Evidence shows that Tipe1 restrains protein polyubiquitination.[50, 51] Importantly, the ubiquitin‐proteasome system impaired in islet β cells is directly associated with β cell dysfunction and the incidence of T2D in humans.[56, 57, 58] For the first time, we identified the ubiquitination modification of Gαs protein, and Tipe1 inhibited the K48‐linked polyubiquitination level of Gαs through the deubiquitinase USP5. Here, TIPE1 is linked to type 2 diabetes mellitus.