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J Clin Invest ; 127(1): 230-243, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27941241

RESUMO

Type 2 diabetes is thought to involve a compromised ß cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult ß cell identity and function. PAX6 was downregulated in ß cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in ß cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of ß cell function and expansion of α cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of ß cell genes, thus maintaining mature ß cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human ß cells. We conclude that reduced expression of PAX6 in metabolically stressed ß cells may contribute to ß cell failure and α cell dysfunction in diabetes.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Cetoacidose Diabética/metabolismo , Células Secretoras de Glucagon/metabolismo , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Fator de Transcrição PAX6/biossíntese , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Cetoacidose Diabética/genética , Cetoacidose Diabética/patologia , Elementos Facilitadores Genéticos , Deleção de Genes , Regulação da Expressão Gênica , Células Secretoras de Glucagon/patologia , Hiperglicemia/genética , Hiperglicemia/patologia , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX6/genética
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