7311 Endoplasmic reticulum (ER) stress and its associated signaling modulate incretin receptor signaling in pancreatic β cells

Abstract Disclosure: J. Lee: None. Pancreatic β-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D), and endoplasmic reticulum (ER) stress and its associated signaling have been implicated in these β-cell pathologies. However, the precise molecular events surrounding ER stress and its signaling responses in β-cell dysfunction remain unknown. A notable β-cell dysfunction during obesity and T2D progression is an impaired β-cell response to incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Despite the fact that GIP loses most of its insulinotropic efficacy, GLP-1 receptor (GLP-1R) agonists remain effective owing to GLP-1R’s signaling switch from Gs to Gq. Here, we discovered that ATF4, an ER stress-associated signaling factor, promotes the expression of PDE4D, which disrupts β-cell function, including incretin action, 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 similar to accelerated T2D. Also, we revealed that nuclear localization of ATF4 and PDE4D expression was increased β cells of obese and diabetic (db/db) mice. Accordingly, pharmacological inhibition of the ATF4 or PDE4 activity in the islets alleviated β-cell dysfunction and promoted incretin-simulated insulin secretion in db/db mice. ER stress also induced GLP-1R’s signaling transition from Gs to Gq in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R’s Gq utilization rather than reversing GLP-1R’s signaling switch induced by ER stress or obesity. In addition, the activation of XBP1 or ATF6, two other key ER stress-associated signaling factors, promoted Gs utilization in GLP-1R signaling, whereas they had no effect on Gq employment under ER stress conditions. Our findings show that ER stress and its associated signaling events alter incretin receptor signaling, which could be a therapeutic target for protecting β-cell function during the progression of T2D. Presentation: 6/3/2024