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

iScience (Aug 2023)

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

Journal volume & issue: Vol. 26, no. 8
p. 107311

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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