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 beta-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in beta-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 beta-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of beta-cells and accumulation of p16(INK4a). 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 beta-cell mass and increased beta-cell apoptosis. Our data indicate that short telomeres can affect beta-cell metabolism even in the presence of intact beta-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of beta-cell function and diabetes pathogenesis.
