DUARTE, Calif. -- 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 ongoing research led by City of Hope.
Genomic instability can cause and promote the progression of cancer, said John Termini, Ph.D., professor in the Department of Molecular Medicine at City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases.
"As the incidence of diabetes continues to rise, the cancer rate will likely increase as well," Termini said. "In an ironic twist of fate, some cancer treatments increase the risk of diabetes, which in turn increases the risk of cancer. The destructive machine feeds itself. That's why City of Hope - best known for its leading-edge cancer therapies - has also taken on the challenge of finding a cure for diabetes."
The diabetes and cancer link has been discussed in scientific circles for years; however, researchers are still searching for the disease-causing catalyst. We may be one step closer to finding it. Termini will present his ongoing research at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition on Aug. 25. He will be in Gallery 1 at the Omni San Diego Hotel at 10:35 a.m. He will elaborate on early findings at an ACS press conference on Aug. 26 at 3 p.m. (mezzanine level of the San Diego Convention Center, room 14B).
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. People with type 2 diabetes (the most common form) are 2.5 times more likely to develop 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 mortality rate than women with breast cancer alone.
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.
Termini and his colleagues showed, in tissue culture and diabetic mouse models, that elevated glucose increased the presence of DNA adducts - 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 removal of CEdG. The result is genome instability that could cause cancer.
Recently, Termini and colleagues completed a clinical study that measured the levels of CEdG and its RNA counterpart (CEG) in people with type 2 diabetes. People with diabetes had significantly higher levels of both CEdG and CEG than people without the disease.
The scientists identified two proteins that appear to be involved: transcription factor HIF1α and signaling protein mTORC1, both of which are less active in people with diabetes. HIF1α activates several genes involved in the repair process. The scientists found that if they stabilized HIF1α in a high-glucose environment, they increased DNA repair and reduce DNA damage. mTORC1 controls HIF1α, so if mTORC1 is stimulated, then HIF1α is stimulated, Termini said.
In theory, a medication that lowers blood sugar levels in diabetics could also potentially fight cancer by "starving" malignant cells to death. Evidence exists showing that diabetics who take metformin, the No. 1 drug for treating type 2 diabetes, may be less likely to develop cancer. Moreover, if they contract cancer, they are significantly less likely to die from it.
"Metformin helps lower blood glucose levels and stimulates DNA repair," Termini said. "We're looking to test metformin in combination with drugs that specifically stabilize HIF1α or enhance mTORC1 signaling in diabetic animal models."
These studies were supported by the National Institutes of Health. The ACS is the world's largest scientific society. This year's ACS National Meeting & Exposition from Aug. 25-29 in San Diego features more than 9,500 presentations on a wide range of science topics.
City of Hope, with support from The Wanek Family Project for Type 1 Diabetes, is committed to designing highly effective treatments, preventions and cures for patients coping with type 1 diabetes. Building on the pivotal breakthroughs made in precision medicine over the past few years, City of Hope experts are creating powerful new approaches to treating type 1 diabetes -- approaches that will move beyond just managing the disease to curing it.
About City of Hope
City of Hope is an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as one of only 49 comprehensive cancer centers, the highest recognition bestowed by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network, with research and treatment protocols that advance care throughout the world. City of Hope's main campus is in Duarte, California, just northeast of Los Angeles, with additional locations throughout Southern California. It is ranked as one of "America's Best Hospitals" in cancer by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation, diabetes and numerous breakthrough cancer drugs based on technology developed at the institution. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.