DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes

Brawerman, Gabriel; Pipella, Jasmine; Thompson, Peter J.

doi:10.1016/j.molmet.2022.101524

Cited by 15 publications

(39 citation statements)

References 61 publications

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“…If the glucagon secretory phenotype was due to direct DNA damage and toxicity in a cells, then it should not be amenable to rescue by iBET-762, whereas, if it is a consequence of SASP after DNA damage, then iBET-762 should rescue the phenotype. We confirmed that iBET-762 treatment had an inhibiting effect on SASP by carrying out Luminex assays on the conditioned media from senescent and control islets, which confirmed a significant reduction in the secretion of GDF15 (Figure 6E), a putative SASP factor that is consistently induced in our human islet senescence model (17). We next performed secretion assays using 3 mM and 16.7 mM glucose in the presence of amino acids to more closely mimic physiological glucagon stimulation.…”

Section: Human a Cells Do Not Show Evidence Of Senescence In T1dsupporting

confidence: 65%

“…At this time-point we monitored glucagon secretion under low (2 mM) and high (20 mM) glucose conditions from three different islet donor preparations (Figure 5C). We previously examined insulin secretion during senescence induction in these same islet donor preparations and found that bleomycin-induced senescence did not impact islet insulin secretion (17). Using these same samples to measure glucagon secretion, we found that senescent islets had reduced glucagon secretion under low and high glucose in two donors, whereas the third donor showed increased glucagon secretion under both conditions (Figure 5C).…”

Section: Human a Cells Do Not Show Evidence Of Senescence In T1dmentioning

confidence: 76%

“…Details of specific donors are listed in Supplementary Table 1. DNA damage-induced senescence was induced in human islets using our previous methods (14,16,17). Islets were rested for 24 h after receipt in normal islet growth media (RPMI-1640 containing 10% FBS, 5.5 mM glucose and 1% antibiotic-antimycotic).…”

Section: Human Donor Islets and Pancreas Sectionsmentioning

confidence: 99%

“…Western blot analysis was carried out as previously (17), with minor modifications. Briefly human islets were lysed in radioimmunoprecipitation assay (RIPA) buffer (ThermoFisher) containing 1X protease inhibitor cocktail and 1X phosphatase inhibitor cocktail (ThermoFisher).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Senescent b and non-b cells in our model could exert a paracrine effect on non-senescent a cells via SASP factor secretion, thereby altering glucagon secretion. To test this possibility, we induced senescence in islets and after bleomycin removal during the development of SASP, we cultured islets in the Bromodomain ExtraTerminal domain (BET) protein family inhibitor iBET-762 (23), which blocks transcriptional activation and secretion of SASP factors in human islets following bleomycin-induced DNA damage and senescence (17). If the glucagon secretory phenotype was due to direct DNA damage and toxicity in a cells, then it should not be amenable to rescue by iBET-762, whereas, if it is a consequence of SASP after DNA damage, then iBET-762 should rescue the phenotype.…”

Section: Human a Cells Do Not Show Evidence Of Senescence In T1dmentioning

confidence: 99%

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Alpha cell dysfunction in type 1 diabetes is independent of a senescence program

Brawerman¹,

Ntranos²,

Thompson³

2022

Front. Endocrinol.

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Type 1 Diabetes (T1D) is caused by insulin deficiency, due to progressive autoimmune destruction of pancreatic β cells. Glucagon-secreting α cells become dysfunctional in T1D and contribute to pathophysiology, however, the mechanisms involved are unclear. While the majority of β cells are destroyed in T1D, some β cells escape this fate and become senescent but whether α cell dysfunction involves a senescence program has not been explored. Here we addressed the question of whether α cells become senescent during the natural history of T1D in the non-obese diabetic (NOD) mouse model and humans. NOD mice had several distinct subpopulations of α cells, but none were defined by markers of senescence at the transcriptional or protein level. Similarly, α cells of human T1D donors did not express senescence markers. Despite the lack of senescence in α cells in vivo, using a human islet culture model, we observed that DNA damage-induced senescence led to alterations in islet glucagon secretion, which could be rescued by inhibiting the senescence-associated secretory phenotype (SASP). Together our results suggest that α cell dysfunction in T1D is not due to activation of a senescence program, however, senescent β cell accumulation in the islet microenvironment may have a negative effect on α cell function.

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Section: Human a Cells Do Not Show Evidence Of Senescence In T1dsupporting

confidence: 65%

Section: Human a Cells Do Not Show Evidence Of Senescence In T1dmentioning

confidence: 76%

Section: Human Donor Islets and Pancreas Sectionsmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Human a Cells Do Not Show Evidence Of Senescence In T1dmentioning

confidence: 99%

See 3 more Smart Citations

Alpha cell dysfunction in type 1 diabetes is independent of a senescence program

Brawerman¹,

Ntranos²,

Thompson³

2022

Front. Endocrinol.

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Advances in the Use of Biologics and Biomaterials toward the Improvement of Pancreatic Islet Graft Survival in Type 1 Diabetes

Yitayew,

Luginina,

Tabrizian

2024

Advanced NanoBiomed Research

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Islet transplantation is a curative treatment for patients suffering from type 1 diabetes and has the potential to replace current treatment strategies involving the exogenous administration of insulin. Despite this potential, there are many hurdles in achieving successful long‐term graft survival due to autoimmune and foreign body reactions leading to graft rejection coupled with donor shortage and potential adverse effects from the need for long‐term administration of immunosuppressive drugs. As a result, various approaches have been proposed to increase the viability and function of islet grafts during isolation and ex vivo culture with the use of growth factors, hormones, and other therapeutic agents. In addition, other strategies have addressed how to enhance or maintain islet graft performance after implantation with improvements on immunosuppressive drug regimens and the use of biomaterials to encapsulate and protect the cells from graft rejection. This review focuses on the recent advances in strategies to improve islet viability and function with the addition of exogenous compounds and the implementation of conformal coating as a promising tool for immunoprotection of islet transplants.

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Stress-induced β cell early senescence confers protection against type 1 diabetes

Lee,

Sahin,

Chen

et al. 2023

Cell Metabolism

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DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes

Cited by 15 publications

References 61 publications

Alpha cell dysfunction in type 1 diabetes is independent of a senescence program

Alpha cell dysfunction in type 1 diabetes is independent of a senescence program

Advances in the Use of Biologics and Biomaterials toward the Improvement of Pancreatic Islet Graft Survival in Type 1 Diabetes

Stress-induced β cell early senescence confers protection against type 1 diabetes

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