Loss of EGR-1 uncouples compensatory responses of pancreatic ß cells.
Theranostics
; 10(9): 4233-4249, 2020.
Article
em En
| MEDLINE
| ID: mdl-32226550
ABSTRACT
Rationale Subjects unable to sustain ß-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence ß-cell compensation in response to metabolic overload. Methods:
Mice deficient in EGR-1 (Egr1-/-) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses.Results:
In response to a high-fat diet, Egr1-/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1-/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for ß-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of ß-cell compensatory genes in the non-diabetic group, but not in the diabetic group.Conclusion:
These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of ß-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Tipo 2
/
Células Secretoras de Insulina
/
Proteína 1 de Resposta de Crescimento Precoce
/
Glucose
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article