New Key Publication: Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1 d/- mice

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.

by:

• Ana P Huerta Guevara
• Sara J McGowan
• Melissa Kazantzis
• Tania Rozgaja Stallons
• Tokio Sano
• Niels L Mulder
• Angelika Jurdzinski
• Theo H van Dijk
• Bart J L Eggen
• Johan W Jonker
• Laura J Niedernhofer
• Janine K Kruit

Read more : doi: 10.1016/j.metabol.2021.154711. https://pubmed.ncbi.nlm.nih.gov/33493548/