Adenosine kinase inhibits ß-cell proliferation by upregulating DNA methyltransferase 3A expression.
Diabetes Obes Metab
; 26(7): 2956-2968, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38699782
ABSTRACT
AIM:
To investigate the effects of adenosine kinase (ADK), a key enzyme in determining intracellular adenosine levels, on ß 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 ß cells, was decreased during the process of ß-cell proliferation. Additionally, a transgenic mouse model (ADKtg/tg /Mip-Cre) was generated wherein the mouse Insulin1 gene promoter specifically overexpressed ADK in pancreatic ß cells. The ADKtg/tg /Mip-Cre model exhibited impaired glucose tolerance, decreased fasting plasma insulin, loss of ß-cell mass, and inhibited ß-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 ß-cell line inhibited the expression of ß-cell related regulatory molecules, including FoxO1, Appl1, Pxn, Pdx-1, Creb and Slc16a3. Subsequent in vitro experiments indicated that the inhibition of ß-cell proliferation and the decreased expression of Pdx-1, Creb and Slc16a3 were rescued by DNA methyltransferase 3A (DNMT3A) knockdown in ß cells.CONCLUSION:
In this study, we found that the overexpression of ADK decreased the expression of several genes that regulate ß cells, resulting in the inhibition of ß-cell proliferation and dysfunction by upregulating the expression of DNMT3A.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ratones Transgénicos
/
Regulación hacia Arriba
/
Adenosina Quinasa
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Proliferación Celular
/
ADN (Citosina-5-)-Metiltransferasas
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Células Secretoras de Insulina
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ADN Metiltransferasa 3A
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Diabetes Obes Metab
Asunto de la revista:
ENDOCRINOLOGIA
/
METABOLISMO
Año:
2024
Tipo del documento:
Article
País de afiliación:
China