acid catabolism and insulin sensitivity in adolescents with obesity

Trub

Endocrino Diabet & Metabol

et al. 2022

Self Cite

Objectives Insulin resistance (IR) in adolescents with obesity is associated with a sex‐dependent metabolic ‘signature’ comprising the branched‐chain amino acids (BCAAs), glutamate/glutamine, C3/C5 acylcarnitines and uric acid. Here, we compared the levels of branched‐chain α‐keto acids (BCKAs) and glutamate/glutamine, which are the byproducts of BCAA catabolism and uric acid among adolescents with obesity prior to and following a 6‐month lifestyle‐intervention program. Methods Fasting plasma samples from 33 adolescents with obesity (16 males, 17 females, aged 12–18 year) were analysed by flow‐injection tandem MS and LC–MS/MS. Multiple linear regression models were used to correlate changes in BCKAs, glutamate/glutamine and uric acid with changes in weight and insulin sensitivity as assessed by HOMA‐IR, adiponectin and the ratio of triglyceride (TG) to HDL. In predictive models, BCKAs, glutamate/glutamine and uric acid at baseline were used as explanatory variables. Results Baseline BCKAs, glutamate/glutamine and uric acid were higher in males than females despite comparable BMI‐metrics. Following lifestyle‐intervention, α‐keto‐β‐methylvalerate (α‐KMV, a metabolic by product of isoleucine) decreased in males but not in females. The ratio of BCKA/BCAA trended lower in males. In the cohort as a whole, BCKAs correlated positively with the ratio of TG to HDL at baseline and HOMA‐IR at 6‐month‐follow‐up. Glutamate/glutamine was positively associated with HOMA‐IR at baseline and 6‐month‐follow‐up. A reduction in BCKAs was associated with an increase in adiponectin, and those with higher BCKAs at baseline had higher adiponectin levels at 6‐month‐follow‐up. Interestingly those adolescents with higher uric acid levels at baseline had greater reduction in weight. Conclusions BCKAs and glutamate/glutamine may serve as biomarkers of IR in adolescents with obesity, and uric acid might serve as a predictor of weight loss in response to lifestyle‐intervention. Differential regulation of BCAA catabolism in adolescent males and females implicates critical roles for sex steroids in metabolic homeostasis.

Section: Introductionmentioning

confidence: 99%

Branched‐chain α‐keto acids and glutamate/glutamine: Biomarkers of insulin resistance in childhood obesity

Trub

Endocrino Diabet & Metabol

et al. 2022

Self Cite

“…Ratio C2/C0 was enhanced in patients with GC, which further indicated the increased fatty acyl mitochondrial transport and β-oxidation of fatty acids in GC 35 . Furthermore, it has been reported that short-chain carnitine-acylcarnitine translocase in mitochondria and short-chain acylcarnitine levels may be related to the metabolism of branched-chain amino acids (BCAA) 36 , and changed ratio of C3/C5 implicates altered flux through BCAA metabolic pathways 37 . The abnormal levels of short-chain acylcarnitines may further influence ratio Val/Phe.…”

Section: Discussionmentioning

confidence: 99%

Metabolite biomarker discovery for human gastric cancer using dried blood spot mass spectrometry metabolomic approach

Gao

et al. 2022

Sci Rep

As one of the most common malignancies, gastric cancer (GC) is the third leading cause of cancer-related deaths in China. GC is asymptomatic in early stages, and the majority of GC mortality is due to delayed symptoms. It is an urgent task to find reliable biomarkers for the identification of GC in order to improve outcomes. A combination of dried blood spot sampling and direct infusion mass spectrometry (MS) technology was used to measure blood metabolic profiles for 166 patients with GC and 183 healthy individuals, and 93 metabolites including amino acids, carnitine/acylcarnitines and their derivatives, and related ratios were quantified. Multiple algorithms were used to characterize the changes of metabolic profiles in patients with GC compared to healthy individuals. A biomarker panel was identified in training set, and assessed by tenfold cross-validation and external test data set. After systematic selection of 93 metabolites, a biomarker panel consisting of Ala, Arg, Gly, Orn, Tyr/Cit, Val/Phe, C4-OH, C5/C3, C10:2 shows the potential to distinguish patients with GC from healthy individuals in tenfold cross-validation model (sensitivity: 0.8750, specificity: 0.9006) and test set (sensitivity: 0.9545, specificity: 0.8636). This metabolomic analysis makes contribution to the identification of disease-associated biomarkers and to the development of new diagnostic tools for patients with GC.

