Why do people with type 1 or type 2 diabetes have an increased risk of developing some forms of cancer?


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’s cancer risk.

The researchers will present their results at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition.

“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.”

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.”

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′-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 HIF1α and the signaling protein mTORC1, which both show less activity in diabetes.

HIF1α activates several genes involved in the repair process.

“We found that if we stabilize HIF1α in a high-glucose environment, we increase DNA repair and reduce DNA damage,” Termini says. “And mTORC1 actually controls HIF1α, so if you stimulate mTORC1, you stimulate HIF1α.”

According to Termini, several drugs that stimulate HIF1α 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 HIF1α or enhance mTORC1 signaling 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 glycemic control,” Termini says.

More information: Hyperglycemia induced DNA damage and inhibition of DNA repair – a potential mechanistic link between diabetes and increased cancer risk, the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition. ACS.

Men and women with type 2 diabetes had a 32% and 64% greater risk of developing cancer, respectively, compared with their peers in the general population, in a large study in Shanghai, China.

The researchers analyzed data from more than 400,000 adults with type 2 diabetes who had close to 8500 incident cancers during an average 3-year follow-up.

Men with type 2 diabetes were more likely to have 11 types of cancer than other men of the same age, whereas women with type 2 diabetes were more likely to have 13 types of cancer than other women of the same age.    

The findings imply that clinicians who treat type 2 diabetes may need to perform more physical examinations and pay closer attention to managing a patient’s other risk factors for cancer, senior author Bin Cui, PhD, Shanghai Jiao Tong University, China, told Medscape Medical News in an email.

“We suggest that establishing strategies for regular cancer-specific screening and prevention care among patients with [type 2 diabetes] are necessary,” the group concludes.

The study by Jiying Qi, a master’s degree student at Shanghai Jiao Tong University, and colleagues was published online May 9 in the Journal of Diabetes.

Worldwide, an estimated 8.5% of the adult population (422 million people) have type 2 diabetes, and about a quarter of them (148 million; 10.9% of the population) live in China.

Meanwhile, cancer is the leading cause of death in China.

Only some previous studies have found that type 2 diabetes is associated with an increased risk of cancer.

It is important to clarify the risk of cancer among patients with diabetes, especially in China where so many have type 2 diabetes, yet there have been few published studies of the relationship between the diseases in this population.  

To investigate this, the authors obtained data from a centralized database from 60 hospitals in Shanghai, which was set up in 2013.

They identified 410,191 patients aged 20 to 99 years who had been treated for type 2 diabetes in these hospitals during July 2013 to December 2016.

They further identified the new incidence of 23 common types of cancer in these patients, with follow-up through December 2017. The patients were a mean age of 61.8 years and were followed for a mean 3.2 years. 

11 Types of Cancer in Men, 13 Types in Women

Among 204,080 men with type 2 diabetes, there were 4312 incident cases of cancer.

Men with type 2 diabetes had a significantly higher risk of prostate cancer(standardized incidence ratio [SIR], 1.86) compared with men in the general population.

Men with diabetes also had a significantly higher incidence of leukemia (SIR, 1.55), skin cancer (1.55), thyroid cancer (1.52), lymphoma (1.48), kidney cancer (1.45), liver cancer (1.39), pancreatic cancer (1.35), lung cancer (1.27), colorectal cancer (1.22), and stomach cancer (1.16) compared with their peers without diabetes.

On the other hand, men with type 2 diabetes had a significantly lower risk of esophageal cancer (SIR, 0.71).

Moreover, the risk of cancers of the nasopharynx, small intestine, gallbladder, larynx, bladder, or genital sites other than the prostate, were similar among men with or without type 2 diabetes. 

Among the 206,111 women with diabetes, there were 4173 incident cases of cancer.

Women with type 2 diabetes had a significantly higher incidence of cancer of the liver (SIR, 2.13), esophagus (2.07), thyroid (1.95), lung (1.84), and pancreas (1.61), as well as lymphoma (1.59), uterine cancer (1.58), colorectal cancer (1.51), leukemia (1.50), breast cancer (1.48), cervical cancer (1.38), or stomach cancer (1.30) compared with women without diabetes.

Women with type 2 diabetes also had a significantly higher risk of nasopharynx cancer (SIR, 2.33), although this type of cancer was very rare, occurring in only 15 women.

On the other hand, women with type 2 diabetes had a significantly decreased risk of gallbladder cancer (SIR, 0.77) compared with their peers in the general population.

And risks of cancer of the small intestine, larynx, skin, kidney, bladder, or ovary or other genital cancers were similar in women with or without diabetes. 

Future Studies Needed

The findings of an increased risk of stomach, colorectal, liver, pancreatic, lung, and thyroid cancer, as well as lymphoma and leukemia in adults with type 2 diabetes are in line with results of previous studies.

For example, prior studies have also shown that women with type 2 diabetes have a higher risk of breast, cervical, and uterine cancer.

Similarly, the elevated rate of prostate cancer among men with diabetes has been seen in previous studies in China but contrasts with studies in Western populations.

“There may be differences in the exposure to risk factors, such as tobacco smoking, obesity, and genetic background, for populations from different geographical areas, which may also contribute to the inconsistent results,” Qi and colleagues write.

The current study was not designed to consider obesity or body mass index as risk factors for cancer, Cui told Medscape Medical News.

However, because the current results were generally consistent with most past studies, “it is unlikely that these [confounders] explain the entire association between [type 2 diabetes] and cancer risk,” the authors write. 

Nevertheless, “future studies are needed to distinguish the effects of [type 2 diabetes] from those of common risk factors,” Qi and colleagues conclude.

The study was funded by grants from the National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Education Commission-Gaofeng Clinical Medicine, and Shanghai Sailing Program. 


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