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.

Publisher: BioMed Central Country of Publication: England NLM ID: 101147637 Publication Model: Electronic Cited Medium: Internet ISSN: 1475-2840 (Electronic) Linking ISSN: 14752840 NLM ISO Abbreviation: Cardiovasc Diabetol Subsets: MEDLINE

Original Publication: London : BioMed Central, [2002-

Pediatric Obesity*/diagnosis ; Pediatric Obesity*/blood ; Pediatric Obesity*/physiopathology ; Insulin Resistance* ; Erythrocytes*/metabolism ; Metabolomics* ; Biomarkers*/blood ; Insulin*/blood; Humans ; Child ; Male ; Adolescent ; Female ; Case-Control Studies ; Blood Glucose/metabolism ; Glucose Tolerance Test ; Predictive Value of Tests ; Energy Metabolism ; Age Factors

Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(© 2024. The Author(s).)

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Keywords: Childhood obesity; Erythrocytes; Insulin resistance; Metabolomics

0 (Biomarkers)
0 (Insulin)
0 (Blood Glucose)

Date Created: 20240911 Date Completed: 20240912 Latest Revision: 20241001

20241002

PMC11391635

10.1186/s12933-024-02395-9

39261864