Why do people with diabetes have an increased risk of cancer? It’s a medical mystery that scientists have been trying to solve for years…
People with type 1 or type 2 diabetes have an increased risk of developing some forms of cancer and now there’s a possible explanation.
Research has 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’s cancer risk.
Diabetics have 2,5-fold increased risk for certain cancers
“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,” says John Termini, Ph.D., who 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.”
Insulin can stimulate cell growth, possibly leading to cancer
Scientists have suspected that the elevated cancer risk for diabetics arises from hormonal dysregulation.
“In people with type 2 diabetes, their insulin is not effectively carrying glucose into cells,” Termini explains. “So the pancreas makes more and more insulin, and they get what’s called hyperinsulinemia.”
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.
“The most common idea is that the increased cancer risk has to do with hormones,” Termini says. “That’s probably part of it, but there hasn’t been a lot of solid evidence.”
How diabetes affects DNA
Termini 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′-deoxyguanosine, or CEdG, that occurred more frequently in the diabetic models than in normal cells or mice. What’s more, high glucose levels interfered with the cells’ process for fixing it. “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 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’t stop there. They wanted to determine the molecular reasons why the adducts weren’t being fixed properly by the cells. They identified two proteins that appear to be involved: the transcription factor HIF1? and the signalling protein mTORC1, which both show less activity in diabetes. HIF1? activates several genes involved in the repair process.
“We found that if we stabilise HIF1? in a high-glucose environment, we increase DNA repair and reduce DNA damage,” Termini says. “And mTORC1 actually controls HIF1?, so if you stimulate mTORC1, you stimulate HIF1?.”
Common diabetes medication stimulates DNA repair
According to Termini, several drugs that stimulate HIF1? 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.
“We’re looking at testing metformin in combination with drugs that specifically stabilize HIF1? or enhance mTORC1 signalling in diabetic animal models,” he says.
In the meantime, a more immediate way for diabetics to reduce their cancer risk could be better control of their blood sugar.
“That sounds like such an easy solution, but it’s extremely difficult for most people to maintain glycaemic control,” Termini says.
Source: American Chemical Society via www.sciencedaily.com
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