Introduction and Objective: Rare loss-of-function mutations in the DYRK1B gene are associated with early-onset coronary artery disease, metabolic syndrome, and type 2 diabetes.Methods: To investigate its role in metabolism, we generated global Dyrk1b knockout (KO) mice and conducted detailed metabolic and cellular analyses.Results: IPGTT, ITT, and plasma insulin and C-peptide in adult mice revealed impaired glucose tolerance in Dyrk1b KO mice, driven by reduced insulin secretion. Pancreatic islets were smaller in both neonatal (P6) and adult KO mice, suggesting a role for Dyrk1b in pancreatic beta cell proliferation. Markers of cell proliferation were reduced in Dyrk1b KO islets, accompanied by upregulation of p27 and suppression of Cyclin D1. Mechanistic studies revealed reduced phosphorylation of GSK3β, mTORC2, and Stat3, alongside increased nuclear Foxo1 in KO islets. Accordingly, beta cells from KO mice lacked functional cilia. In INS-1 cells, Dyrk1b knockdown impaired Akt, Foxo1, mTOR, Erk1/2, and Stat3 phosphorylation, resulting in decreased Cyclin D1, ciliogenesis, and cell proliferation. Insulin restored Akt pathway, provided only a temporary recovery of beta cell cilia but failed to rescue Stat3 phosphorylation or cell division, emphasizing the critical role of Stat3 in maintaining ciliogenesis and promoting beta cell proliferation. Overexpression of Dyrk1b in INS-1 cells enhanced phosphorylation of Akt, Foxo1, mTOR, GSK3β, and Erk1/2, and Cyclin D1 and promoting ciliogenesis and mitosis in a kinase activity-dependent manner. Remarkably, Dyrk1b overexpression also increased pancreatic islet size and improved beta cell function in wildtype and diabetic liver-specific Rictor KO mice.Conclusion:Dyrk1b regulates beta cell development by modulating Stat3/Akt/GSK3β pathways, ciliogenesis, and mitosis. These findings position DYRK1B as a promising therapeutic target for preserving beta cell health and improving outcomes in both type 1/2 diabetes.
H. Kim: None. A. Mani: None.
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