Type 2 diabetes (T2D) is characterized by β-cell dysfunction and loss. Endoplasmic reticulum (ER) stress responses, especially the PERK-ATF4 pathway, promote β-cell disorders. The role of the PERK-ATF4 pathway in β-cell dysfunction is still unknown. We report that ATF4 induces PDE4D production which impairs β-cell function by downregulating cAMP signaling. Transgenic expression of ATF4 in β-cells caused early β-cell dysfunction and loss, resembling accelerated T2D. ATF4 expression enhanced PDE4D, decreased cAMP signaling, and inhibited incretin and glucose responses in β-cells. In leptin receptor-deficient diabetic (db/db) mice, β-cells displayed higher nuclear ATF4 localization along with elevated PDE4D expression. Inhibiting PDE4 activity with selective pharmacological agents increased β-cell function in db/db and ATF4 transgenic mice.

In summary, ER stress promotes β-cell failure via ATF4-mediated PDE4D synthesis, proposing PDE4D as a therapeutic target for safeguarding β-cell function in T2D.


J. Lee: None.


National Research Foundation of Korea (2019R1A4A102972413, 2020M3A9D8038660)

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