Endoplasmic Reticulum Stress in Pancreatic β-Cells Induces Incretin Desensitization and β-Cell Dysfunction via ATF4-Mediated PDE4D Expression

Am J Physiol Endocrinol Metab. 2023 Sep 20. doi: 10.1152/ajpendo.00156.2023. Online ahead of print.ABSTRACTPancreatic β-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 PERK-ATF4 pathway, have been implicated in promoting these β-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in β-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts β-cell function via a downregulation of cAMP signaling. We found that β-cell-specific transgenic expression of ATF4 led to early β-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than CHOP, promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that β-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired β-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 β-cell function in both db/db mice and β-cell-specific ATF4 transgenic mice. In ...
Source: American Journal of Physiology. Endocrinology and Metabolism - Category: Physiology Authors: Source Type: research