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

Endoplasmic reticulum stress has been implied to cause multiple β-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 β cells, attenuated β-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 β-cell dysfunction, suggesting its therapeutic usefulness against T2D.