How diabetes can increase the risk of cancer

Scientists have been trying for years to solve a medical mystery: why do people with type 1 or type 2 diabetes have an increased risk of developing certain forms of cancer? Today, researchers report a possible explanation for this double blow. They found that DNA suffers more damage and attaches less often when blood glucose is high than when blood glucose is normal and healthy, which increases the risk of cancer.

The researchers will present their findings at the 2019 fall national meeting and exhibition of the American Chemical Society (ACS).

"It has long been known that people with diabetes are up to 2.5 times more likely to get certain cancers," said John Termini, Ph.D., who presented the work at the meeting. These cancers include ovarian, breast, kidney and others. "With the incidence of diabetes steadily increasing, the cancer rate will likely increase as well."

Scientists suspect that the high risk of cancer in diabetics comes from hormonal dysregulation. "In people with type 2 diabetes, their insulin does not carry glucose efficiently into the cells," says Termini. "So, the pancreas produces more and more insulin and gets what's called hyperinsulinemia." In addition to controlling blood sugar, the hormone insulin can stimulate cell growth, possibly leading to cancer. In addition, most type 2 diabetics are overweight and their excess adipose tissue produces higher adipokine levels than those with a healthy weight. These hormones promote chronic inflammation, related to cancer. "The most common idea is that the increased risk of cancer is hormone-related," Termini said. "That's probably part of it, but there was not a lot of solid evidence."

Termini, who is in City of Hope, a center for cancer and diabetes research and treatment, had a different idea. He wondered if the high blood sugar levels seen in diabetes could damage the DNA and make the genome unstable, which could lead to cancer. Thus, Termini and his colleagues sought a specific type of damage in the form of chemically modified DNA bases, called adducts, in tissue culture models and diabetes in rodents. Indeed, they found a DNA adduct, called NOT^2-(1-carboxyethyl) -2-deoxyguanosine, or CEdG, appeared more frequently in diabetic models than in normal cells or mice. In addition, high blood glucose interfered with the process of cell attachment. "Exposure to high glucose levels results in both DNA adducts and suppression of their repair, which, in combination, could cause genome instability and cancer" said Termini.

Termini and colleagues recently completed a clinical study measuring CEG levels, as well as its RNA homologue (CEG), in people with type 2 diabetes. As in mice, diabetics had significantly higher levels of CEG and CEG that non-affected.

But the team did not stop there. They wanted to determine the molecular reasons why adducts were not properly fixed by the cells. They identified two proteins that seem to be involved: the HIF1α transcription factor and the mTORC1 signaling protein, both of which have less activity in diabetes. HIF1α activates several genes involved in the repair process. "We found that if we stabilize HIF1α in a glucose-rich environment, we increase DNA repair and reduce DNA damage," Termini said. "And mTORC1 actually controls HIF1α, so if you stimulate mTORC1, you stimulate HIF1α."

According to Termini, several HIF1α or mTORC1 stimulating drugs already exist. Researchers are looking to see if these drugs lower the risk of cancer in diabetic animal models and, if so, they will test them in humans. Termini notes that metformin, a common diabetes medicine that helps reduce blood sugar, also stimulates DNA repair. "We are considering testing metformin in combination with drugs that specifically stabilize HIF1α or improve mTORC1 signaling in diabetic animal models," he said. In the meantime, a more immediate way for diabetics to reduce their risk of cancer might be better control of their blood sugar levels. "It seems like an easy solution, but it's extremely difficult for most people to maintain control of their blood glucose levels," says Termini.