Molecular mechanism of telomeric proteins dysfunction in diabetes associated neurodegenerative disorder: Targeting pathways leading to shelterin

The growing global prevalence of diabetes mellitus and its established role as an independent risk factor for Alzheimer’s disease (AD) ( a type of neurodegenerative diseases), which together represent a major and escalating public health challenge. Epidemiological evidence consistently demonstrating a 1.5 to 2-fold elevated risk of AD with diabetic individuals. The defining metabolic consequence of diabetes imposes unrelenting oxidative and bioenergetic stress to neurons, and it is within this hostile metabolic environment that two interconnected systems begin to fail in concert. Despite advances in understanding amyloid and tau pathology in AD, the contribution of genomic instability specifically telomere attrition as a mechanistic bridge between diabetes and AD remains poorly explored, representing a significant gap in our understanding of diabetes-associated neurodegenerative disease. Telomeres, the hexanucleotide repeat sequences (TTAGGG) capping eukaryotic chromosomes, are maintained by the shelterin complex a multiprotein assembly comprising TRF1, TRF2, POT1, TPP1, TIN2, and RAP1 which shields telomeric DNA from aberrant DNA damage response activation. Under conditions of chronic hyperglycaemia, sustained ROS production displaces critical shelterin components, most notably TRF1 and TRF2, thereby exposing chromosome ends to nucleolytic degradation and driving accelerated telomere shortening. This telomeric instability does not operate in isolation; rather, it converges upon a second axis of dysfunction that involves the mitochondrial regulatory network governed by PGC-1α and SIRT3. In the diabetic neuronal conditions, reduced PGC-1α expression and impaired SIRT3 activity compromise mitochondrial biogenesis and antioxidant capacity, resulting in bioenergetic collapse, resulting increase expression of ROS further exacerbates telomere instability through shelterin architecture, establishing a pathological loop in which telomere attrition and mitochondrial failure mutually accelerate one another toward the AD phenotype and this pathological feedback loop may represent a critical driver of diabetes-associated neurodegeneration