Hydrogen Sulfide–Releasing Insulin Polypeptide Mitigates Hyperglycemia-Induced Neurotoxicity and Cognitive Deficits <i>In Vivo</i>

Hyperglycemia, a characteristic of diabetes, is increasingly associated with an elevated risk of neurodegenerative disorders, such as Parkinson's disease. Hyperglycemia serves as a comorbidity and hastens neurodegenerative processes in Parkinson's disease. We report the development of H₂S-releasing human insulin polypeptide (SHI), which will colocalize metabolic release of H₂S near insulin action, and a thorough investigation of their combined efficacy in mitigating Parkinson's disease and hyperglycemia-associated symptoms. SHI demonstrated notable neuroprotective effects in SH-SY5Y human neuroblastoma cells subjected to elevated glucose concentrations and the neurotoxin 6-OHDA. In transgenic <i>Caenorhabditis elegans</i> Parkinson's disease model, SHI reduced the levels of human α-Synuclein, while increasing the levels of dopamine transporter. Moreover, SHI showed behavioral improvements in both <i>Drosophila</i> and <i>C. elegans</i>, highlighting its potential therapeutic applications. This approach addresses both neurodegenerative and metabolic pathways, providing dual benefits for these interrelated conditions.