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Journal ArticleDOI

Circulating branched‐chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents

TL;DR: BCAAs are elevated in adults with diet‐induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors.
Abstract: SummaryWhat is already known about this subject Circulating concentrations of branched-chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet-induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors. What this study adds Increased concentrations of BCAAs are already present in young obese children and their metabolomic profiles are consistent with increased BCAA catabolism. Elevations in BCAAs in children are positively associated with insulin resistance measured 18 months later, independent of their initial body mass index. Background Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children. Objective To determine whether paediatric obesity is associated with elevations in fasting circulating concentrations of BCAAs (isoleucine, leucine and valine), and whether these elevations predict future insulin resistance. Methods Sixty-nine healthy subjects, ages 8–18 years, were enrolled as a cross-sectional cohort. A subset of subjects who were pre- or early-pubertal, ages 8–13 years, were enrolled in a prospective longitudinal cohort for 18 months (n = 17 with complete data). Results Elevations in the concentrations of BCAAs were significantly associated with body mass index (BMI) Z-score (Spearman's Rho 0.27, P = 0.03) in the cross-sectional cohort. In the subset of subjects that followed longitudinally, baseline BCAA concentrations were positively associated with homeostasis model assessment for insulin resistance measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex and pubertal stage (P = 0.046). Conclusions Elevations in the concentrations of circulating BCAAs are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance.
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Journal ArticleDOI
TL;DR: Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review, and a BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM.
Abstract: Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.

942 citations

Journal ArticleDOI
TL;DR: Progress in metabolomics and challenges for the future are reviewed here.

477 citations


Cites background or result from "Circulating branched‐chain amino ac..."

  • ...…a positive correlation between BCAAs, BMI, andHOMAIR (Newbern et al., 2014; Perng et al., 2014), and another showed 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…...

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  • ...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)....

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  • ...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....

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Journal ArticleDOI
TL;DR: How metabolomics is yielding important new insights into a number of important biological and physiological processes is explored, with a major focus on illustrating how metabolomics and discoveries made through metabolomics are improving the understanding of both normal physiology and the pathophysiology of many diseases.
Abstract: Metabolomics uses advanced analytical chemistry techniques to enable the high-throughput characterization of metabolites from cells, organs, tissues, or biofluids. The rapid growth in metabolomics ...

408 citations

Journal ArticleDOI
TL;DR: Current evidence supports BCAAs and their derivatives as the potential biomarkers of diseases such as insulin resistance, type 2 diabetes mellitus, cancer, and cardiovascular diseases (CVDs), and optimizing dietary BCAA levels should have a positive effect on the parameters associated with health and diseases.
Abstract: Branched chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), play critical roles in the regulation of energy homeostasis, nutrition metabolism, gut health, immunity and disease in humans and animals. As the most abundant of essential amino acids (EAAs), BCAAs are not only the substrates for synthesis of nitrogenous compounds, they also serve as signaling molecules regulating metabolism of glucose, lipid, and protein synthesis, intestinal health, and immunity via special signaling network, especially phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway. Current evidence supports BCAAs and their derivatives as the potential biomarkers of diseases such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), cancer, and cardiovascular diseases (CVDs). These diseases are closely associated with catabolism and balance of BCAAs. Hence, optimizing dietary BCAA levels should have a positive effect on the parameters associated with health and diseases. This review focuses on recent findings of BCAAs in metabolic pathways and regulation, and underlying the relationship of BCAAs to related disease processes.

372 citations


Cites background from "Circulating branched‐chain amino ac..."

  • ...also reported that elevations in BCAAs concentrations are significantly related to obesity in children and adolescents, and may be independently predict future IR [96]....

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Journal ArticleDOI
TL;DR: In addition, abnormally elevated BCAA levels in the blood (decreased BCAA catabolism) are a good biomarker for the early detection of obesity, diabetes and other metabolic diseases.
Abstract: It is widely known that branched chain amino acids (BCAA) are not only elementary components for building muscle tissue but also participate in increasing protein synthesis in animals and humans. BCAA (isoleucine, leucine and valine) regulate many key signaling pathways, the most classic of which is the activation of the mTOR signaling pathway. This signaling pathway connects many diverse physiological and metabolic roles. Recent years have witnessed many striking developments in determining the novel functions of BCAA including: (1) Insufficient or excessive levels of BCAA in the diet enhances lipolysis. (2) BCAA, especially isoleucine, play a major role in enhancing glucose consumption and utilization by up-regulating intestinal and muscular glucose transporters. (3) Supplementation of leucine in the diet enhances meat quality in finishing pigs. (4) BCAA are beneficial for mammary health, milk quality and embryo growth. (5) BCAA enhance intestinal development, intestinal amino acid transportation and mucin production. (6) BCAA participate in up-regulating innate and adaptive immune responses. In addition, abnormally elevated BCAA levels in the blood (decreased BCAA catabolism) are a good biomarker for the early detection of obesity, diabetes and other metabolic diseases. This review will provide some insights into these novel metabolic and physiological functions of BCAA.

358 citations


Cites background from "Circulating branched‐chain amino ac..."

  • ...Recently, the relationship between metabolomics and obesity (insulinresistant) was revealed by a series of studies [114]....

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References
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Journal ArticleDOI
TL;DR: An alternative approach, based on graphical techniques and simple calculations, is described, together with the relation between this analysis and the assessment of repeatability.

43,884 citations


"Circulating branched‐chain amino ac..." refers methods in this paper

  • ...99), using identical linear scales, without systemic differences in the results of the assays by Bland–Altman analysis (21)....

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Journal ArticleDOI
TL;DR: The correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

29,217 citations


"Circulating branched‐chain amino ac..." refers methods in this paper

  • ...The primary outcome variable in the longitudinal cohort was future insulin resistance, as estimated by the homeostasis model assessment for insulin resistance (HOMA-IR) (17)....

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Journal Article

17,468 citations

Journal ArticleDOI
TL;DR: In this article, an alternative approach, based on graphical techniques and simple calculations, is described, together with the relation between this analysis and the assessment of repeatability, which is often used in clinical comparison of a new measurement technique with an established one.

9,160 citations

Journal ArticleDOI
TL;DR: A novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the oral glucose tolerance test (OGTT).
Abstract: OBJECTIVE: Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. RESEARCH DESIGN AND METHODS: In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. RESULTS: The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. CONCLUSIONS: Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.

4,988 citations


"Circulating branched‐chain amino ac..." refers methods in this paper

  • ...This index is defined as 10 000/square root of [fasting glucose ¥ fasting insulin] ¥ [mean glucose ¥ mean insulin] during the OGTT and is associated with the rate of glucose disposal as assessed by euglycemic clamp (19)....

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