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Short telomeres compromise β-cell signaling and survival

ABSTRACT: The factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, known to decrease with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. Islets from mice with short telomeres displayed evidence of β-cell dysfunction, and in response to glucose, had defective mitochondrial membrane depolarization as well as Ca2+ handling which limited insulin release. Short telomeres induced the hallmarks of senescence including premature accumulation of p16INK4a, and altered gene expression of key pathways essential for signaling and insulin secretion. Short telomeres also had an additive damaging effect to endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This manifested as more severe hyperglycemia in insulin mutant Akita mice which had a more profound loss of β-cell mass and increased β-cell apoptosis. Our data identify impaired signaling in the setting of senescence as a novel mechanism of telomere-mediated disease, and implicate telomere length as a determinant of risk and pathogenesis in diabetes.

ORGANISM(S): Mus musculus

PROVIDER: GSE25040 | GEO | 2013/10/01

SECONDARY ACCESSION(S): PRJNA134537

REPOSITORIES: GEO

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Short telomeres compromise M-NM-2-cell signaling and survival

Project description:The factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, known to decrease with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact M-NM-2-cell mass. Islets from mice with short telomeres displayed evidence of M-NM-2-cell dysfunction, and in response to glucose, had defective mitochondrial membrane depolarization as well as Ca2+ handling which limited insulin release. Short telomeres induced the hallmarks of senescence including premature accumulation of p16INK4a, and altered gene expression of key pathways essential for signaling and insulin secretion. Short telomeres also had an additive damaging effect to endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This manifested as more severe hyperglycemia in insulin mutant Akita mice which had a more profound loss of M-NM-2-cell mass and increased M-NM-2-cell apoptosis. Our data identify impaired signaling in the setting of senescence as a novel mechanism of telomere-mediated disease, and implicate telomere length as a determinant of risk and pathogenesis in diabetes. The experiment is designed to analyze gene expression profiles of islets from mice with short telomeres compared to those of wildtype mice.

2013-10-01 | E-GEOD-25040 | biostudies-arrayexpress

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Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence

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Project description:The risk of type 2 diabetes increases with age. Although changes in function and proliferation of aged beta cells resemble those preceding the development of diabetes, the contribution of beta cell aging and senescence remains unclear. The proportion of aged beta cells increases with animal age but even in young mice, senescent beta cells can be found. We showed that different models of insulin resistance accelerated aging and senescence marker expression in beta cells, BGal, led to loss of function and impaired glucose tolerance. Clearance of p16Ink4a+ cells, using the INK-ATTAC mouse model, ameliorated glucose metabolism, insulin secretion and decreased expression of aging, senescence and SASP genes in pancreatic islets. Senolytic drug ABT263 also improved glucose metabolism and beta cell identity when administered during insulin resistance. Human beta cells from diabetic and non-diabetic donors shared some of the same biology laying the foundation for translation into humans. These novel findings lay the framework to pursue senolysis of beta cells as a preventive and alleviating strategy for T2D.

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2013-05-31 | E-GEOD-36649 | biostudies-arrayexpress

Expression data by telomere elongation in vivo (xenograft)

Project description:Limitless reproductive potential is one of the hallmarks of cancer cells1. This ability is accomplished by maintaining telomeres, which erosion otherwise causes cellular senescence or death. Human cancer cells often maintain shorter telomeres than do cells in surrounding normal tissues2-5. While most cancer cells activate telomerase, which can elongate telomeres6, it remains elusive why cancer cells keep telomeres short. Here we show that forced elongation of telomeres in cancer cells promotes their differentiation in a tumor microenvironment in vivo. We elongated telomeres of human prostate cancer PC-3 cells, which possess short telomeres7, by enhancing their telomerase activity. The resulting cells with long telomeres retain an ability to form tumors in a mouse xenograft model. Strikingly, these tumors exhibit many duct-like structures and reduced N-cadherin expression, reminiscent of well-differentiated adenocarcinoma. These phenotypic changes are caused by telomere elongation per se but not enhanced telomerase activity. Gene expression profiling revealed that telomere elongation correlates with inhibition of cell-cycle processes. Together, our results suggest a functional contribution of short telomeres to tumor malignancy by regulating cancer cell differentiation. Two cell lines are telomere-elongated cells, both in the presence and absence of the exogenous hTERT. The other two lines are control PC-3 cell lines. We extracted RNA from four independent xenograft tumors per original cell line.

2013-05-31 | E-GEOD-41559 | biostudies-arrayexpress

Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2019]

Project description:Short telomeres induce a DNA damage response (DDR) that evokes apoptosis or senescence in human cells. An extant question is the contribution of this DDR to the phenotypes observed in telomeropathies. One exemplar is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knock-in mouse containing a Rap1 variant unable to bind telomeres but which did not result in eroded telomeres or a DDR. Rap1 variant MEFs exhibited decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in aging human fibroblasts. Rap1 knock-in mice were viable, but exhibited transcriptional alterations, proinflammatory cytokine/chemokine signaling, decreased lifespans, increased body weight/fasting blood glucose levels, increased spontaneous tumor incidence, and behavioral deficits. Taken together, our data indicate that some of the underlying mechanisms that drive telomeropathies may arise from phenotypes distinct from a telomere-induced DDR.

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Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2017]

2022-11-04 | GSE193520 | GEO

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2014-07-17 | E-GEOD-48973 | biostudies-arrayexpress

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