Decreased Mitochondrial Respiration in Peripheral Mononuclear Blood Cells in Chil-dren and Adolescents with Obesity and Type 2 Diabetes Mellitus

Background: The prevalence of childhood obesity continues to rise worldwide. Obesity leads to major health risks already early in life, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The pathogenesis of these conditions includes mitochondrial alterations, however, data on mitochondrial health in pediatric populations are scarce to date. Methods: The study evaluated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from children and adolescents (6-18 years) with obesity with different stages of IR or T2DM, respectively. Participants were stratified according to pubertal stage and metabolic status. Mitochondrial health was determined by key parameters of mitochondrial respiration (ATP production, coupling efficiency, proton leak), and the Bioenergetic Health Index (BHI) served as an integrative marker of mitochondrial performance. Results: A total of 162 participants were included. The Bioenergetic Health Index (BHI) was significantly lower in postpubertal T2DM adolescents compared to postpubertal IR partici-pants, despite of equal pubertal stage and BMI (p=0,0126). The mitochondrial respiration rates and BHI between prepubertal and peripubertal children with obesity and IR showed no statistical differences. However, GlycoATP was correlated to higher insulin and HbA1c levels in children with obesity and IR. In line, the T2DM group demonstrated significantly reduced coupling efficiency (p = 0.003), reduced mitoATP and elevated glycoATP production, indicat-ing impaired mitochondrial efficiency. Conclusion: These data suggest for the first time, that progression of IR towards manifest T2DM in children with obesity leads to impaired mitochondrial function. Thus, mitochondrial alterations in PBMCs may detect early metabolic impairment in young people with obesity and altered glucose metabolism.