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

• Published in: American journal of physiology: endocrinology and metabolism 2023-11, Vol.325 (5), p.E448-E465
• Main Authors: Lee, Ji-Hye, Ryu, Hanguk, Lee, Hyejin, Yu, Hye Ram, Gao, Yurong, Lee, Kyeong-Min, Kim, Young-Joon, Lee, Jaemin
• Format: Article
• Language: English
• Subjects: Activating transcription factor 4; Beta cells; CCAAT/enhancer-binding protein; Cyclic AMP; Desensitization; Diabetes mellitus (non-insulin dependent); Down-regulation; Endoplasmic reticulum; Glucose; Glucose tolerance; Inhibitors; Insulin secretion; Kinases; Localization; Pancreas; Pharmacology; Phenotypes; Phosphodiesterase; Proteins; Signal transduction; Therapeutic targets; Transgenic mice
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00156.2023

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. Pancreatic 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 protein kinase RNA-like ER kinase and activating transcription factor 4 (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 C/EBP homologous protein (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 summary, our results indicate that ER stress causes β-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting β-cell function during the progression of T2D. NEW & NOTEWORTHY 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 rema