Abstract
BACKGROUND: Sulfonylureas have long been utilized in the management of type-2 diabetes mellitus (T2DM) due to their insulin-secretagogue properties. However, their clinical efficacy is hindered by the risk of severe hypoglycemia and secondary sulfonylurea failure. While the mechanisms underlying sulfonylurea-induced hypoglycemia are well-documented, the precise factors contributing to sulfonylurea resistance (SR) remain poorly understood. This study aims to elucidate the molecular basis of SR in insulinoma cells and an animal model. METHODS: INS-1E, rat insulinoma cells, were exposed to 10 μM glibenclamide for 7 days to induce sulfonylurea resistance (SR). Sprague-Dawley (SD) rats were fed a diet containing 0.01% glibenclamide for 3 weeks to induce sulfonylurea resistance. RESULTS: Insulinoma cells resistant to sulfonylureas exhibited elevated resting membrane potentials compared to sensitive cells. Transcriptome analysis revealed differential expression of genes, notably highlighting the significance of kcnn3 (Potassium Calcium-Activated Channel Subfamily N Member 3) in SR insulinoma cells. Western blot analysis confirmed the upregulation of SK3 protein in correlation with the duration of sulfonylurea exposure. Long-term administration of sulfonylureas in SD rats led to a diminished anti-diabetic response and increased SK3 expression in islets. CONCLUSION: This study elucidates the molecular mechanisms underlying SR, with a specific focus on the overexpression of the SK3 channel in insulinoma cells. These findings enhance our understanding of the challenges associated with prolonged sulfonylurea therapy in the management of T2DM.