Sex-specific Metabolic Signatures of Insulin Resistance, Body Mass Index, and Visceral Adiposity in Fasting and Postprandial States

The rising prevalence of obesity and insulin resistance, a risk factor for type 2 diabetes (T2D), among adolescents is a growing public health concern. Understanding the metabolic underpinnings of adiposity and insulin resistance in adolescence can provide insights into the development of metabolic dysfunction, and potentially facilitate early intervention strategies to prevent the progression of these conditions into more severe metabolic disorders in adulthood. We explored the metabolic signatures of insulin resistance, Body Mass Index (BMI), and visceral adiposity in adolescents, in both fasting and postprandial states. A meal challenge was undertaken on 18-year-olds (154 females; 144 males), and their blood metabolites were profiled using Nuclear Magnetic Resonance spectroscopy (NMR). Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for modeling and variable selection, in a sex-stratified manner. The results show distinct metabolic patterns between sexes, with males showing more pronounced postprandial responses and stronger associations between blood metabolome and insulin resistance, BMI, and visceral adiposity. Key metabolites such as lipid metabolites, Branched-Chain Amino Acids (BCAAs), glucose, and Glycoprotein Acetylation (GlycA) were selected as important metabolic entities in predicting insulin resistance and adiposity in adolescence. The findings underscore the complex interplay of metabolites with metabolic health and sex, and can pave the way for developing targeted interventions and preventive strategies specifically tailored to adolescents. Such interventions can potentially mitigate the risk of progression to more severe metabolic disorders.