title: Short telomeres compromise β-cell signaling and survival.
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 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.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Nini
authors.initials: N
authors.lastname: Guo
authors.forename: Erin M
authors.initials: EM
authors.lastname: Parry
authors.forename: Luo-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Frant
authors.initials: F
authors.lastname: Kembou
authors.forename: Naudia
authors.initials: N
authors.lastname: Lauder
authors.forename: Mehboob A
authors.initials: MA
authors.lastname: Hussain
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Mary
authors.initials: M
authors.lastname: Armanios
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000209:etiology; D019871:Dyskeratosis Congenita / Q000150:complications; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006801:Humans; D015994:Incidence; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects; D016615:Telomere / Q000473:pathology*
chemical_list: D007328:Insulin; D005947:Glucose