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Life Sci ; 289: 120213, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34902439

RESUMO

BACKGROUND: Regardless of the etiology, any type of DM presents a reduction of insulin-secreting cell mass, so it is important to investigate pathways that induce the increase of this cell mass. AIM: Based on the fact that (1) HNF4α is crucial for ß-cell proliferation, (2) DEX-induced IR promotes ß-cell mass expansion, and (3) the stimulation of ß-cell mass expansion may be an important target for DM therapies, we aimed to investigate whether DEX-induced proliferation of ß pancreatic cells is dependent on HNF4α. METHODS: We used WildType (WT) and Knockout (KO) mice for HNF4-α, treated or not with 100 mg/Kg/day of DEX, for 5 consecutive days. One day after the last injection of DEX the IR was confirmed by ipITT and the mice were euthanized for pancreas removal. RESULTS: In comparison to WT, KO mice presented increased glucose tolerance, lower fasting glucose and increased glucose-stimulates insulin secretion (GSIS). DEX induced IR in both KO and WT mice. In addition, DEX-induced ß-cell mass expansion and an increase in the Ki67 immunostaining were observed only in WT mice, evidencing that IR-induced ß-cell mass expansion is dependent on HNF4α. Also, we observed that DEX-treatment, in an HNF4α-dependent way, promoted an increase in PDX1, PAX4 and NGN3 gene expression. CONCLUSIONS: Our results strongly suggest that DEX-induced IR promotes ß-cell mass expansion through processes of proliferation and neogenesis that depend on the HNF4α activity, pointing to HNF4α as a possible therapeutic target in DM treatment.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dexametasona/farmacologia , Fator 4 Nuclear de Hepatócito/metabolismo , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proliferação de Células/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Secreção de Insulina/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição Box Pareados/biossíntese , Fatores de Transcrição Box Pareados/genética , Transativadores/biossíntese , Transativadores/genética
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