Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1 mice
Ana 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
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 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.