Both low and high mitochondrial DNA copy number (mtDNA-CN) levels were associated with higher incident type 2 diabetes mellitus (T2DM) risk in younger adults, according to a large cohort analysis published in Diabetes Care. The findings suggest that the relationship between mitochondrial function markers and future diabetes risk may vary by age and may not be linear.

The study included 34,835 adults without diabetes from the Kunshan Aging Research With E-Health (KARE) cohort and 289,338 adults from the UK Biobank (UKB). Blood mtDNA-CN was evaluated against incident T2DM using Cox proportional hazards models and restricted cubic spline analyses, with additional age-stratified analyses.

In KARE, a U-shaped association was observed (P<0.001). Hazard ratios across increasing mtDNA-CN quartiles were 1.00 (reference), 0.94 (95% CI, 0.88-1.00), 0.85 (95% CI, 0.79-0.91), and 0.93 (95% CI, 0.87-1.00). In UKB, the overall pattern was predominantly inverse and linear. 

Age-stratified analyses showed that the U-shaped relationship was most evident in younger participants, defined as age <65 years in KARE and <50 years in UKB, where both lower and higher mtDNA-CN levels corresponded with elevated T2DM risk. mtDNA-CN also declined with age in both cohorts, with accelerated decreases beyond approximately 65 years in KARE and 50 years in UKB.

The analysis showed that blood mtDNA-CN had a U-shaped association with incident T2DM in younger adults, while age appeared to modify the overall pattern.