CompromisedDNArepair is responsible for diabetes‐associated fibrosis

Abstract

Diabetes-associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. Intriguingly, the mechanism underlying this association remained unknown. Moreover, insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting notion that thus far unknown mechanisms must be operative. Here, we show that experimental type 1 and type 2 diabetes impairs DNA repair, leading to senescence, inflammatory phenotypes, and ultimately fibrosis. Carbohydrates were found to trigger this cascade by decreasing the NAD + /NADH ratio and NHEJ-repair in vitro and in diabetes mouse models. Restoring DNA repair by nuclear overexpression of phosphomimetic RAGE reduces DNA damage, inflammation, and fibrosis, thereby restoring organ function. Our study provides a novel conceptual framework for understanding diabetic fibrosis on the basis of persistent DNA damage signaling and points to unprecedented approaches to restore DNA repair capacity for resolution of fibrosis in patients with diabetes.

Why does COVID-19 disproportionately affect older people?

“…Mice lacking SIRT1, for example, display aggravated inflammasome activation, with increased production of lung proinflammatory mediators, including intercellular adhesion molecule 1 (ICAM-1) and high-mobility group box 1 (HMGB1), and a dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression [128]. Further, as a result of NAD + depletion in mouse models of uncontrolled diabetes, DNA repair is blunted leading to pulmonary inflammation, senescence and fibrosis [129], which could explain why diabetics are more susceptible to COVID-19. SIRT1 also attenuates the acute inflammatory response through deacetylation of H4K16 in the TNF-α promoter [130].…”

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

“…Hepatocytes can exhibit an altered cell division process whereby mitosis occurs without the completion of cytokinesis, leading to the formation of binuclear polyploid cells [ 21 ]. This happens physiologically downstream of the insulin signaling pathway [ 22 ] and may serve to protect against loss of tumor suppressors upon genomic aberrations induced by a nutrient-rich environment [ 23 , 24 ]. Interestingly, polyploidization involving mononuclear polyploid cells that do not complete mitosis, termed “pathological polyploidization”, has been observed in diseased liver of viral hepatitis and NAFLD patients [ 12 , 25 ], implicating pathological polyploidization as a possible etiological factor in liver disease.…”

Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy

“…on 6 subsequent days. Intradermal insulin injections were given bi-weekly as soon as the blood glucose levels reached 300 mg/dL 81 . Experiments were performed 12 weeks post-onset of hyperglycemia in female mice and 6 weeks post-onset in male mice.…”