| First Author | Lee JH | Year | 2023 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 325 |
| Issue | 5 | Pages | E448-E465 |
| PubMed ID | 37729023 | Mgi Jnum | J:358293 |
| Mgi Id | MGI:7778551 | Doi | 10.1152/ajpendo.00156.2023 |
| Citation | Lee JH, et al. (2023) Endoplasmic reticulum stress in pancreatic beta cells induces incretin desensitization and beta-cell dysfunction via ATF4-mediated PDE4D expression. Am J Physiol Endocrinol Metab 325(5):E448-E465 |
| abstractText | Pancreatic beta-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 beta-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in beta-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts beta-cell function via a downregulation of cAMP signaling. We found that beta-cell-specific transgenic expression of ATF4 led to early beta-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 beta-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired beta-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 beta-cell function in both db/db mice and beta-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes beta-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting beta-cell function during the progression of T2D.NEW & NOTEWORTHY Endoplasmic reticulum stress has been implied to cause multiple beta-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 beta cells, attenuated beta-cell proliferation and impaired insulin secretion via PDE4D-mediated downregulation of cAMP signaling. Additionally, we demonstrated that pharmacological inhibition of the ATF4 pathway or PDE4D activity alleviated beta-cell dysfunction, suggesting its therapeutic usefulness against T2D. |
