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SAN DIEGO, Aug. 25, 2019 鈥� For years, scientists have been trying to solve a medical mystery: Why do people with type 1 or type 2 diabetes have an increased risk of developing some forms of cancer? Today, researchers report a possible explanation for this double whammy. They found that DNA sustains more damage and gets fixed less often when blood sugar levels are high compared to when blood sugar is at a normal, healthy level, thereby increasing one鈥檚 cancer risk.

The researchers will present their results at the American Chemical 中国365bet中文官网 (ACS) Fall 2019 National Meeting & Exposition. ACS, the world鈥檚 largest scientific society, is holding the meeting here through Thursday. It features more than 9,500 presentations on a wide range of science topics.

鈥淚t鈥檚 been known for a long time that people with diabetes have as much as a 2.5-fold increased risk for certain cancers,鈥� says John Termini, Ph.D., who is presenting the work at the meeting. These cancers include ovarian, breast, kidney and others. 鈥淎s the incidence of diabetes continues to rise, the cancer rate will likely increase, as well.鈥�

Scientists have suspected that the elevated cancer risk for diabetics arises from hormonal dysregulation. 鈥淚n people with type 2 diabetes, their insulin is not effectively carrying glucose into cells,鈥� Termini explains. 鈥淪o the pancreas makes more and more insulin, and they get what鈥檚 called hyperinsulinemia.鈥� In addition to controlling blood glucose levels, the hormone insulin can stimulate cell growth, possibly leading to cancer. Also, most people with type 2 diabetes are overweight, and their excess fat tissue produces higher levels of adipokines than those at a healthy weight. These hormones promote chronic inflammation, which is linked to cancer. 鈥淭he most common idea is that the increased cancer risk has to do with hormones,鈥� Termini says. 鈥淭hat鈥檚 probably part of it, but there hasn鈥檛 been a lot of solid evidence.鈥�

Termini, who is at City of Hope, a research and treatment center for cancer and diabetes, had a different idea. He wondered if the elevated blood glucose levels seen in diabetes could harm DNA, making the genome unstable, which could lead to cancer. So Termini and colleagues looked for a specific type of damage in the form of chemically modified DNA bases, known as adducts, in tissue culture and rodent models of diabetes. Indeed, they found a DNA adduct, called N²-(1-carboxyethyl)-2鈥�-deoxyguanosine, or CEdG, that occurred more frequently in the diabetic models than in normal cells or mice. What鈥檚 more, high glucose levels interfered with the cells鈥� process for fixing it. 鈥淓xposure to high glucose levels leads to both DNA adducts and the suppression of their repair, which in combination could cause genome instability and cancer,鈥� Termini says.

Recently, Termini and colleagues completed a clinical study that measured the levels of CEdG, as well as its counterpart in RNA (CEG), in people with type 2 diabetes. As in mice, people with diabetes had significantly higher levels of both CEdG and CEG than people without the disease.

But the team didn鈥檛 stop there. They wanted to determine the molecular reasons why the adducts weren鈥檛 being fixed properly by the cells. They identified two proteins that appear to be involved: the transcription factor HIF1伪 and the signaling protein mTORC1, which both show less activity in diabetes. HIF1伪 activates several genes involved in the repair process. 鈥淲e found that if we stabilize HIF1伪 in a high-glucose environment, we increase DNA repair and reduce DNA damage,鈥� Termini says. 鈥淎nd mTORC1 actually controls HIF1伪, so if you stimulate mTORC1, you stimulate HIF1伪.鈥�

According to Termini, several drugs that stimulate HIF1伪 or mTORC1 already exist. The researchers plan to see if these drugs decrease cancer risk in diabetic animal models, and if so, they will test them in humans. Termini notes that metformin, a common diabetes medication that helps lower blood glucose levels, also stimulates DNA repair. 鈥淲e鈥檙e looking at testing metformin in combination with drugs that specifically stabilize HIF1伪 or enhance mTORC1 signaling in diabetic animal models,鈥� he says. In the meantime, a more immediate way for diabetics to reduce their cancer risk could be better control of their blood sugar. 鈥淭hat sounds like such an easy solution, but it鈥檚 extremely difficult for most people to maintain glycemic control,鈥� Termini says.

The researchers acknowledge support and funding from the .

The American Chemical 中国365bet中文官网, the world鈥檚 largest scientific society, is a not-for-profit organization chartered by the U.S. Congress. ACS is a global leader in providing access to chemistry-related information and research through its multiple databases, peer-reviewed journals and scientific conferences. ACS does not conduct research, but publishes and publicizes peer-reviewed scientific studies. Its main offices are in Washington, D.C., and Columbus, Ohio.