| First Author | Huerta Guevara AP | Year | 2021 |
| Journal | Metabolism | Volume | 117 |
| Pages | 154711 | PubMed ID | 33493548 |
| Mgi Jnum | J:313319 | Mgi Id | MGI:6705449 |
| Doi | 10.1016/j.metabol.2021.154711 | Citation | Huerta Guevara AP, et al. (2021) Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1(d/-) mice. Metabolism 117:154711 |
| abstractText | 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 Ercc1(d/-) mice, which model a human progeroid syndrome. RESULTS: Ercc1(d/-) mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivity was increased, whereas, plasma insulin levels were decreased in Ercc1(d/-) mice. Fasting induced hypoglycemia in Ercc1(d/-) mice, which was the result of increased glucose disposal. Ercc1(d/-) 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 Ercc1(d/-) mice. Islets isolated from Ercc1(d/-) 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 Ercc1(d/-) mice. |
