Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, 11009, Spain.
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, 10029, USA.
Cardiovasc Diabetol. 2024 Sep 11;23(1):336. doi: 10.1186/s12933-024-02395-9.
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.
尽管胰岛素抵抗（IR）是伴随儿童肥胖症最常见和最具病理相关性的并发症之一，但它在调节和加剧肥胖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症和 IR 之间的相互作用，我们利用了一种综合实验设计，该设计基于观察性数据、体内挑战测试（即口服葡萄糖耐量测试）和体外测定（即红血细胞与胰岛素孵育）的组合，使用包括肥胖伴 IR、肥胖不伴 IR 和健康对照的儿童人群，从这些儿童中采集血浆和红细胞样本，用于随后的代谢组学分析。
同时伴有 IR 的儿童表现出内源性、微生物和环境决定因素之间相互作用的代谢紊乱加剧，包括能量平衡、氨基酸代谢、氧化应激、类固醇激素和胆汁酸合成、膜脂质组成的失败，以及与饮食、暴露于内分泌干扰物和肠道微生物群相关的暴露组代谢物的差异。此外，挑战测试和体外测定揭示了 IR 对个体代谢灵活性的有害影响，这反映在系统和红血细胞水平对高胰岛素血症的稳态调节能力减弱。
因此，我们首次证明了红细胞中的代谢物改变可以作为区分 IR 和儿童肥胖症代谢复杂性的可靠和敏感的生物标志物。本研究强调了需要解决个体间变异性因素（如合并症的存在），以更准确地了解肥胖相关的分子机制。
