High blood sugar levels can cause greater DNA damage and increase the risk of developing cancer, says study
It seems researchers have now found a possible answer to the long-pending question: Why do people with type 1 or type 2 diabetes have an increased risk of developing some forms of cancer?
According to their findings, DNA sustains more damage and gets fixed less often when blood sugar levels are high as compared to when blood sugar is at a normal, healthy level, thereby increasing one's cancer risk.
"Higher-than-normal blood sugar levels are linked to heightened DNA damage that is fixed less often, which could explain why people with diabetes have an increased risk of developing cancer," according to the results of ongoing research led by City of Hope, California, a research and treatment center for cancer and diabetes. The findings were presented at the American Chemical Society (ACS) Fall 2019 National Meeting and Exposition on August 25.
The link between diabetes and certain cancers may be due, in part, to shared risk factors such as aging, obesity, increased inflammation, dietary choices, and inactive lifestyles. According to Dr. John Termini, a professor in the Department of Molecular Medicine at City of Hope, who presented the findings, it has been long known that people with type 2 diabetes - which is the most common form - have as much as a 2.5-fold increased risk for certain cancers such as liver or pancreatic cancer. They also run a higher-than-normal risk of developing colon, bladder, and breast cancer. Diabetic women with breast cancer have a higher death rate than women with breast cancer alone. "As the incidence of diabetes continues to rise, the cancer rate will likely increase, as well," Dr. Termini stated in the findings.
The research team says that what is ironical is that some cancer treatments increase the risk of diabetes, which, in turn, increases the risk of cancer.
"Conversely, some forms of chemotherapy induce insulin resistance, bringing on diabetic symptoms. Immunotherapy, one of the most exciting advances in cancer treatment, may bring on the less common type 1 diabetes, which is essentially an autoimmune disorder. With immunotherapy, the body's immune system is 'unleashed,' and it may attack critical insulin-producing cells in the pancreas," the findings state.
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Scientists, so far, have suspected that the increased cancer risk for diabetes is due to hormonal dysregulation. The researchers explain that in people with type 2 diabetes, their insulin is not effectively carrying glucose into cells. Accordingly, the pancreas makes more and more insulin, and they get what is known as 'hyperinsulinemia.' In addition to controlling blood glucose levels, the hormone insulin can stimulate cell growth, possibly leading to cancer.
"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," they add.
The research team, however, says while the common idea is that the increased cancer risk has to do with hormones, there has not been a lot of 'solid' evidence.
For their study, the team decided to explore another idea: if the elevated blood glucose levels seen in diabetes could harm DNA, making the genome unstable, which could lead to cancer.
The team showed, in tissue culture and diabetic mouse models, that elevated glucose increased the presence of DNA adducts - which are chemical modifications of the DNA. Specifically, they found that a DNA adduct called "N2-(1-carboxyethyl)-2'-deoxyguanosine, or CEdG" occurred more frequently in diabetic models than in normal cells or mice. Moreover, high glucose levels increased “DNA strand breaks” and interfered with DNA repair, which is required for the removal of the adduct CEdG.
The result is genome instability that could cause cancer, the researchers conclude.
"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," the findings state.
To further validate their results, the research team completed a clinical study that measured the levels of CEdG, as well as its counterpart in RNA (CEG), in people with type 2 diabetes. They found that as in mice, people with diabetes had significantly higher levels of both CEdG and CEG than people without the disease. "Genomic instability can cause and promote the progression of cancer," the findings state.
But the team did not stop there. They wanted to determine the reasons why the adducts were not being fixed properly by the cells and identified two proteins that appear to be involved. The researchers also found that if they stabilized one of the proteins, they could increase DNA repair and reduce DNA damage.
The next phase of the research would be to examine if existing drugs can decrease cancer risk in diabetic animal models, and if so, the researchers will test them in humans.
The researchers further say that metformin - a common diabetes medication that helps lower blood glucose levels - also stimulates DNA repair. There is proof that suggests diabetics who take metformin, may be less likely to develop cancer. Accordingly, the team is looking at testing metformin in combination with drugs that can specifically stabilize the protein identified in their current study.
"In the meantime, a more immediate way for people with diabetes to reduce their cancer risk could be better control of their blood sugar. That sounds like such an easy solution, but it's tough for most people to maintain glycemic control," says Dr. Termini.