Probing erythrocytes as sensitive and reliable sensors of metabolic disturbances in the crosstalk between childhood obesity and insulin resistance: findings from an observational study, in vivo challenge tests, and ex vivo incubation assays
Álvaro González-Domínguez, Otto Savolainen, Jesús Domínguez-Riscart, Rikard Landberg, Alfonso Lechuga-Sancho, Raúl González-Domínguez
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引用次数: 0
Abstract
Although insulin resistance (IR) is among the most frequent and pathogenically relevant complications accompanying childhood obesity, its role in modulating and exacerbating obesity pathophysiology has not yet been completely clarified. To get deeper insights into the interplay between childhood obesity and IR, we leveraged a comprehensive experimental design based on a combination of observational data, in vivo challenge tests (i.e., oral glucose tolerance test), and ex vivo assays (i.e., incubation of erythrocytes with insulin) using a population comprising children with obesity and IR, children with obesity without IR, and healthy controls, from whom plasma and erythrocyte samples were collected for subsequent metabolomics analysis. Children with concomitant IR showed exacerbated metabolic disturbances in the crosstalk between endogenous, microbial, and environmental determinants, including failures in energy homeostasis, amino acid metabolism, oxidative stress, synthesis of steroid hormones and bile acids, membrane lipid composition, as well as differences in exposome-related metabolites associated with diet, exposure to endocrine disruptors, and gut microbiota. Furthermore, challenge tests and ex vivo assays revealed a deleterious impact of IR on individuals’ metabolic flexibility, as reflected in blunted capacity to regulate homeostasis in response to hyperinsulinemia, at both systemic and erythroid levels. Thus, we have demonstrated for the first time that metabolite alterations in erythrocytes represent reliable and sensitive biomarkers to disentangle the metabolic complexity of IR and childhood obesity. This study emphasizes the crucial need of addressing inter-individual variability factors, such as the presence of comorbidities, to obtain a more accurate understanding of obesity-related molecular mechanisms.
虽然胰岛素抵抗(IR)是儿童肥胖症最常见、最具病理相关性的并发症之一,但它在调节和加重肥胖症病理生理学方面的作用尚未完全阐明。为了更深入地了解儿童肥胖与 IR 之间的相互作用,我们采用了综合实验设计,将观察数据、体内挑战测试(即口服葡萄糖耐量测试)和体外检测(即用胰岛素培养红细胞)结合起来,研究对象包括肥胖合并 IR 的儿童、肥胖合并 IR 的儿童以及健康对照组,并收集他们的血浆和红细胞样本进行代谢组学分析。在内源性、微生物和环境决定因素的相互影响下,合并有红外症的儿童表现出更严重的代谢紊乱,包括能量平衡失调、氨基酸代谢、氧化应激、类固醇激素和胆汁酸的合成、膜脂组成,以及与饮食、内分泌干扰物暴露和肠道微生物群相关的暴露相关代谢物的差异。此外,挑战测试和体内外试验显示,红外热反应对个体的代谢灵活性有有害影响,这反映在对高胰岛素血症做出反应时,在全身和红细胞水平上调节平衡的能力减弱。因此,我们首次证明,红细胞中代谢物的改变是可靠而灵敏的生物标志物,可用于揭示红外热与儿童肥胖症代谢的复杂性。这项研究强调,要更准确地了解与肥胖相关的分子机制,就必须解决个体间的变异因素,如是否存在合并症等。
期刊介绍:
Cardiovascular Diabetology is a journal that welcomes manuscripts exploring various aspects of the relationship between diabetes, cardiovascular health, and the metabolic syndrome. We invite submissions related to clinical studies, genetic investigations, experimental research, pharmacological studies, epidemiological analyses, and molecular biology research in this field.