The Journal of Clinical Endocrinology &Amp; Metabolism

“…In a lifestyle intervention study with 266 adults ( 15 ), a decrease in BCAAs in the intervention group was not associated with the change in analyzed glycemia measures after a 2-year follow-up. In adolescents (n = 33) the BCAA concentration was associated with insulin resistance after a 6-month lifestyle intervention ( 14 ), but the change in BCAA concentration during the intervention was not significant and no association between the changes in BCAAs and changes in glycemia measures from baseline was seen. A 7-day BCAA-restricted diet ( 16 ) decreased BCAA concentration and reduced insulin resistance in healthy volunteers (n = 12).…”

Section: Discussionmentioning

confidence: 99%

“…The distribution of intervention and control participants in the BCAA clusters did not differ either. Previous studies have detected that different lifestyle interventions ( 14 , 15 , 17 ) and weight-loss diets ( 33 ) have led to a decreased circulating BCAA concentration after a one-year follow-up. The absence of difference between the intervention and control group in our study might have been due to differences in the lifestyle intervention or lack of power.…”

Section: Discussionmentioning

confidence: 99%

“…Lifestyle interventions promoting healthy diet with high intake of fruit and vegetables and whole grains, and restricted intake of high sugar and saturated fat combined with increased physical activity are known to decrease the risk for T2D, especially in high-risk people ( 9-13 ). Nevertheless, few studies have explored how lifestyle intervention may modify the association between circulating BCAAs and the risk of T2D or insulin resistance ( 14-17 ). These studies have been relatively small and lifestyle interventions and endpoints have varied, and therefore the results have remained inconsistent.…”

mentioning

confidence: 99%

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Longitudinal Branched-Chain Amino Acids, Lifestyle Intervention, and Type 2 Diabetes in the Finnish Diabetes Prevention Study

Kivelä

Meinilä

Uusitupa

et al. 2022

Background and aims Circulating branched-chain amino acids (BCAAs) are associated with the risk of type 2 diabetes (T2D). We examined to what extent lifestyle intervention aiming to prevent T2D interacts with this association and how BCAA concentrations change during the intervention. Materials and methods We comprised trajectory clusters by k-means clustering of serum fasting BCAAs analysed annually by mass spectrometry during four-year intervention. We investigated whether baseline BCAAs, BCAA trajectories and BCAA change trajectories predict T2D and whether BCAAs predict T2D differently in the intervention (n=198) and control group (n=196). Results Elevated baseline BCAAs predicted the incidence of T2D in the control group (HR 1.05 per 10 μmol/l, p=0.01), but not in the intervention group. BCAA concentration decreased during the first year in the whole cohort (mean -14.9 μmol/l, p<0.001), with no significant difference between the groups. We identified five BCAA trajectory clusters and five trajectory clusters for the change in BCAAs. Trajectories with high mean BCAA levels were associated with an increased HR for T2D compared with the trajectory with low BCAA levels (trajectory with highest vs lowest BCAA, HR 4.0; p-value 0.01). A trajectory with increasing BCAA levels had a higher HR for T2D compared with decreasing trajectory in the intervention group only (HR 25.4, p-value <0.001). Conclusion Lifestyle intervention modified the association of the baseline BCAA concentration and BCAA trajectories with the incidence of T2D. Our study adds to the accumulating evidence on the mechanisms behind the effect of lifestyle changes on the risk of T2D.