Insulin resistance in prepubertal obese children correlates with sex-dependent early onset metabolomic alterations

Abstract

Background:Insulin resistance (IR) is usually the first metabolic alteration diagnosed in obese children and the key risk factor for development of comorbidities. The factors determining whether or not IR develops as a result of excess body mass index (BMI) are still not completely understood.Objectives:This study aimed to elucidate the mechanisms underpinning the predisposition toward hyperinsulinemia-related complications in obese children by using a metabolomic strategy that allows a profound interpretation of metabolic profiles potentially affected by IR.Methods:Serum from 60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMIs) were analyzed by using liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry and capillary electrophoresis–mass spectrometry following an untargeted metabolomics approach. Validation was then performed on a group of 100 additional children with the same characteristics.Results:When obese children with and without IR were compared, 47 metabolites out of 818 compounds (P<0.05) obtained after data pre-processing were found to be significantly different. Bile acids exhibit the greatest changes (that is, approximately a 90% increase in IR). The majority of metabolites differing between groups were lysophospholipids (15) and amino acids (17), indicating inflammation and central carbon metabolism as the most altered processes in impaired insulin signaling. Multivariate analysis (OPLS-DA models) showed subtle differences between groups that were magnified when females were analyzed alone.Conclusions:Inflammation and central carbon metabolism, together with the contribution of the gut microbiota, are the most altered processes in obese children with impaired insulin signaling in a sex-specific fashion despite their prepubertal status.

Recent advances in capillary electrophoresis‐mass spectrometry: Instrumentation, methodology and applications

“…Besides previously mentioned biomarker discovery, metabolite profiling on human biofluids was also used in more general research on metabolism, including the analysis of serum/plasma , urine and saliva . Yamamoto et al.…”

“…Due to the high variety in physicochemical properties of metabolites, CE‐MS is widely used in multiplatform approaches with complementary separation principles to gas and liquid chromatography as shown by the group of Coral Barbas for the analysis of metabolic biomarkers for obesity or cancer . Li and co‐workers analyzed tobacco leaves in different stages of development, where CE‐MS allowed the determination of 89 out of 412 metabolites (saccharides, phosphates and polyamines) that were not covered by LC and GC .…”

A novel approach to childhood obesity: circulating chemokines and growth factors as biomarkers of insulin resistance

“…The study and protocols for recruitment were approved by the Scientific and Ethics Committee of the Hospital Infantil Universitario Niño Jesús of Madrid in accordance with the ‘Ethical Principles for Medical Research Involving Human Subjects’ adopted in the Declaration of Helsinki by the World Medical Association (64th WMA General Assembly, Fortaleza, Brazil, October 2013), Recommendation No. R [97] 5 of the Committee of Ministers to Member States on the Protection of Medical Data (1997), and Spanish data protection act ( Ley Orgánica 15/1999 de Protección de Datos ).…”

Epicardial Fat Thickness in Non-Obese Neurologically Impaired Children: Association with Unfavorable Cardiometabolic Risk Profile

“…Insulin resistance has been largely postulated as the trigger for metabolic comorbidities in children and predictive of type 2 diabetes, which in turn leads to a higher risk for CVD [34]. While, in patients with type 2 diabetes mellitus, insulin resistance in the adipose tissue leads to an increase of the intracellular hydrolysis of TGs and plays a key role in promoting atherosclerosis [35].…”