Endoplasmic reticulum stress leads to pancreatic beta-cell desensitization to incretin and beta-cell dysfunction via ATF4-mediated PDE4D expression

Pancreatic beta-cell dysfunction and eventual beta-cell loss are key steps in the course of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress, in particular the PERK-ATF4 pathway, has been implicated in promoting these beta-cell pathologies. However, the exact molecular events surrounding the PERK-ATF4 pathway in beta-cell dysfunction remain unknown. Here, we discovered that ATF4 transcriptionally promotes expression of PDE4D, which results in beta-cell dysfunction via downregulation of cAMP signaling. Beta-cell-specific transgenic expression of ATF4 resulted in early beta-cell dysfunction and loss, resembling accelerated T2D. ATF4 expression, rather than CHOP, promoted PDE4D expression, decreased cAMP signaling, and attenuated responses to incretins and elevated glucose. Further, beta-cells of leptin receptor-deficient diabetic (db/db) mice expressed increased levels of ATF4 and PDE4D, accompanying impaired beta-cell function. Moreover, inhibiting PDE4D activity with selective pharmacological inhibitors significantly ameliorated beta-cell dysfunction in both db/db mice and beta-cell-specific ATF4 transgenic mice. In summary, our findings support that ER stress causes beta-cell failure via ATF4-mediated PDE4D production, and this is a highly promising therapeutic target for protecting beta-cell function during progression of T2D. Islet mRNA profiles of 5-wk-old wild type (WT) and beta-cell-specific ATF4 transgenic mice