Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1d/- mice.
Metabolism
; 117: 154711, 2021 04.
Article
en En
| MEDLINE
| ID: mdl-33493548
ABSTRACT
BACKGROUND:
Type 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whether DNA damage plays a role in the pathogenesis of the disease is unclear. Here, we used mice deficient for the DNA excision-repair gene Ercc1 to study the impact of persistent endogenous DNA damage accumulation on energy metabolism, glucose homeostasis and beta-cell function.METHODS:
ERCC1-XPF is an endonuclease required for multiple DNA repair pathways and reduced expression of ERCC1-XPF causes accelerated accumulation of unrepaired endogenous DNA damage and accelerated aging in humans and mice. In this study, energy metabolism, glucose metabolism, beta-cell function and insulin sensitivity were studied in Ercc1d/- mice, which model a human progeroid syndrome.RESULTS:
Ercc1d/- mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivity was increased, whereas, plasma insulin levels were decreased in Ercc1d/- mice. Fasting induced hypoglycemia in Ercc1d/- mice, which was the result of increased glucose disposal. Ercc1d/- mice exhibit a significantly reduced beta-cell area, even compared to control mice of similar weight. Glucose-stimulated insulin secretion in vivo was decreased in Ercc1d/- mice. Islets isolated from Ercc1d/- mice showed increased DNA damage markers, decreased glucose-stimulated insulin secretion and increased susceptibility to apoptosis.CONCLUSION:
Spontaneous DNA damage accumulation triggers an adaptive response resulting in improved insulin sensitivity. Loss of DNA repair, however, does negatively impacts beta-cell survival and function in Ercc1d/- mice.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Resistencia a la Insulina
/
Proteínas de Unión al ADN
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Reparación del ADN
/
Endonucleasas
/
Células Secretoras de Insulina
/
Insulina
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
Idioma:
En
Revista:
Metabolism
Año:
2021
Tipo del documento:
Article
País de afiliación:
Países Bajos