Pathogenic Mechanism of Diabetes Development Due to Dysfunction of Unfolded Protein Response

The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and membrane proteins are folded and assembled. Various stresses cause the accumulation of unfolded or misfolded proteins in the ER, resulting in ER dysfunction. This condition is termed ER stress. To cope with ER stress, cells activate a signaling pathway termed the unfolded protein response (wUPR). Recently, accumulating evidence suggests that the UPR plays a pivotal role in pancreatic beta cells. Pancreatic beta cells producing a large amount of insulin are highly sensitive when the UPR is impaired. In mammalian cells, three principal ER stress sensors, PERK, IRE1, and ATF6, initiate the UPR. Activated PERK attenuates protein translation through eIF2 alpha phosphorylation to cope with the ER stress. PERK KO mice develop diabetes by 2-4 weeks of age due to progressive beta-cell loss. IRE1 alpha noncanonically splices the XBP1 mRNA, leading to the up regulation of the ERAD components and ER molecular chaperones. This pathway is constitutively activated in pancreatic beta cells. To clarify the physiological role of the IRE1 alpha pathway in beta cells, we generated pancreatic-beta-cell-specific IRE1 alpha-conditional KO (cKO) mice and IRE1 alpha-cKO insulinoma cell lines. Here, we show that IRE1 alpha is required for the upregulation of insulin-folding enzymes in pancreatic beta cells to balance insulin-folding enzymes with insulin.