The Conundrum Continues: Possible Links Between Breast Cancer and Diabetes

A recent study published in September 2012 in the British Journal of Cancer suggests that having type 2 diabetes appears to give post-menopausal women a 27% higher risk of developing breast cancer. The link between obesity and breast cancer has been talked about and researched for quite some time, but this is one of the first recent studies to explore whether having type 2 diabetes affects breast cancer risk directly.

The study, conducted by researchers at the International Prevention Research Institute (i-PRI), in Lyon, France, did a comprehensive review of 40 separate studies into possible links between type 2 diabetes and breast cancer. Their data included more than 56,000 breast cancer cases from four continents.

President of i-PRI and lead author of the study, Peter Boyle, told the press "Our study found a significantly increased risk of breast cancer in women who had diabetes, which was restricted to those of post-menopausal age."

It is interesting to note that the study found no evidence to support such a link in women of pre-menopausal age, or those with type 1 diabetes.

While this news has gained a tremendous amount of recent media attention, this is not the first time this link has been suggested. As far back as June 2003 the Nurses’ Health Study identified 6,220 women with type 2 diabetes and 5,189 incident cases of invasive breast cancer. The study found that women with type 2 diabetes had a modestly elevated incidence of breast cancer compared with women without diabetes. These findings were independent of age, obesity, family history of breast cancer, history of benign breast disease, reproductive factors, physical activity, and alcohol consumption. In the 2003 study it was also noted that this association was apparent among postmenopausal women but not premenopausal women. In the Nurses’ Health Study, it was also found that the association was predominant among women with estrogen receptor-positive breast cancer.

Evidence linking diabetes and high insulin levels to certain cancers has grown stronger over the past several years

A growing body of evidence is finding that having diabetes or signs of insulin resistance may lead to an increased risk of certain cancers.

“The emerging trend is that the type 2 diabetes associated with high insulin levels is the biggest problem relating to cancer risk,” said Michael Pollak, M.D., a professor at the Department of Oncology and Director of the Cancer Prevention Research Unit at McGill University. But it’s not just type 2 diabetes, he added, this link is evident for everyone with prediabetes, which is a much larger group.

According to the Centers for Disease Control and Prevention, approximately 40 percent of Americans – 41 million people – are estimated to have prediabetes, a condition that increases the risk of developing diabetes. Hyperinsulinemia, too much insulin in the blood, is a sign of prediabetes. People can be unaware they have prediabetes for years before symptoms and rising glucose levels result in a diabetes diagnosis.

The hormonal changes spurred by high body fat may be leading to increased risk of cancer and type 2 diabetes. Hyperinsulinemia could also act independent of body fat to increase cancer risk. “We know that lots of tumors have insulin receptors and research suggests insulin plays an important role in cancer, but it does not have to be a direct link,” said Dr. Pollak. “There may be other areas that insulin could affect.” Yet insulin, which stimulates cell proliferation and growth, appears to be one of the key mediators.

Giving some perspective to the associated risks

The most dramatic increases in risk seen in people with type 2 diabetes:

• Liver cancer is about two-and-a-half times more common
  Pancreatic cancer is about 73 percent more common
• Endometrial cancer is about 60 to 100 percent more common

Additionally,

• Bladder cancer is about 43 percent more common
• Non-Hodgkin lymphoma is about 41 percent more common
• Colorectal cancer is about 29 percent more common

Colorectal and breast cancer are particularly worrisome since, although the increase in risk is not as great as for some other cancers, because these are among the most common cancers in the U.S., even a modest increase represents many additional cases of cancer.

The inflammation connection in a nutshell

We know now that heart disease, diabetes, Alzheimer's, stroke and cancer all have something in common—inflammation—but exactly what does this mean? Here is a basic overview: Let’s say you cut your fingertip with a dirty knife, bacteria from the blade enters the wound where they run into “sentinel” immune cells acting as watchdogs in the body. The cells are covered with sensitive receptors that recognize an invading cell, like a bacterium, and call for help.

That’s when the immune system swings into action. In this comparison, the signs of battle are visible from outside the body. We’ve all had this sort of inflammation at one time or another. The finger turns red, swollen, and warm; there may even be a little bit of pus. The inflammation is a sign our immune cells are responding aggressively to the infection. “From being harmless sentinel cells, they become specialized warriors,” says Mario Kratz, PhD, a researcher at the Fred Hutchinson Cancer Research Center in Seattle. “It’s a well-organized, cool process that tends to be strong—and limited in its time frame.”

What is supposed to happen is that once the invader is defeated, the active immune cells are replaced by passive guardians, ready for the next attack. Unfortunately, when it comes to chronic inflammation, this is not the case. With the help of a grant from the American Diabetes Association, Kratz is studying the links between inflammation and diabetes. In the past six or seven years, research in mice has demonstrated a strange phenomenon. In obese mice, scientists have found an unusually high concentration of immune cells in fat tissue. “It’s almost as if there was an infectious agent in fat tissue that triggers the same response as if you had cut your finger,” Kratz says.

Unlike an infected cut, however, a chronic, low-grade inflammation appears even when there’s no underlying infection and no sickness to prompt a typical immune response. “It’s associated particularly with obesity and seems to play a role in all of the major diseases—heart disease, diabetes, and certain cancers,” says Kratz.

It gets even more perplexing. The immune cells aren’t just watching; they’re activated, ready to take on an invader that isn’t there. Just as in humans, the obese mice with chronic inflammation were more likely to become insulin resistant.

