Stage dependent alterations in PBMC mitochondrial bioenergetics in pediatric obesity: from insulin resistance to type 2 diabetes

BACKGROUND: Pediatric obesity is associated with early-onset cardiometabolic disorders related to metabolic syndrome (MetS), including insulin resistance (IR) and type 2 diabetes (T2DM). Mitochondrial dysfunction plays a key role in their pathogenesis, but evidence on mitochondrial health in children and adolescents with obesity remains limited. METHODS: cells) were assessed using extracellular flux analysis in peripheral blood mononuclear cells (PBMCs) from 212 children and adolescents (6-18 years) with obesity, stratified by pubertal stage and degree of IR or T2DM. RESULTS: In the prepubertal group, IR participants had higher total (126.82 ± 7.92 vs. 109.38 ± 35.31, p = 0.028) and mitochondrial (86.04 ± 20.29 vs. 73.84 ± 23.55, p = 0.028) ATP production than insulin-sensitive (IS) peers. Postpubertal adolescents with T2DM showed lower basal OCR (14.21 ± 4.03 vs. 19.61 ± 7.51, p = 0.049), ATP-linked OCR (11.51 ± 3.69 vs. 16.90 ± 6.83, p = 0.016), and mitochondrial ATP production (64.35 ± 34.39 vs. 91.63 ± 34.92, p = 0.040) compared to IS, as well as lower coupling efficiency than the IR group (80.11 ± 8.87 vs. 86.70 ± 5.14 %, p = 0.002). CONCLUSION: PBMC-based mitochondrial bioenergetic profiling suggests mitochondrial differences across different stages of IS, IR, and T2DM in pediatric obesity and may serve as a minimally invasive biomarker of early metabolic impairment.