The previous report on GLP-1R’s signaling switch from Gs to Gq (Oduori et al., 2020) and our prior study on ATF4′s role in incretin resistance (Lee et al., 2023) helped us comprehend incretin resistance and sustained GLP-1R agonists' efficacy compared with a loss of GIP’s action under T2D conditions. Here, GLP1R is linked to type 2 diabetes mellitus.