Diabetes Forecast

Diabetes and Cancer: What's the Connection?

By Erika Gebel, PhD ,

When Michelle Hall was diagnosed with breast cancer two years ago, she was shocked. "The standing joke in the family was that I came from a long line of stocky French women who lived forever," says Hall, 62, of Salem, N.H. "We had no breast cancer in the family." Hall had been diagnosed with type 2 diabetes in 2001, so she would have special challenges while facing down cancer.

As diseases, cancer and diabetes seem a world away from each other. Yet, numerous studies suggest the conditions are linked. People with diabetes are more likely to be diagnosed with cancer than those without diabetes, but why remains unclear.

Scientists are still trying to answer even the most basic questions: Does diabetes cause cancer? If so, what kinds of cancer and how? As the interplay between diabetes and cancer becomes clearer, researchers hope to gain an edge against both diseases.

Common Risk Factors

The link between diabetes and cancer may be partially explained by risk factors that underlie and raise the risk of both diseases.
Sex: Overall, men are more likely to develop both cancer and type 2 diabetes than women.
Weight: Overweight and obese people are more likely to develop cancer than lean people. The association between type 2 diabetes and weight is also well established. While it's clear that losing weight reduces the risk for type 2 diabetes, less is known about whether weight loss combats cancer.
Diet: Eating patterns that are thought to help prevent and treat type 2 diabetes—limited red and processed meats and abundant vegetables, fruits, and whole grains—are also associated with a lower risk for many types of cancer.
Exercise: Studies show that regular physical activity lowers the risk of developing several types of cancer. Likewise, 30 minutes of moderate-intensity exercise per day can reduce the risk for type 2 diabetes by 25 to 36 percent.
Smoking: Tobacco smoking is associated with lung and several other types of cancer. It's also a risk factor for type 2 diabetes and some diabetes complications.

Cause and Effect?

The diabetes-cancer link varies among cancer types, which may give researchers some insight into what lies behind the association. Cancers of the liver, pancreas, and endometrium (uterus lining) are twice as likely to occur in people with diabetes as those without the disease, while the link between colon, rectal, breast, and bladder cancers and diabetes is only half as strong. Other cancers either aren't associated with diabetes or there isn't enough evidence to say one way or the other. One exception to the rule is prostate cancer; the data suggest that diabetes may protect against prostate cancer, perhaps because it's associated with lower testosterone levels.

Most studies exploring the link between cancer and diabetes have focused on type 2. "The evidence for type 2 is strong," according to Derek LeRoith, MD, PhD, an endocrinologist and professor at Mount Sinai Medical Center in New York City. "With type 1, it's unclear." He says this is because few studies have looked at type 1 specifically, and they have tended to be small and include mostly young people, who are less likely to develop cancer in the first place.

Even the many large studies done in type 2 can't say definitively whether diabetes causes cancer. Researchers can't rule out that a trait, such as obesity, raises the risk for both cancer and diabetes. That would mean the two conditions would be likely to occur together, but without one disease causing the other ("Common Risk Factors," below).

Insulin & Co.

If researchers can prove that diabetes contributes to cancer, the next question will be: How? The three most obvious means by which diabetes could influence the development and spread of cancer are insulin, blood glucose, and inflammation. "Probably all play a role," says LeRoith.

Recent studies have failed to find a connection between insulin taken as a medication and cancer. However, some research suggests that when the body itself makes too much insulin, the risk for cancer goes up. "For cancer, while not definitively proven at this point, it is believed that high insulin is the main culprit," says Edward Giovannucci, MD, ScD, professor of nutrition and epidemiology at Harvard University.

People with type 2 diabetes are insulin resistant, which drives up the body's production of insulin, sometimes for years, while the disease progresses. "High insulin levels in individuals are associated with higher [cancer] risk," says Giovannucci. "In animal models, high insulin is a growth factor for tumors." It's unclear whether extremely high levels of insulin received through a pump or needle would also drive up cancer risk.

The pancreas makes insulin, which is then sent straight to the liver, so these two organs see particularly high insulin levels. Some experts argue that this is why these organs are particularly susceptible to cancer in people with type 2 diabetes. High insulin levels increase the production of sex hormones by the ovaries, which may be linked to cancers of the ovaries, uterus, and breast.

