Diabetes compromises DNA damage repair and telomere maintenance in adipose tissue stromal cells leading to cellular senescence.

Abstract

Diabetes mellitus (DM) is characterized by chronic metabolic stress that promotes oxidative damage, genomic instability, and premature cellular aging, with adipose tissue senescence being a pivotal contributor to metabolic dysfunction. Yet the impact on DNA damage repair (DDR) and telomere maintenance in adipose tissue remains poorly defined. This study investigated DDR capacity, telomere integrity, and the senescence-associated secretory phenotype (SASP) in adipose tissue and adipose-derived stromal cells (ADSCs) under diabetic conditions. Using an obese diabetic (ob/ob) mouse model, we confirmed whole-blood telomere shortening, significant adipose tissue hypertrophy, metabolic dysregulation, and elevated DNA damage, evidenced by increased γH2AX-positive staining. In vitro, ADSCs exposed to a diabetic microenvironment (AGEs and TNFα) exhibited increased reactive oxygen species and DNA damage without a corresponding activation of DDR pathways, as indicated by unchanged PARP1 levels and broad downregulation of key DNA repair genes, including sensors (ATM, ABL1, RAD17) and effectors across MMR, NER, HR, and NHEJ pathways. This impaired genomic surveillance was accompanied by premature cellular senescence and significant repression of genes involved in telomere protection (shelterin complex), telomerase activity, and telomere maintenance, together with marked telomere shortening following prolonged exposure. Furthermore, diabetic conditions increased the secretion of pro-inflammatory cytokines, chemokines, and growth factors. Collectively, these findings demonstrate that the diabetic microenvironment is associated with maladaptive DDR responses, telomere dysfunction, cellular senescence, and a pro-inflammatory secretory phenotype. This study highlights compromised genomic maintenance as a potential key mechanism underpinning adipose tissue dysfunction in DM and emphasizes the need for future investigations into the mechanisms underlying dysregulated DDR and telomere biology.