Endoplasmic reticulum stress in pancreatic b cells induces incretin desensitization and b-cell dysfunction via ATF4-mediated PDE4D expression

Pancreatic b-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the protein kinase RNA-like ER kinase and activating transcription factor 4 (PERK-ATF4) pathway, have been implicated in promoting these b-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in b-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts b-cell function via a downregulation of cAMP signaling. We found that b-cell-specific transgenic expression of ATF4 led to early b-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than C/EBP homologous protein (CHOP), promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that b-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired b-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved b-cell function in both db/db mice and b-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes b-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting b-cell function during the progression of T2D. NEW & NOTEWORTHY Endoplasmic reticulum stress has been implied to cause multiple b-cell pathologies during the progression of type 2 diabetes (T2D). However, the precise molecular events underlying this remain unknown. Here, we discovered that elevated ATF4 activity, which was seen in T2D b cells, attenuated b-cell proliferation and impaired insulin secretion via PDE4Dmediated downregulation of cAMP signaling. Additionally, we demonstrated that pharmacological inhibition of the ATF4 pathway or PDE4D activity alleviated b-cell dysfunction, suggesting its therapeutic usefulness against T2D.