Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1d/− mice

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. 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. 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. 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. •Loss of DNA repair gene Ercc1 resulted in suppression of the somatotropic axis.•Ercc1d/− mice displayed altered energy metabolism and increased insulin sensitivity.•Beta-cell area was reduced in Ercc1d/− mice.•Beta-cells of Ercc1d/− mice showed decreased function and survival.