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

Autor: Chen T; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Yu J; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Guo X; Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China., Wang S; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Wang Z; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Chen Y; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Hu X; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Li H; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Chen L; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China., Zheng J; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2024 Jul; Vol. 26 (7), pp. 2956-2968. Date of Electronic Publication: 2024 May 03.
DOI: 10.1111/dom.15621
Abstrakt: 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 (ADK tg/tg /Mip-Cre) was generated wherein the mouse Insulin1 gene promoter specifically overexpressed ADK in pancreatic β cells. The ADK tg/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.
(© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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