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

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 Caenorhabditis elegans 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 Drosophila and C. elegans, highlighting its potential therapeutic applications. This approach addresses both neurodegenerative and metabolic pathways, providing dual benefits for these interrelated conditions.