β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes

Horwitz, E. P.; Krogvold, Lars; Zhitomirsky, Sophia; Swisa, Avital; Fischman, Maya; Lax, Tsuria; Dahan, Tehila; Hurvitz, Noa; Weinberg-Corem, Noa; Klochendler, Agnes; Powers, Alvin C.; Jörns, Anne; Lenzen, Sigurd; Gläser, Benjamin; Dahl‐Jørgensen, Knut; Dor, Yuval

doi:10.2337/db17-1006

Cited by 41 publications

(53 citation statements)

References 48 publications

(64 reference statements)

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“…In pancreatic sections derived from nPOD donors, SASP β‐cells have been identified through the immunohistochemical codetection of CDKN1A, SERPINE1, and IL‐6, whose presence gradually increased from non‐diabetic controls to islet autoantibody positive and T1D donors. Collectively, these data show that the appearance of SASP β‐cells is triggered by inflammatory mediators, which are particularly active on a specific subtype of β‐cells, thus enhancing islet inflammation and resembling a β‐cell fragility model and an inflammatory loop. As a matter of fact, SASP β‐cells have been demonstrated to express and secrete proinflammatory chemokines as well.…”

Section: β‐Cell and α‐Cell Responses To Islet Inflammation In T1dsupporting

confidence: 71%

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

Nigi

Maccora

Dotta

et al. 2019

Diabetes Metabolism Res

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The histological analysis of human pancreatic samples in type 1 diabetes (T1D) has been proven essential to move forward in the evaluation of in situ events characterizing T1D. Increasing availability of pancreatic tissues collected from diabetic multiorgan donors by centralized biorepositories, which have shared tissues among researchers in the field, has allowed a deeper understanding of T1D pathophysiology, using novel immunohistological and high-throughput methods. In this review, we provide a comprehensive update of the main recent advancements in the characterization of cellular and molecular events involving endocrine and exocrine pancreas as well as the immune system in the onset and progression of T1D. Additionally, we underline novel elements, which provide evidence that T1D pathological changes affect not only islet β-cells but also the entire pancreas.

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Section: β‐Cell and α‐Cell Responses To Islet Inflammation In T1dsupporting

confidence: 71%

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

Nigi

Maccora

Dotta

et al. 2019

Diabetes Metabolism Res

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show abstract

“…Notably, patients with ATM loss of function mutations have a higher incidence of (obesity-independent) diabetes [23]. On the other hand, ATM activation was detected in beta cells of T1D patients, and in a recent report, beta cell specific ATM ablation protected against chemically induced beta cell death in mice [24]. While ATM can regulate P53 activity via phosphorylation, recent investigations have focused on either P53 or ATM, but not if both act additively, synergistically or independent of each other.…”

Section: Introductionmentioning

confidence: 99%

ATM and P53 differentially regulate pancreatic beta cell survival in Ins1E cells

et al. 2020

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Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult.

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“…Besides, ATM kinase increases the phosphorylation levels of H2AX and 53BP1, thus promoting DNA damage repair, improving the effectiveness of homologous recombinant DNA repair to inhibit beta-cell proliferation and reduce their apoptosis. Conditional deletion of the master DNA repair gene-ATM kinase in mouse pancreatic beta-cells protects mice against STZ-induced diabetes (69). Importantly, it has been reported that Cdkn1a and ATM kinase are involved in DNA damage repair process in islet beta-cells induced by STZ, and the expression of Cdkn1a and ATM kinase were up-regulated after STZ intervention (42,43,70).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment

et al. 2020

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Objective: To clarify the role and mechanism of miR-17-92 cluster in islet beta-cell repair after streptozotocin intervention. Methods: Genetically engineered mice (miR-17-92βKO) and control RIP-Cre mice were intraperitoneally injected with multiple low dose streptozotocin. Body weight, random blood glucose (RBG), fasting blood glucose, and intraperitoneal glucose tolerance test (IPGTT) were monitored regularly. Mice were sacrificed for histological analysis 8 weeks later. Morphological changes of pancreas islets, quantity, quality, apoptosis, and proliferation of beta-cells were measured. Islets from four groups were isolated. MiRNA and mRNA were extracted and quantified. Results: MiR-17-92βKO mice showed dramatically elevated fasting blood glucose and impaired glucose tolerance after streptozotocin treatment in contrast to control mice, the reason of which is reduced beta-cell number and total mass resulting from reduced proliferation, enhanced apoptosis of beta-cells. Genes related to cell proliferation and insulin transcription repression were significantly elevated in miR-17-92βKO mice treated with streptozotocin. Furthermore, genes involved in DNA biosynthesis and damage repair were dramatically increased in miR-17-92βKO mice with streptozotocin treatment. Conclusion: Collectively, our results demonstrate that homozygous deletion of miR-17-92 cluster in mouse pancreatic beta-cells promotes the development of experimental diabetes, indicating that miR-17-92 cluster may be positively related to beta-cells restoration and adaptation after streptozotocin-induced damage.

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β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes

Cited by 41 publications

References 48 publications

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

ATM and P53 differentially regulate pancreatic beta cell survival in Ins1E cells

MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment

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