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

Abstract

To investigate the effects of adenosine kinase (ADK), a key enzyme in determining intracellular adenosine levels, on β cells, and their underlying mechanism. 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. 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. 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.