eNews May 13, 2011

Short telomeres exacerbate diabetes in mice


Disease susceptibility increases as people age. Scientists have suspected that this increased disease susceptibility is mediated by progressive telomere shortening with age. According to findings by a research team led by Mary Armanios, M.D., at John Hopkins University School of Medicine, Baltimore, Md., this may be the case for type 2 diabetes. Armanios' group found that short telomeres increase diabetes susceptibility and severity in mice (Guo et al. 2011). Their findings may lead to new ways of diagnosing and treating type 2 diabetes.

Short telomeres impair beta cell functions

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To determine if age-related telomere shortening mediates age-related beta cell dysfunction, Armanios and colleagues compared glucose homeostasis in wild-type CAST/EiJ (CAST, 000928) and C57BL/6J (B6J, 000664) mice to late generation (i.e., short-telomere) CAST mice heterozygous for a mutation in the RNA component of telomerase (Terc) gene and short-telomere B6.Cg-Terctm1Rdp/J (Terc-/- B6J, 004132) mice. The researchers found that although the short-telomere mice have normal beta cell mass, size, number, and insulin content, they exhibit beta cell dysfunctions that lead to hyperglycemia, glucose intolerance, hypoinsulinemia and low glucose-stimulated insulin release. Islets cultured from the short-telomere mice also have insulin-secreting defects.

To determine why the beta cells of short-telomere mice are dysfunctional, the Armanios team analyzed cultures of these cells. They found that the cells have defects in mitochondrial polarization and calcium ion (Ca2+) membrane transport, high levels of 53BP1 foci (a marker of DNA damage) and low proliferation rates and high levels of p16INK4a transcripts (both markers of senescence). A microarray analysis identified 1,153 downregulated and 782 upregulated genes in Terc-/- B6J mice. Many of the genes function in insulin secretion pathways, including signal transduction, Ca2+ and K+ transport, cell cycle and stress response, substantiating the correlation between short telomeres and beta cell dysfunction.

Short telomeres exacerbate type 2 diabetes in mice

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CAST/EiJ (above) with short telomeres and short-telomere B6.Cg-Terctm1Rdp/J mice (below) have normal beta cell mass, size, number, and insulin content but exhibit beta cell dysfunctions that lead to hyperglycemia, glucose intolerance, hypoinsulinemia, and low glucose-stimulated insulin release.

Having established that short telomeres cause beta cell dysfunction, Armanios and her team wondered if they would exacerbate the diabetes severity in C57BL/6-Ins2Akita/J ("Akita", 003548) mice, in which insulin 2 mis-folding causes diabetes and ER stress. They generated short-telomere Terc-/- Akita mice and found that they are more hypoinsulinemic and glucose-intolerant than wild-type Akita mice. However, in contrast to the wild-type Akita mice, their glucose intolerance is accompanied by a loss of beta cell mass and number.



People with short telomeres appear to be at risk for type 2 diabetes

People with TERC mutations have short telomeres and exhibit degeneration of highly proliferative tissues, such as the skin, mucosa and bone marrow. This degeneration is characteristic of dyskeratosis congenita (DC), a disease that manifests as progressive organ dysfunction and premature aging and death. Armanios and colleagues found evidence that people with DC have a high risk of developing diabetes, corroborating the association between short telomeres and diabetes susceptibility in mice.

In summary, the Armanios team produced compelling evidence that mice with short telomeres have an increased susceptibility to and more severe diabetes than controls. They also found evidence that the same relationship exists in people. The association between telomere-shortening and increased diabetes susceptibility with age may lead to earlier identification, the ability to prevent, and more effective treatments for diabetes and other age-related diseases.

Reference

Guo N, Parry EM, Li LS, Kembou F, Lauder N, Hussain MA, Berggren PO, Armanios M. 2011. Short telomeres compromise β-cell signaling and survival. PLoS One 6:e17858.