John Termini, PhD, professor in the Department of Molecular Medicine, and colleagues explored the relationship between diabetes and cancer and challenged the previous hypothesis that this more than twofold increase was exclusively due to a hormonal dysregulation seen in diabetic patients. According to Dr. Termini, “It’s been known for a long time that people with diabetes have as much as a 2.5-fold increased risk for certain cancers.” He added, “These cancers include ovarian, breast, kidney and others and as the incidence of diabetes continues to rise, the cancer rate will likely increase, as well.” 

Funded through the National Institutes of Health, the team conducted a clinical study to determine whether the increased blood glucose could cause altered DNA and subsequently make cells more vulnerable to damage, resulting in genomic instability and increased risk of cancer.  The study examined tissue cultures and diabetic mice for the presence of adducts (a specific type of damage in the form of chemically modified DNA bases). The researchers discovered that a DNA adduct called N2-(1-carboxyethyl)-2’-deoxyguanosine, or CEdG, was found more frequently in diabetic mice than in normal cells or mice. 

Even more compelling is that when the researchers looked at why cells were not repairing the adducts, they found that two normally occurring proteins (the signaling protein mTORC1 and the transcription factor HIF-alpha) were involved. Both the specific transcription factor HIF-alpha and the signaling protein mTORC1are less active in diabetic patients compared with individuals without diabetes. These proteins can be influenced by drugs that are currently available but have not yet been tested in human clinical trials, however. Dr. Termini and his team plan to conduct animal trials, and if these are successful, to carry out trials with humans. “We found that if we stabilize HIF-alpha in a high-glucose environment, we increase DNA repair and reduce DNA damage,” Dr. Termini said. “And mTORC1 actually controls HIF1-alpha, so if you stimulate mTORC1, you stimulate HIF1-alpha.” 

Until the drug trials are completed, the team suggests promoting prevention through efforts to manage and lower blood glucose with medications such as metformin. “We’re looking at testing metformin in combination with drugs that specifically stabilize HIF1-alpha or enhance mTORC1 signaling in diabetic animal models,” Dr. Termini said. “Until then, better glucose control would be advisable whether through lifestyle interventions, pharmacotherapy or both. That sounds like such an easy solution, but it’s extremely difficult for most people to maintain glycemic control,” he  concluded.

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