Short telomeres compromise β-cell signaling and survival

Nini Guo, Erin M. Parry, Luo Sheng Li, Frant Kembou, Naudia Lauder, Mehboob Hussain, Per Olof Berggren, Mary Armanios

Research output: Contribution to journalArticle

Abstract

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 Ca2+ 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 p16INK4a. Specifically, we identified gene expression changes in pathways which are essential for Ca2+-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.

Original languageEnglish (US)
Article numbere17858
JournalPLoS One
Volume6
Issue number3
DOIs
StatePublished - 2011

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Cell signaling
telomeres
Telomere
Medical problems
Cell Survival
cells
Insulin
Apoptosis
diabetes
Metabolism
Gene expression
apoptosis
Membranes
Glucose
Defects
calcium
incidence
Endoplasmic Reticulum Stress
Glucose Intolerance
exocytosis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Short telomeres compromise β-cell signaling and survival. / Guo, Nini; Parry, Erin M.; Li, Luo Sheng; Kembou, Frant; Lauder, Naudia; Hussain, Mehboob; Berggren, Per Olof; Armanios, Mary.

In: PLoS One, Vol. 6, No. 3, e17858, 2011.

Research output: Contribution to journalArticle

Guo, N, Parry, EM, Li, LS, Kembou, F, Lauder, N, Hussain, M, Berggren, PO & Armanios, M 2011, 'Short telomeres compromise β-cell signaling and survival', PLoS One, vol. 6, no. 3, e17858. https://doi.org/10.1371/journal.pone.0017858
Guo, Nini ; Parry, Erin M. ; Li, Luo Sheng ; Kembou, Frant ; Lauder, Naudia ; Hussain, Mehboob ; Berggren, Per Olof ; Armanios, Mary. / Short telomeres compromise β-cell signaling and survival. In: PLoS One. 2011 ; Vol. 6, No. 3.
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