Hopkins scientists have found new evidence from studies in mice that shorter than normal telomeres, or “caps,” at the end of chromosomes may predispose people to age-related diabetes.
Telomeres are repetitive sequences of DNA that protect the ends of chromosomes and normally shorten with each cell division. After many divisions, the telomeres become so eroded that cells lose the ability to divide normally and they eventually die. Telomere shortening has been linked to cancer, lung disease and other age-related conditions.
The research, described in the March 10 issue of PLoS One, arose from observations that the occurrence of diabetes seems more common in patients with dyskeratosis congenita, a rare inherited disease caused by short telomeres. Patients with this condition are also prone to prematurely graying hair and early organ failure.
“Type II diabetes is an inherited disease. Its incidence increases consistently with age with as many as one in four adults affected by the age of 65,” Mary Armanios, the study’s principal investigator, said. “We didn’t understand why the incidence of diabetes increases with age. Telomeres shorten with age. Telomere length is also inherited. We therefore wondered if short telomeres might contribute to the age-related onset of diabetes.” Armanios is an assistant professor of oncology at the Kimmel Cancer Center.
Armanios and her team studied the insulin-producing beta cells of mice with short telomeres. Humans with diabetes do not produce sufficient insulin and have cells resistant to its efficient use, causing disruption to the regulation of blood sugar levels.
“Normally, blood glucose levels are maintained in a very tight range, but we found that mice with short telomeres had higher levels,” Armanios said. “We could link the higher blood sugar levels to beta cells, the cells that secrete insulin. Insulin is a hormone that is essential for glucose maintenance and in type II diabetes, the efficiency of insulin secretion is impaired. Although insulin levels were lower in mice with short telomeres, the cells that secrete them were present.
“However, there was evidence of senescence of dysfunction that led them not to secrete insulin properly. In essence, these mice had the same defects in insulin secretions that are known to be present in humans with early forms of diabetes.”
In beta cells from mice with short telomeres, the researchers found disregulation of p16, a gene linked to aging and diabetes. No such disregulation was found in the controls. In addition, many of the gene pathways essential for insulin secretion in beta cells, including pathways controlling calcium signaling, were altered in beta cells from mice with short telomeres.
According to Armanios, some studies have suggested that diabetic patients may have short telomeres, but it was not clear whether this contributes to the risk of diabetes or is a consequence of the disease.
Armanios believes the study may have several implications for the future of predicting diabetes risk and combating the condition.
“First, the work may lead us to use telomere length to identify those at [an] increased risk for developing diabetes. For these individuals we may be able to implement prevention efforts,” she said. “Also, the treatment of diabetes is still limited. By identifying new insights into how it evolves on a molecular level, we may be able to find approaches to combat its progression.”
Armanios and her colleagues are planning to conduct research to examine whether telomere length can predict the risk of diabetes prospectively.
