Identification of an endoplasmic reticulum proteostasis modulator that enhances insulin production in pancreatic β cells

Perturbation of endoplasmic reticulum (ER) proteostasis is associated with impairment of cellular function in diverse diseases, especially the function of pancreatic β cells in type 2 diabetes. Restoration of ER proteostasis by small molecules thus shows therapeutic promise for type 2 diabetes. Here, we report the discovery of a new chemical chaperone-like small molecule, KM04794, that alleviates ER stress using cell-based screening. KM04794 prevented protein aggregation and cell death caused by ER stressors and a mutant insulin protein. We also found that this compound increased intracellular and secreted insulin levels in pancreatic β cells. Chemical biology and biochemical approaches revealed that the compound accumulated in the ER and directly interacted with the ER molecular chaperone BiP. Our data show that this new corrector of ER proteostasis can enhance insulin storage and pancreatic β cell function.

© 2022. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/