Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic β-cell proliferation via phosphorylation of HDAC5

Shugo Sasaki; Cuilan Nian; Eric E Xu; Daniel J Pasula; Helena Winata; Sanya Grover; Dan S Luciani; Francis C Lynn

doi:10.1016/j.isci.2023.107311

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic β-cell proliferation via phosphorylation of HDAC5

iScience. 2023 Jul 10;26(8):107311. doi: 10.1016/j.isci.2023.107311. eCollection 2023 Aug 18.

Authors

Shugo Sasaki^{1

2}, Cuilan Nian^{1

2

3}, Eric E Xu^{1

3}, Daniel J Pasula^{1

2}, Helena Winata^{1

2

3}, Sanya Grover¹, Dan S Luciani^{1

2}, Francis C Lynn^{1

2

3

4}

Affiliations

¹ BC Children's Hospital Research Institute, Vancouver, BC, Canada.
² Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
³ Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, BC, Canada.
⁴ School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada.

Abstract

Restoring functional β cell mass is a potential therapy for those with diabetes. However, the pathways regulating β cell mass are not fully understood. Previously, we demonstrated that Sox4 is required for β cell proliferation during prediabetes. Here, we report that Sox4 regulates β cell mass through modulating expression of the type 2 diabetes (T2D) susceptibility gene GRK5. β cell-specific Grk5 knockout mice showed impaired glucose tolerance with reduced β cell mass, which was accompanied by upregulation of cell cycle inhibitor gene Cdkn1a. Furthermore, we found that Grk5 may drive β cell proliferation through a pathway that includes phosphorylation of HDAC5 and subsequent transcription of immediate-early genes (IEGs) such as Nr4a1, Fosb, Junb, Arc, Egr1, and Srf. Together, these studies suggest GRK5 is linked to T2D through regulation of β cell growth and that it may be a target to preserve β cells during the development of T2D.

Keywords: Cell biology; Human metabolism.