Open AccessMenin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation
Author(s) -
Ma Jian,
Xing Bowen,
Cao Yan,
He Xin,
Bennett Kate E,
Tong Chao,
An Chiying,
Hojnacki Taylor,
Feng Zijie,
Deng Sunbin,
Ling Sunbin,
Xie Gengchen,
Wu Yuan,
Ren Yue,
Yu Ming,
Katona Bryson W,
Li Hongzhe,
Naji Ali,
Hua Xianxin
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013524
Subject(s) - cell growth , beta cell , foxm1 , cancer research , endocrinology , medicine , microbiology and biotechnology , biology , cell cycle , cell , diabetes mellitus , islet , biochemistry
Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. While pathways such as FoxM1 are involved in regulating compensatory beta cell proliferation, given the lack of therapeutics effectively targeting beta cell proliferation, other targetable pathways need to be identified. Herein, we show that Pbk, a serine/threonine protein kinase, is essential for high fat diet (HFD)‐induced beta cell proliferation in vivo using a Pbk kinase deficiency knock‐in mouse model. Mechanistically, JunD recruits menin and HDAC3 complex to the Pbk promoter to reduce histone H3 acetylation, leading to epigenetic repression of Pbk expression. Moreover, menin inhibitor (MI) disrupts the menin–JunD interaction and augments Pbk transcription. Importantly, MI administration increases beta cell proliferation, ameliorating hyperglycemia, and impaired glucose tolerance (IGT) in HFD‐induced diabetic mice. Notably, Pbk is required for the MI‐induced beta cell proliferation and improvement of IGT. Together, these results demonstrate the repressive role of the menin/JunD/Pbk axis in regulating HFD‐induced compensatory beta cell proliferation and pharmacologically regulating this axis may serve as a novel strategy for type 2 diabetes therapy.