Short telomeres compromise β-cell signaling and survival

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. The experiment is designed to analyze gene expression profiles of islets from mice with short telomeres compared to those of wildtype mice.