In addition, we uncovered that the UPR transcription factors, XBP1 and ATF6, facilitated GLP-1R’s Gs use in β-cells under ER stress in part by downregulating cAMP-targeting PDEs (Fig. 3, Supplementary Figs. S5, S6, and S8), which is the opposite of ATF4, inhibiting incretin receptor’s Gs signaling via elevation of PDE4D under T2D conditions (Lee et al., 2023). This evidence concerns the gene PDE4D and type 2 diabetes mellitus.