Investigating the Impact of Hyperglycemia on Zebrafish Development: Implications for Bone, Cartilage, and Mobility

Abstract

Diabetes is associated with widespread complications like diabetic peripheral neuropathy (DPN), osteoporosis, and osteoarthritis, which are challenging to study in mammalian models. Zebrafish (Danio rerio) are a valuable model for studying diabetic complications due to their conserved glucoregulatory mechanisms, regenerative capabilities, and transparent nature. Previous work with our glucose immersion model demonstrated deficits in peripheral nerves, bones, and behavior. While nerve function and muscle structure recovered following a return to euglycemia, bone mineralization and behavioral deficits persisted, suggesting long-term impacts of hyperglycemia on the skeletal system. Building on this foundation, we explored the developmental timeline of these deficits. Significant bone deficits became evident as early as 7 days post-fertilization (dpf) and got progressively worse throughout the treatment period. These skeletal deficiencies coincided with alterations in locomotive behavior, suggesting a potential link between structural abnormalities and motor function impairments. Additionally, swimming behavior was impaired as early as 7 dpf during the hyperglycemic period which persisted at 12dpf. While cartilage defects were inconclusive at 12 dpf, significant impairments of multiple cartilaginous areas were apparent when analyzed following the 10-day recovery period, demonstrating the lasting impacts of hyperglycemia. These findings highlight the zebrafish model’s utility in elucidating the mechanisms underlying diabetic complications, particularly in understanding the interplay between nerve and skeletal systems. By identifying critical windows of vulnerability to hyperglycemia, this research paves the way for developing targeted interventions to mitigate the long-term effects of diabetes during development.