Associations among amino acid, lipid, and glucose metabolic profiles in childhood obesity

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Abstract

Background

Plasma-free amino acid profiles have been reported to correlate with obesity and glucose metabolism, and have been studied as potentially useful biomarkers of lifestyle-related diseases affecting metabolism in adulthood. However, knowledge of these relationships is lacking in children, despite the growing public health problem posed by childhood obesity.

The aim of this study was to assess whether plasma-free amino acid profiles can serve as useful biomarkers of lifestyle-related diseases in children with obesity.

Methods

This retrospective study used the medical records of 26 patients (15 male, 11 female) aged 9 or 10 years presenting with moderate to severe obesity and hyperlipidemia between April 2015 and March 2017. A degree of obesity of 30% or more was defined as moderate or severe. Amino acid levels were compared between obese children with and without impaired glucose tolerance using a t-test or Mann–Whitney U test. In addition, the influence of factors such as intima media thickness, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, amino acids, and homeostasis model assessment-insulin resistance (HOMA-IR) were analyzed pairwise using Pearson’s correlation or Spearman’s rank correlation.

Results

HOMA-IR was positively correlated with valine, leucine (Leu), isoleucine, phenylalanine, tryptophan, methionine, threonine, lysine, alanine, tyrosine, glutamate (Glu), proline, arginine, ornithine, total free amino acids (all P < 0.01), and aspartate ( P = 0.010). Moreover, blood uric acid levels were positively correlated with Leu ( P = 0.005) and Glu ( P = 0.019), and negatively correlated with serine, glycine, and asparagine ( P = 0.007, P = 0.003, and P = 0.013, respectively).

Conclusions

Amino acid profile reflects impaired glucose tolerance and hyperuricemia at an early stage of obesity. It is therefore a useful marker to inform early intervention in children with obesity, as in adults.

Electronic supplementary material

The online version of this article (10.1186/s12887-019-1647-8) contains supplementary material, which is available to authorized users.

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Most cited references 26

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A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.

Christopher B. Newgard, Jie An, James Bain … (2009)

Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

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Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells.

Paul Tremblay, A Marette (2001)

Amino acids have emerged as potent modulators of the mTOR/p70 S6 kinase pathway. The involvement of this pathway in the regulation of insulin-stimulated glucose transport was investigated in the present study. Acute exposure (1 h) to a balanced mixture of amino acids reduced insulin-stimulated glucose transport by as much as 55% in L6 muscle cells. The effect of amino acids was fully prevented by the specific mTOR inhibitor rapamycin. Time course analysis of insulin receptor substrate 1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity revealed that incubation with amino acids speeds up its time-dependent deactivation, leading to a dramatic suppression (-70%) of its activity after 30 min of insulin stimulation as compared with its maximal activation (5 min of stimulation). This accelerated deactivation of PI 3-kinase activity in amino acid-treated cells was associated with a concomitant and sustained increase in the phosphorylation of p70 S6 kinase. In marked contrast, inhibition of mTOR by rapamycin maintained PI 3-kinase maximally activated for up to 30 min. The marked inhibition of insulin-mediated PI 3-kinase activity by amino acids was linked to a rapamycin-sensitive increase in serine/threonine phosphorylation of IRS-1 and a decreased binding of the p85 subunit of PI 3-kinase to IRS-1. Furthermore, amino acids were required for the degradation of IRS-1 during long term insulin treatment. These results identify the mTOR/p70 S6 kinase signaling pathway as a novel modulator of insulin-stimulated glucose transport in skeletal muscle cells.

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Is Open Access

Circulating Metabolite Predictors of Glycemia in Middle-Aged Men and Women

Peter Würtz, Mika Tiainen, Ville-Petteri Mäkinen … (2012)

OBJECTIVE Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level. RESEARCH DESIGN AND METHODS Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 years for 618 individuals in one of the cohorts. Metabolites were quantified by nuclear magnetic resonance spectroscopy from fasting serum samples. Associations were studied by linear regression models adjusted for established risk factors. RESULTS Nineteen circulating metabolites, including amino acids, gluconeogenic substrates, and fatty acid measures, were cross-sectionally associated with fasting and/or postload glucose (P < 0.001). Among these metabolic intermediates, branched-chain amino acids, phenylalanine, and α1-acid glycoprotein were predictors of both fasting and 2-h glucose at 6.5-year follow-up (P < 0.05), whereas alanine, lactate, pyruvate, and tyrosine were uniquely associated with 6.5-year postload glucose (P = 0.003–0.04). None of the fatty acid measures were prospectively associated with glycemia. Changes in fatty acid concentrations were associated with changes in fasting and postload glycemia during follow-up; however, changes in branched-chain amino acids did not follow glucose dynamics, and gluconeogenic substrates only paralleled changes in fasting glucose. CONCLUSIONS Alterations in branched-chain and aromatic amino acid metabolism precede hyperglycemia in the general population. Further, alanine, lactate, and pyruvate were predictive of postchallenge glucose exclusively. These gluconeogenic precursors are potential markers of long-term impaired insulin sensitivity that may relate to attenuated glucose tolerance later in life.

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Author and article information

Contributors

Shirou Matsumoto:

ORCID: http://orcid.org/0000-0003-1986-0951

+81-096-373-5191 , s-pediat@gpo.kumamoto-u.ac.jp

Journal

Journal ID (nlm-ta): BMC Pediatr

Journal ID (iso-abbrev): BMC Pediatr

Title: BMC Pediatrics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2431

Publication date (Electronic): 6 August 2019

Publication date PMC-release: 6 August 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 273

Affiliations

[1 ]ISNI 0000 0001 0660 6749, GRID grid.274841.c, Department of Pediatrics, Graduate School of Medical Sciences, , Kumamoto University, ; 1-1-1 Honjo, Kumamoto City, Kumamoto Prefecture 860-8556 Japan

[2 ]Department of Central Radiology, Kumamoto University Hospital, Kumamoto University, Kumamoto City, Kumamoto Japan

Author information

Shirou Matsumoto http://orcid.org/0000-0003-1986-0951

Article

Publisher ID: 1647

DOI: 10.1186/s12887-019-1647-8

PMC ID: 6683574

PubMed ID: 31387549

SO-VID: 8de7d252-6971-43c5-ad24-abeefc767c27

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 January 2019

Date accepted : 29 July 2019

Funding

Funded by: a Grant-in-Aid for JSPS KAKENHI

Award ID: JP15K09625

Award Recipient : Shirou Matsumoto

Funded by: a Grant-in-Aid for The International Council on Amino Acid Science Japan Research Funding

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ScienceOpen disciplines: Pediatrics

Keywords: amino acids,homeostasis model assessment-insulin resistance,obesity,uric acid

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ScienceOpen disciplines: Pediatrics

Keywords: amino acids, homeostasis model assessment-insulin resistance, obesity, uric acid

Associations among amino acid, lipid, and glucose metabolic profiles in childhood obesity

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Pediatric Pulse: Advancing Neonatal and Child Health

Most cited references 26

A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.

Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells.

Circulating Metabolite Predictors of Glycemia in Middle-Aged Men and Women

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