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
Affiliations
Shugo Sasaki
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada
Cuilan Nian
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada; Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, BC, Canada
Eric E. Xu
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, BC, Canada
Daniel J. Pasula
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada
Helena Winata
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada; Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, BC, Canada
Sanya Grover
BC Children’s Hospital Research Institute, Vancouver, BC, Canada
Dan S. Luciani
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada
Francis C. Lynn
BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada; Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, BC, Canada; School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada; Corresponding author
Summary: 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.
