Insulin Resistance during normal child growth and development is associated with a distinct blood metabolic phenotype (Earlybird 72)

Abstract

Background While insulin resistance (IR) is associated with specific metabolite signatures in adults, there have been few truly longitudinal studies in healthy children, either to confirm which abnormalities are present, or to determine whether they precede or result from IR. Therefore, we investigated the association of serum metabolites with IR in childhood in the Earlybird cohort. Methods The Earlybird cohort is a well‐characterized cohort of healthy children with annual measurements from age 5 to 16 years. For the first time, longitudinal association analyses between individual serum metabolites and homeostatic model assessment (HOMA) of insulin resistance (HOMA‐IR) have been performed taking into account the effects of age, growth, puberty, adiposity, and physical activity. Results IR was higher in girls than in boys and was associated with increasing body mass index (BMI). In longitudinal analysis IR was associated with reduced concentrations of branched‐chain amino acids (BCAA), 2‐ketobutyrate, citrate and 3‐hydroxybutyrate, and higher concentrations of lactate and alanine. These findings demonstrate the widespread biochemical consequences of IR for intermediary metabolism, ketogenesis, and pyruvate oxidation during normal child growth and development. Conclusions Longitudinal analysis can differentiate metabolite signatures that precede or follow the development of greater levels of IR. In healthy normal weight children, higher levels of IR are associated with reduced levels of BCAA, ketogenesis, and fuel oxidation. In contrast, elevated lactate concentrations preceded the rise in IR. These changes reveal the metabolite signature of insulin action during normal growth, and they contrast with previous findings in obese children and adults that represent the consequences of IR and obesity.

Contributions of Fat and Carbohydrate Metabolism to Glucose Homeostasis in Childhood Change With Age and Puberty: A 12-Years Cohort Study (EARLYBIRD 77)

“…As previously reported, fasting insulin and HOMA-IR decreased until around 8 years, and then increased during puberty until the age of 14 years, before decreasing until the age of 16 years. This pattern was dependent on the time of APHV and BMI z-scores ( 15 ).…”

“…Our observations suggest that changes in the serum LDL and VLDL fatty acid signature are positively associated with fasting glycemia throughout childhood. We previously reported how IR development in the Earlybird cohort was marked by decreased phospholipids (mainly in HDL particles) and increased LDL fatty acid signature in both males and females in the EarlyBird cohort ( 15 ). Such an observation further illustrates the remodeling of lipid mobilization and metabolism that underpins structural growth and changing energy storage ( 36 , 37 ).…”

“…For technical feasibility and to ensure optimal data reproducibility for cohort analysis, a threshold of 1,800 blood serum samples (e.g., 150 different subjects) was determined. Metabolic profiling was carried out by means of proton nuclear magnetic resonance spectroscopy ( 1 H NMR) spectroscopy, as reported previously ( 14 , 15 ). Briefly, 400 μL of blood serum were mixed with 200 μL of deuterated phosphate buffer solution 0.6 M KH 2 PO 4 .…”

“…However, prediabetes did not appear until puberty, when insulin resistance was at its highest ( 12 ). We successfully applied a longitudinal analysis to explore the metabolite signatures that precede or follow the development of greater levels of insulin resistance (IR) during childhood ( 14 , 15 ). These analyses provide key insights into metabolite pathways (ketogenesis, fatty acid oxidation, branched-amino acids), with distinct patterns according to chronological age, and different contribution to glucose metabolism ( 14 , 15 ).…”

“…We successfully applied a longitudinal analysis to explore the metabolite signatures that precede or follow the development of greater levels of insulin resistance (IR) during childhood ( 14 , 15 ). These analyses provide key insights into metabolite pathways (ketogenesis, fatty acid oxidation, branched-amino acids), with distinct patterns according to chronological age, and different contribution to glucose metabolism ( 14 , 15 ). In addition, we reported that interpretation of HbA1c for the diagnosis of impaired fasting glycemia was limited due to factors other than glycaemia systematically influencing the variance of HbA1c in youth ( 16 ).…”