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

Restoring functional beta cell mass is a potential therapy for those with diabetes. However, the pathways regulating beta cell mass are not fully understood. Previously, we demonstrated that Sox4 is required for beta cell proliferation during pre diabetes. Here, we report that Sox4 regulates beta cell mass through modulating expression of the type 2 diabetes (T2D) susceptibility gene GRK5. beta cell-specific Grk5 knockout mice showed impaired glucose tolerance with reduced beta cell mass, which was accompanied by upregulation of cell cycle inhibitor gene Cdkn1a. Furthermore, we found that Grk5 may drive beta 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 beta cell growth and that it may be a target to preserve beta cells during the development of T2D.