Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1(d/-) 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*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

2 Citaten (Scopus)
28 Downloads (Pure)

Samenvatting

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 andmice. 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 sensitivitywas increased, whereas, plasma insulin levelswere decreased in Ercc1(d/-) mice. Fasting induced hypoglycemia in Ercc1(d/-) mice, whichwas 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. (C) 2021 The Author(s). Published by Elsevier Inc.

Originele taal-2English
Artikelnummer154711
Pagina's (van-tot)1-9
Aantal pagina's9
TijdschriftMetabolism: Clinical and Experimental
Volume117
Vroegere onlinedatum22-jan-2021
DOI's
StatusPublished - apr-2021

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