GRB10 regulates β-cell mass by inhibiting β-cell proliferation and stimulating β-cell dedifferentiation
Zixin Cai, Fen Liu, Yan Yang, Dandan Li, Shanbiao Hu, Lei Song, Shaojie Yu, Ting Li, Bilian Liu, Hairong Luo, Weiping Zhang, Zhiguang Zhou, Jingjing Zhang
Abstract
Decreased functional β-cell mass is the hallmark of diabetes, but the cause of this metabolic defect remains elusive. Here, we show that the levels of the growth factor receptor-bound protein 10 (GRB10), a negative regulator of insulin and mTORC1 signaling, are markedly induced in islets of diabetic mice and high glucose-treated insulinoma cell line INS-1 cells. β-cell-specific knockout of Grb10 in mice increased β-cell mass and improved β-cell function. Grb10-deficient β-cells exhibit enhanced mTORC1 signaling and reduced β-cell dedifferentiation, which could be blocked by rapamycin. On the contrary, Grb10 overexpression induced β-cell dedifferentiation in MIN6 cells. Our study identifies GRB10 as a critical regulator of β-cell dedifferentiation and β-cell mass, which exerts its effect by inhibiting mTORC1 signaling.