Sex Differences in Biomarkers Associated With Insulin Resistance in Obese Adolescents: Metabolomic Profiling and Principal Components Analysis

Abstract

<jats:sec> <jats:title>Objective</jats:title> <jats:p>Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as biomarkers or determinants of IR in obese teens.</jats:p> </jats:sec> <jats:sec> <jats:title>Research Design and Methods</jats:title> <jats:p>Fasting blood samples were analyzed by tandem mass spectrometry in 82 obese adolescents. A principal components analysis and multiple linear regression models were used to correlate metabolic components with surrogate measures of IR: homeostasis model assessment index of insulin resistance (HOMA-IR), adiponectin, and triglyceride (TG) to high-density lipoprotein (HDL) ratio.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Branched-chain amino acid (BCAA) levels and products of BCAA catabolism were higher (P &amp;lt; .01) in males than females with comparable body mass index (BMI) z-score. In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation (R2 = 0.659, P &amp;lt; .0001). In contrast, only BMI z-score correlated with HOMA-IR in females. Adiponectin correlated inversely with BCAA and uric acid (R2 = 0.268, P = .0212) in males but not females. TG to HDL ratio correlated with BMI z-score and the BCAA signature in females but not males.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score. A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females. Likewise, byproducts of fatty acid oxidation associate inversely with HOMA-IR in males but not females. Our findings underscore the roles of sex differences in metabolic function and outcomes in pediatric obesity.</jats:p> </jats:sec>

Sex differences in the association of phospholipids with components of the metabolic syndrome in young adults

“…There are several studies showing similar results as our study concerning the sex differences in metabolites [3, 15, 17]. However, to our knowledge there is only one other study that has examined sex differences with respect to HC use and metabolomics or that has investigated associations between metabolomics with different components of the MetS [3, 15]. Given a significant number of women of childbearing age are taking HC, this is a large group that is not represented or analysed in many clinical studies.…”

“…Most of the metabolomics studies conducted to date have either not taken potential sex differences into account or have used males and females in the same model. There are several studies showing similar results as our study concerning the sex differences in metabolites [3, 15, 17]. However, to our knowledge there is only one other study that has examined sex differences with respect to HC use and metabolomics or that has investigated associations between metabolomics with different components of the MetS [3, 15].…”

“…In the field of metabolomics, however, there are few studies addressing sex differences, and how they affect the metabolome underlying diseases risk factors [3, 15, 16]. Most of the metabolomics studies conducted to date have either not taken potential sex differences into account or have used males and females in the same model.…”

Metabolomics and Metabolic Diseases: Where Do We Stand?

“…Findings in pediatric cohorts have been inconsistent (Frohnert and Rewers, 2016). Thus, two studies showed a positive correlation between BCAA, BMI and HOMA-IR (Newbern et al, 2014; Perng et al, 2014), and another an association with obesity (McCormack et al, 2013), but still others found no significant differences in BCAA levels in normal weight compared to obese adolescents (Wahl et al, 2012), and even a positive correlation between BCAA/BCAA metabolites and insulin sensitivity (Si) (Michaliszyn, et al, 2012). However, in a group of 17 pre- or early-pubertal children (age 8–13 years), baseline BCAA levels were found to be associated with HOMA-IR measured 18 months later, suggesting that, as in adults, BCAA levels may be predictive of future disease risk in adolescent subjects (McCormack et al, 2013).…”

Development of High-purity Certified Reference Materials for 17 Proteinogenic Amino Acids by Traceable Titration Methods

“…For diagnostic use, changes in the concentration of amino acids in blood plasma and urine are used as an index of many diseases, such as an inborn error of amino acid metabolism, [1][2][3] liver disease, 4 renal disease, 5 and endocrine disease. 6 In addition, 17 kinds of proteinogenic amino acids are targeted for amino acid composition analysis or accurate quantification of protein/peptide. [7][8][9][10][11][12][13][14][15] In these methods, the constituent amino acids released from the original protein/ peptide through hydrolysis are quantified.…”