Abstract
Type 2 diabetes mellitus (T2DM) is associated with elevated fracture risk despite normal bone mineral density (BMD), suggesting deficits in bone quality. Advanced glycation end-products (AGEs), formed under chronic hyperglycemia, alter collagen cross-linking and osteocyte signaling, impairing bone remodeling. Irisin, a myokine secreted after exercise, may counteract these effects by improving glucose metabolism and promoting osteoblast activity, but its role in osteocyte function remains unknown. We investigated how hyperglycemia and AGEs influence osteocyte behavior and tested irisin’s potential to mitigate these effects. Using the mature osteocyte cell line Ocy454-12H, we assessed cell viability and gene/protein expression of key bone remodeling markers (RANKL, SOST, IL-6, and RAGE) under no-sugar, high-sugar, and irisin-treated high-sugar conditions. We hypothesized that high glucose would reduce osteocyte viability and upregulate pro-resorptive signals, while irisin would restore viability and promote pro-formative pathways. Our findings demonstrate that hyperglycemia increased osteocyte apoptosis and upregulated pro-resorptive and inflammatory markers, while irisin treatment attenuated these effects, suggesting a protective role for irisin in preserving bone quality under diabetic conditions. By linking AGE-driven osteocyte dysfunction to irisin’s therapeutic potential, this work provides new data regarding potential novel strategies for improvement of bone quality in T2DM, addressing a critical gap in diabetic bone pathology.