Failure to repair endogenous DNA damage in β-cells causes adult-onset diabetes in mice

Matthew J Yousefzadeh, Ana P Huerta Guevara, Andrea C Postmus, Rafael R Flores, Tokio Sano, Angelika Jurdzinski, Luise Angelini, Sara J McGowan, Ryan D O'Kelly, Erin A Wade, Lisa V Gonzalez-Espada, Danielle Henessy-Wack, Shannon Howard, Tania A Rozgaja, Christy E Trussoni, Nicholas F LaRusso, Bart J L Eggen, Johan W Jonker, Paul D Robbins, Laura J NiedernhoferJanine K Kruit*

*Corresponding author for this work

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Abstract

Age is the greatest risk factor for the development of type 2 diabetes mellitus (T2DM). Age-related decline in organ function is attributed to the accumulation of stochastic damage, including damage to the nuclear genome. Islets of T2DM patients display increased levels of DNA damage. However, whether this is a cause or consequence of the disease has not been elucidated. Here, we asked if spontaneous, endogenous DNA damage in β-cells can drive β-cell dysfunction and diabetes, via deletion of Ercc1, a key DNA repair gene, in β-cells. Mice harboring Ercc1-deficient β-cells developed adult-onset diabetes as demonstrated by increased random and fasted blood glucose levels, impaired glucose tolerance, and reduced insulin secretion. The inability to repair endogenous DNA damage led to an increase in oxidative DNA damage and apoptosis in β-cells and a significant loss of β-cell mass. Using electron microscopy, we identified β-cells in clear distress that showed an increased cell size, enlarged nuclear size, reduced number of mature insulin granules, and decreased number of mitochondria. Some β-cells were more affected than others consistent with the stochastic nature of spontaneous DNA damage. Ercc1-deficiency in β-cells also resulted in loss of β-cell function as glucose-stimulated insulin secretion and mitochondrial function were impaired in islets isolated from mice harboring Ercc1-deficient β-cells. These data reveal that unrepaired endogenous DNA damage is sufficient to drive β-cell dysfunction and provide a mechanism by which age increases the risk of T2DM.

Original languageEnglish
Number of pages10
JournalAging Biology
Volume1
Issue number1
DOIs
Publication statusPublished - Oct-2023

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