One piece of evidence that suggests that insulin affects cancer cells is that the cells have insulin receptors on their surfaces. A 2008 study in Cancer Research found that people with many insulin receptors on their breast cancer cells have a worse prognosis than those with sparse receptors, though more research is needed for confirmation. When a cancer cell captures insulin, Giovannucci says, it's a double whammy: Insulin encourages cell growth and discourages cell death, bolstering the proliferation of cancer cells. At the same time, studies suggest that insulin makes cancer cells more invasive and more likely to spread.

Though insulin is the main suspect, researchers are also exploring whether high blood glucose may contribute to cancer. One trait of cancer cells is that they are adept at absorbing glucose from the blood with no need for insulin. Since cancer runs on glucose, high blood glucose levels may help fuel the growth of cancer cells.

A third suspect is inflammation. People with diabetes, as well as those who are obese, show signs of chronic inflammation, a state defined by elevated levels of certain molecules in the blood such as C-reactive protein. Some of these same molecules have been linked to certain types of cancer, suggesting that inflammation may connect diabetes, obesity, and cancer.

Diabetes Medications and Cancer Risk

Some studies have found tenuous links between diabetes medications and cancer, but none definitively cause cancer.
Metformin: Research suggests that this first-line type 2 diabetes medication lowers the risk of developing cancer and improves survival in people with cancer. An ongoing clinical trial is testing metformin as a breast cancer treatment in people without type 2 diabetes.
TZDs: Some studies suggest that thiazolidinediones lower the risk for certain forms of cancer. However, in 2011 the Food and Drug Administration added a warning to pioglitazone (Actos) labels warning users of the potential for bladder cancer.
Incretin therapies: None of these medications have been linked to cancer in humans, but liraglutide (Victoza) increased thyroid cancer in rats. This class of medications is relatively new, so long-term side effects and risks need further study.
Insulin: Scientists suspect that the link between cancer and diabetes is insulin levels that are higher than normal. Even so, studies have failed to find consistent associations between cancer and insulin taken as a medication.

Prevention and Treatment

People with diabetes have an increased risk of dying from cancer compared with those without the disease. It's unclear why this is true. A 2001 study in Diabetes found that women with diabetes were less likely to be screened for breast cancer than those without diabetes; other studies have found similar results. Experts attribute this in part to time constraints during office visits dedicated to diabetes care. This may be one reason why cancer is deadlier in people with diabetes. Early detection dramatically improves chances of cancer survival.

Today, there are many effective treatments for cancer, but some approaches can affect blood glucose levels. "Some [cancer] therapies can make [blood glucose control] worse," says LeRoith. The answer, he says, is not to limit cancer medications but to "just treat the diabetes more intensively." Another issue is that certain cancer medications can worsen diabetes complications, such as kidney, nerve, and heart disease. For example, cisplatin, a widely used chemotherapy medication, can damage nerves and kidneys.

Susan Gimilaro, 52, of Bedford, N.H., has type 1 diabetes and struggled to control her blood glucose while receiving chemotherapy for multiple myeloma, a blood cancer. "It got up in the 300s," she says, for the 24 hours following a dose of dexamethasone, a glucocorticoid. This steroid is used to control side effects during chemotherapy and is known to worsen blood glucose control. People already using insulin sometimes require two to three times their usual dose when undergoing the steroid therapy. "Through trial and error I found a good way to control my blood glucose levels," Gimilaro says, which involved increasing her insulin doses by 20 percent on the day following steroid treatment. For people with type 2 diabetes, oral medications may not be adequate for blood glucose control during glucocorticoid treatment, and they may need to start insulin treatment.

Some people need dietary supplements to get adequate nutrition while undergoing chemotherapy, which can lead to high blood glucose levels. Others might experience nausea or vomiting, which may put them at risk for low blood glucose. Doctors may need to adjust diabetes medication doses in these situations.

Michelle Hall knew that chemotherapy could worsen her blood glucose levels and worked with her doctor to devise a plan to minimize her use of steroids by taking antinausea medications to manage some side effects. It worked, and she kept her blood glucose under control throughout treatment. Hall urges people with both diabetes and cancer to "be informed. You have to take responsibility and … be your own best advocate."



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