Short Telomeres Compromise β-Cell Signaling and Survival
Open accessAbstract
The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten 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. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca(2+) influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16(INK4a). Specifically, we identified gene expression changes in pathways which are essential for Ca(2+)-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis.
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Telomere-induced senescence acts mainly through p53-dependent pathways, though the RB pathway may also be involved in some contexts.
“The downstream effector pathways of telomere-induced senescence are largely p53-dependent96, but there may be involvement of the retinoblastoma protein (RB) pathway in some settings97.”
From The telomere syndromes (2012) · cites this paper as [97]
Telomere dysfunction produces notable phenotypes in tissues that divide slowly.
“more recently it has been recognized that telomere dysfunction causes prominent phenotypes in slow-turnover tissues97,99,100,103 (Table 2).”
From The telomere syndromes (2012) · cites this paper as [97]
The telomerase-knockout mouse is a valuable model for studying telomere-mediated disease mechanisms because its phenotypes closely match those in humans.
“The telomerase-knockout mouse has provided an important model for understanding telomere-mediated disease mechanisms because there is a remarkable convergence with human disease phenotypes (an overview is shown in Table 2)36,82,84,85,97,99–111.”
From The telomere syndromes (2012) · cites this paper as [97]
Altered gene expression in these cells disrupts pathways needed for insulin secretion signalling and exocytosis, such as mitochondrial function and calcium handling.
“The dysregulation of gene expression affects pathways that are essential for insulin secretion signalling and exocytosis, including mitochondrial function and Ca2+ handling97.”
From The telomere syndromes (2012) · cites this paper as [97]
In mice, short telomeres reduce the threshold for disease from additional external or internal insults, including γ-irradiation and ER stress from misfolded proteins.
“Indeed, in mouse models, short telomeres have been shown to lower the disease threshold to other exogenous and endogeneous damage, such as γ-irradiation119 and endoplasmic reticulum stress due to protein misfolding97 (Fig. 5a).”
From The telomere syndromes (2012) · cites this paper as [97]
In adult mouse β-cells, short telomeres produce spontaneous defects in insulin secretion both in vivo and in vitro, despite preserved β-cell mass.
“Short telomeres cause spontaneous insulin secretion defects in vivo and in vitro, even when the β-cell mass is intact97 (Fig. 5b).”
From The telomere syndromes (2012) · cites this paper as [97]
Senescence caused by telomere dysfunction is not merely loss of replicative capacity; it can impair cell function while cells still look normal.
“Therefore, it seems that telomere-induced senescence represents more than a loss of replicative potential and can limit cellular function even when cells appear morphologically intact97.”
From The telomere syndromes (2012) · cites this paper as [97]
Although they look normal, mouse β-cells carrying dysfunctional telomeres display senescence features: DNA damage response activation, reduced proliferation, increased p16INK4A, and changed gene expression.
“Although they appear morphologically normal, mouse β-cells with dysfunctional telomeres show the hallmarks of senescence. They have an activated DNA damage response, impaired proliferation, p16INK4A upregulation and altered gene expression97.”
From The telomere syndromes (2012) · cites this paper as [97]
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- Authors
- Guo, N., Parry, E. M., Li, L.-S., Kembou, F., Lauder, N., Hussain, M. A., Berggren, P.-O., & Armanios, M.
- Affiliations
- Johns Hopkins University (US)
- Karolinska Institutet (SE)
- Corresponding author
- Armanios, Mary
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-03-10
- Volume
- 6
- Issue
- 3
- Pages
- e17858
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3053388
- OpenAlex
- W1994225766
- Cited by
- 100
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 2 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 9 · 2015: 8 · 2014: 7 · 2013: 7 · 2012: 9
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Vetenskapsrådet
- National Institutes of Health
- National Institute on Aging (AG27406, R01AG027406)
- National Cancer Institute (CA118416, K08CA118416)
- National Institute of General Medical Sciences (T32GM007309, GM007309)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007632)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- telomere length, short telomeres, pancreatic beta cells, insulin secretion, type 2 diabetes, aging, cellular senescence, p16INK4a, endoplasmic reticulum stress, calcium influx, mitochondrial membrane potential, exocytosis, beta-cell apoptosis, Akita mice, impaired glucose tolerance
- MeSH terms
- Insulin Secretion, Animals, Cell Survival, Diabetes Mellitus, Endoplasmic Reticulum, Gene Expression Regulation, Glucose, Glucose Tolerance Test, Humans, Insulin, Mitochondria, Stress, Physiological, Signal Transduction, Incidence, Telomere, Cellular Senescence, Dyskeratosis Congenita, Calcium Signaling, Insulin-Secreting Cells, Mice
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