Insulin Resistance in Children and Adolescents: A Conceptual Framework Linking Candidate Biomarkers to Pathophysiological Domains

Background/Objectives: Insulin resistance (IR) in children and adolescents is heterogeneous and influenced by puberty, adiposity, growth, and developmental factors. Conventional measures such as fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) have limited pediatric specificity because of assay variability and the absence of universally accepted thresholds. This narrative review proposes a conceptual framework linking candidate biomarkers to biological domains relevant to pediatric IR. Methods: PubMed/MEDLINE and Google Scholar were searched through August 2026 using terms related to pediatric IR, obesity, puberty, and candidate biomarkers. Pediatric and adolescent studies were prioritized; adult studies were used selectively for mechanistic context. Biomarkers were selected as representative examples of biological domains, not as a validated diagnostic panel. Results: The framework comprises four interacting domains: intracellular insulin signaling (intracellular magnesium), adipose tissue dysfunction (leptin, adiponectin), inflammatory activation (lipocalin-2, white blood cell count, high-sensitivity C-reactive protein), and endothelial dysfunction (asymmetric dimethylarginine). Sonic hedgehog N-terminal fragment, osteocalcin, oxytocin, and central appetite-regulatory pathways are considered cross-cutting developmental, skeletal, and neuroendocrine modifiers. Evidence maturity, assay standardization, and clinical readiness differ substantially among markers. Conclusions: This framework is hypothesis-generating and does not represent a validated temporal sequence, diagnostic staging system, or routine biomarker panel. Longitudinal pediatric studies with standardized assays, puberty-specific reference ranges, and assessment of incremental clinical value are needed before biomarker-informed approaches can improve risk prediction, classification, or outcomes.