Researchers have uncovered that DNA incurs more damage that is less fixable when faced with high blood sugar levels, which increases the risk of cancer in people with diabetes. These results were presented at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition.
“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,” said John Termini, Ph.D., in a press release about the story. Dr. Termini is presenting the work at the meeting. “These cancers include ovarian, breast, kidney and others. “As the incidence of diabetes continues to rise, the cancer rate will likely increase, as well.”
Scientists had previously hypothesized that diabetes is linked to a higher risk of cancer due to hormonal dysfunction. “The most common idea is that the increased cancer risk has to do with hormones,” explained Termini. “That’s probably part of it, but there hasn’t been a lot of solid evidence.”
Identifying the Culprit
Termini, of City of Hope, a research and treatment center for cancer and diabetes, has a different line of thinking. He believes that elevated blood sugar levels seen in diabetes could harm DNA, making the genome unstable, which could lead to cancer. Termini and his colleagues canvassed for a specific type of DNA damage, called adducts, in diabetic animal-model tissue. Subsequently, they identified a DNA adduct called N2-(1-carboxyethyl)-2′-deoxyguanosine, or CEdG, that occurred more frequently in the diabetic models than in normal cells. “Exposure to high glucose levels leads to both DNA adducts and the suppression of their repair, which in combination could cause genome instability and cancer,” Termini continued.
Recently, Termini and colleagues conducted a clinical study that measured the levels of CEdG, as well as its counterpart in RNA (CEG), in people with type 2 diabetes. Their results showed that people with diabetes possess appreciably higher levels of both CEdG and CEG than people without the disease. Moreover, the team sought determine the molecular reasons why the adducts weren’t being fixed properly by the cells. They discerned two proteins that appear to be involved: the transcription factor HIF1α and the signaling protein mTORC1, which both show less activity in diabetes. HIF1α activates several genes involved in the repair process. “We found that if we stabilize HIF1α in a high-glucose environment, we increase DNA repair and reduce DNA damage,” Termini said. “And mTORC1 actually controls HIF1α, so if you stimulate mTORC1, you stimulate HIF1α.”
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The researchers noted that several drugs that stimulate HIF1α or mTORC1 already exist, naming the common diabetes drug metformin as one example. “We’re looking at testing metformin in combination with drugs that specifically stabilize HIF1α or enhance mTORC1 signaling in diabetic animal models,” Termini added.
While a more immediate strategy for diabetics to reduce their cancer risk could be better control of their blood sugar, Termini cautioned that approach is easier said than done. “That sounds like such an easy solution, but it’s extremely difficult for most people to maintain glycemic control.”
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