DYRK1A aggravates β cell dysfunction and apoptosis by promoting the phosphorylation and degradation of IRS2

Lü, Mei; Ma, Lin; Shan, Peiyan; Liu, Aifen; Yu, Xiaolin; Jiang, Wenjing; Wang, Xinbang; Zhao, Xinjing; Xiang, Yu‐Tao; Wang, Tan

doi:10.1016/j.exger.2019.110659

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…Furthermore, IRS2 expression was slightly reduced in the hippocampus and islets of young APP/PS1 mice (3-month-old), while it was significantly suppressed in older animals (6-month-old mice). It was postulated that it might be related to other mechanisms, e.g., activation of GSK3β and neuroinflammation in the early stage of the disease [182]. These findings also complement the current understanding of the relationship between DM and AD [182].…”

Section: Miscellaneous Scaffolds and Drug Combinationsmentioning

confidence: 60%

“…It was postulated that it might be related to other mechanisms, e.g., activation of GSK3β and neuroinflammation in the early stage of the disease [182]. These findings also complement the current understanding of the relationship between DM and AD [182]. Some evidence was also provided that the combination of any GLP1R agonist class member with any DYRK1A inhibitor class member induces a synergistic increase in human β-cell replication accompanied by an increase in human β-cells mass [50].…”

Section: Miscellaneous Scaffolds and Drug Combinationsmentioning

confidence: 81%

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Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Pucelik

Barzowska

Dąbrowski

et al. 2021

IJMS

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Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition—through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term “diabetic kinome” as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.

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Section: Miscellaneous Scaffolds and Drug Combinationsmentioning

confidence: 60%

Section: Miscellaneous Scaffolds and Drug Combinationsmentioning

confidence: 81%

Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Pucelik

Barzowska

Dąbrowski

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…IRS2 also affects the PI3K-Akt pathway [ 43 ], which in turn affects the expression of FOXO1, P27, P21 and other genes, which are essential for the survival and proliferation of β-cells. DYRK1A interacts directly with IRS2 to promote phosphorylation of IRS2, leading to degradation of the IRS2 proteasome, resulting in β-cell dysfunction and apoptosis [ 44 ].…”

Section: Role Of Dyrk1a In the Proliferation And Function Of Islet β-...mentioning

confidence: 99%

Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors

Guo

Yao

et al. 2022

Metabolites

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The pathogenesis of diabetes mellitus is characterized by insulin resistance and islet β-cell dysfunction. Up to now, the focus of diabetes treatment has been to control blood glucose to prevent diabetic complications. There is an urgent need to develop a therapeutic approach to restore the mass and function of β-cells. Although exogenous islet cell transplantation has been used to help patients control blood glucose, it is costly and has very narrow application scenario. So far, small molecules have been reported to stimulate β-cell proliferation and expand β-cell mass, increasing insulin secretion. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors can induce human β-cell proliferation in vitro and in vivo, and show great potential in the field of diabetes therapeutics. From this perspective, we elaborated on the mechanism by which DYRK1A inhibitors regulate the proliferation of pancreatic β-cells, and summarized several effective natural DYRK1A inhibitors, hoping to provide clues for subsequent structural optimization and drug development in the future.

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