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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number154711
JournalMetabolism: clinical and experimental
Volume117
DOIs
StatePublished - Apr 1 2021

Bibliographical note

Funding Information:
We would like to thank Jan H.J. Hoeijmakers, Erasmus University Medical Center Rotterdam, for providing the mice and useful discussions. We thank H.J.R. van Faassen for technical assistance. AHG was supported by the Mexican National Council of Science and Technology (CONACyT). This work was supported by grants from The Netherlands Organization for Scientific Research (VICI grant 016.176.640 to JWJ), The Netherlands Organization for Scientific Research and the Dutch Diabetes Research Foundation (Diabetes II Breakthrough project 459001005 to JKK), and European Foundation for the Study of Diabetes (award supported by EFSD/ Novo Nordisk to JWJ). SJM, TRS, TS and LJN were supported by NIH P01AG043376 , P01AG062413 , R01AG063543 and U19AG056278 .

Funding Information:
We would like to thank Jan H.J. Hoeijmakers, Erasmus University Medical Center Rotterdam, for providing the mice and useful discussions. We thank H.J.R. van Faassen for technical assistance. AHG was supported by the Mexican National Council of Science and Technology (CONACyT). This work was supported by grants from The Netherlands Organization for Scientific Research (VICI grant 016.176.640 to JWJ), The Netherlands Organization for Scientific Research and the Dutch Diabetes Research Foundation (Diabetes II Breakthrough project 459001005 to JKK), and European Foundation for the Study of Diabetes (award supported by EFSD/Novo Nordisk to JWJ). SJM, TRS, TS and LJN were supported by NIH P01AG043376, P01AG062413, R01AG063543 and U19AG056278.

Publisher Copyright:
© 2021 The Authors

Keywords

  • Beta-cell function
  • DNA repair
  • Energy metabolism
  • Genotoxic stress
  • Glucose homeostasis
  • Somatotropic axis
  • Aging/genetics
  • DNA Damage/genetics
  • Endonucleases/genetics
  • Mice, Inbred C57BL
  • Male
  • Cell Survival/genetics
  • DNA Repair/genetics
  • Insulin-Secreting Cells/physiology
  • Apoptosis/genetics
  • Insulin Resistance/genetics
  • Animals
  • Diabetes Mellitus, Type 2/genetics
  • DNA-Binding Proteins/genetics
  • Insulin/genetics
  • Mice
  • Glucose/genetics

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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