Transcriptomics

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


ABSTRACT: Diabetes onset is accompanied with β-cell deficiency, and thus restoring functional β-cell mass is a promising therapy for those with diabetes. However, the mechanisms of β-cell mass regulation 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 susceptibility gene GRK5. Newly generated β-cell specific Grk5 knockout mice showed impaired glucose tolerance with reduced β-cell mass. In agreement with this phenotype, cell cycle inhibitor genes, Cdkn1a and Ccng1 were upregulated in Grk5 knockout islets. Furthermore, we found that Grk5 positively regulates β-cell mass through 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 type 2 diabetes through regulation of β-cell mass. GRK5 could become a potential target of cell therapy to preserve functional β cells during the progression towards frank diabetes.

ORGANISM(S): Mus musculus

PROVIDER: GSE221716 | GEO | 2023/07/31

REPOSITORIES: GEO

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