2026/03/16 by Xinhao Huang, Zijian Tian, Ying Pan +9 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Hemoglobinopathies and Related Disorders #Metabolism and Genetic Disorders #Mitochondrial Function and Pathology
paper · pdf · doi:10.2337/dc25-2198
openalex publication_date 2026/03/16 · openalex created_date 2026/03/17 · openalex updated_date 2026/07/12
OBJECTIVE: mtDNA copy number (CN) reflects mitochondrial function, but prior studies have reported inconsistent associations with type 2 diabetes risk, ranging from inverse to positive or null findings. We hypothesized that mtDNA-CN is nonlinearly associated with incident type 2 diabetes. RESEARCH DESIGN AND METHODS: We included 34,835 adults without diabetes from the Kunshan Aging Research With E-Health (KARE) cohort and 289,338 from the UK Biobank (UKB). Associations between blood mtDNA-CN and incident type 2 diabetes were evaluated using Cox proportional hazards and restricted cubic spline models stratified by age. RESULTS: A U-shaped association was observed in the KARE cohort (P < 0.001), in which the hazard ratios (95% CIs) across increasing mtDNA-CN quartiles were 1.00 (reference), 0.94 (0.88-1.00), 0.85 (0.79-0.91), and 0.93 (0.87-1.00). In contrast, the UKB cohort exhibited a predominantly inverse linear trend. Age-stratified analyses revealed that this U-shaped association was particularly evident in younger participants (aged <65 years in KARE and <50 years in UKB), indicating elevated diabetes risk at both low and high mtDNA-CN levels. Additionally, mtDNA-CN declined with age in both cohorts, with an accelerated decrease beyond ∼65 years in KARE and ∼50 years in UKB. CONCLUSIONS: Blood mtDNA-CN showed a U-shaped association with incident type 2 diabetes in younger individuals.