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

Abstract

Abstract 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.

Keywords

• branched‐chain amino acid
• branched‐chain α‐keto acid
• childhood obesity
• insulin resistance
• metabolomics