Adenosine kinase inhibits β‐cell proliferation by upregulating DNA methyltransferase 3A expression.

Aim: To investigate the effects of adenosine kinase (ADK), a key enzyme in determining intracellular adenosine levels, on β cells, and their underlying mechanism. Methods: Genetic animal models and transgenic immortalized cells were applied to study the effect of ADK on islet beta‐cell proliferation and function. The beta‐cell mass and response to glucose were measured in vivo using mice with beta‐cell‐specific ADK overexpression, and in vitro using ADK‐overexpressed immortalized beta‐cell. Results: The expression of ADK in human islets at high abundance, especially in β cells, was decreased during the process of β‐cell proliferation. Additionally, a transgenic mouse model (ADKtg/tg /Mip‐Cre) was generated wherein the mouse Insulin1 gene promoter specifically overexpressed ADK in pancreatic β cells. The ADKtg/tg /Mip‐Cre model exhibited impaired glucose tolerance, decreased fasting plasma insulin, loss of β‐cell mass, and inhibited β‐cell proliferation. Proteomic analysis revealed that ADK overexpression inhibited the expression of several proteins that promote cell proliferation and insulin secretion. Upregulating ADK in the β‐cell line inhibited the expression of β‐cell related regulatory molecules, including FoxO1, Appl1, Pxn, Pdx‐1, Creb and Slc16a3. Subsequent in vitro experiments indicated that the inhibition of β‐cell proliferation and the decreased expression of Pdx‐1, Creb and Slc16a3 were rescued by DNA methyltransferase 3A (DNMT3A) knockdown in β cells. Conclusion: In this study, we found that the overexpression of ADK decreased the expression of several genes that regulate β cells, resulting in the inhibition of β‐cell proliferation and dysfunction by upregulating the expression of DNMT3A. [ABSTRACT FROM AUTHOR]