Beta-Cell Tipe1 Orchestrates Insulin Secretion and Cell Proliferation by Promoting Gs/cAMP Signaling via USP5

Inadequate beta-cell mass and insulin secretion are essential for the development of type 2 diabetes (T2D). TNF-alpha-induced protein 8-like 1 (Tipe1) plays a crucial role in multiple diseases, however, a specific role in T2D pathogenesis remains largely unexplored. Herein, Tipe1 as a key regulator in T2D, contributing to the maintenance of beta cell homeostasis is identified. The results show that the beta-cell-specific knockout of Tipe1 (termed Ins2-Tipe1BKO) aggravated diabetic phenotypes in db/db mice or in mice with high-fat diet-induced diabetes. Notably, Tipe1 improves beta cell mass and function, a process that depends on G alpha s, the alpha subunit of the G-stimulating protein. Mechanistically, Tipe1 inhibited the K48-linked ubiquitination degradation of G alpha s by recruiting the deubiquitinase USP5. Consequently, G alpha s or cAMP agonists almost completely restored the dysfunction of beta cells observed in Ins2-Tipe1BKO mice. The findings characterize Tipe1 as a regulator of beta cell function through the G alpha s/cAMP pathway, suggesting that Tipe1 may emerge as a novel target for T2D intervention.