These initial mouse experiments left a major question unanswered: Was inflammation causing the insulin resistance, or was it the other way around? To find out, researchers bred mice that lacked the ability to make certain immune cells. These mice wouldn’t survive long outside a sterile lab, but when they were fed a special diet designed to make them obese, they had no signs of inflammation—and no insulin resistance or diabetes. “That strongly suggests it’s the inflammation response that causes insulin resistance, not just the fat itself,” Kratz says. “It’s totally a paradigm shift. Now it seems pretty clear that inflammation plays a major role in the development of insulin resistance.”

It’s not all gloom and doom

Large studies of people with early signs of insulin resistance and inflammation have shown that lifestyle changes decrease both insulin resistance and markers of inflammation. For example, in the Diabetes Prevention Program, people targeted a 7% weight loss (14 pounds for someone who weighs 200 pounds) and 150 minutes/week of moderate physical activity. In the early years of the study, people in this program were 58% less likely to develop diabetes than people who just continued their usual lifestyle. Even after 10 years, those in the program were 34% less likely to develop diabetes. In addition to the decrease in insulin resistance that causes type 2 diabetes, CRP (C-reactive protein) a marker of inflammation that can be measured in the blood, was reduced in program participants, too.

The Mediterranean eating pattern is also consistently linked to lower levels of inflammation, and in several studies, it decreases insulin resistance and indicators of unhealthy blood glucose levels. This is an eating pattern that features an abundance of delicious vegetables and fruits, limited amounts of meat and a focus on healthy sources of fat (such as olives and olive oil).

Even when these changes come in middle age and beyond by people who have not been eating well or getting recommended amounts of physical activity, blood tests show that metabolic and hormonal changes occur with healthful changes in lifestyle. Obviously, more research is needed to better understand how this plays out regarding cancer risk.

Are there anti-inflammatory solutions?

There is no shortage of food and fitness information available for those of us concerned about our health. Unfortunately, the information changes so quickly and is often so fueled by media sound bites, it’s difficult for the layperson to unravel the truth. You may have heard of certain foods that are supposed to promote or fight off inflammation. A Columbia University study of more than 2200 adults found that a scoring system, introduced in a book for the general public, that was designed to rate the inflammatory impact of foods turned out to be unrelated to blood values of CRP.

Research does suggest that what we eat may influence inflammation. Plant foods (such as vegetables, fruits, whole grains, beans, nuts and seeds) that are not highly processed contain antioxidants that protect cells against damaging molecules called “free radicals” and inhibit inflammation. Omega-3 fats, like those found in salmon and other cold-water fish, promote production of anti-inflammatory hormone-like substances. Scientists used to think that other polyunsaturated fats, the omega-6 fat found in many vegetable oils, increased substances that stimulated inflammation. Now it’s been discovered that they also lead to anti-inflammatory proteins called lipoxins. So the impact on inflammation from the omega-3 to omega-6 ratio, which some once emphasized, is no longer clear cut.

Foods are a mixture of a whole variety of different nutrients and compounds. While we know in laboratory studies that a certain phytochemical, nutrient or type of fat fights inflammation, we may not be as far ahead as it may seem in being able to predict how the combination of compounds in any given food come together to promote or decrease inflammation outside of the lab in our own bodies.

How to combat chronic inflammation

Research shows a variety of lifestyle changes that appear to reduce or prevent chronic, low-grade inflammation. Studies show lower levels of markers of inflammation in those who don’t smoke and those who exercise regularly. In one study, several markers of inflammation dropped within weeks among women in a smoking cessation program. Good dental care that prevents the gum inflammation known as gingivitis may even help to reduce overall body inflammation. Moderate exercise like walking also seems to directly reduce markers of inflammation, even after adjusting for its impact on weight.

Excess body fat, particularly in the abdomen, may be the single largest influence on markers of inflammation, and is also linked to a greater risk of diabetes and other chronic conditions.

Chronic, low-grade inflammation is a significant health risk. Instead of focusing on individual foods or the nutrients in them for protection, a good strategy is to work at creating an all-round healthy lifestyle.

Is there a link between chemotherapy and diabetes?

While compiling this article, no specific papers, studies or research was found to directly link chemotherapy to a diagnosis of diabetes, although many people undergoing chemotherapy do have to deal with elevated blood glucose levels while they are in treatment whether they are diabetic or not.

Individuals who already have diabetes and are undergoing cancer treatments have to be monitored much more closely to make sure their blood glucose levels remain in a safe zone. It is not uncommon for the type of insulin being used to be changed during chemotherapy in order to accomplish this goal.

It is known that certain chemotherapy drugs can cause peripheral neuropathy (nerve damage), such as vinca alkaloids (vincristine), cisplatin, paclitaxel, and the podophyllotoxins (etoposide and teniposide). This also can occur in patients with and without diabetes. Individuals at greatest risk of peripheral neuropathy associated with chemotherapy are those with pre-existing peripheral neuropathy from conditions such as diabetes, alcoholism, severe malnutrition, and previous chemotherapy.

Yet another piece of a very confusing puzzle

A large study has found that diabetic women taking the medicine metformin (brand names: Fortamet, Glucophage, Glumetza, Riomet), which is commonly used to treat type 2 diabetes, had a lower-than-average risk of breast cancer.

The study was published online June 11, 2012 in the Journal of Clinical Oncology. The abstract is available at “Diabetes, Metformin, and Breast Cancer in Postmenopausal Women.”

Metformin is often used by itself as a first treatment for adult-onset diabetes, or later in combination with other diabetes medicines. Metformin helps make diabetics less resistant to insulin and lowers their insulin levels. This could explain, at least in part, why the women treated with metformin had a lower-than-average risk of breast cancer. Still, it’s likely that the link between metformin and lower risk is more complex than just insulin levels. The link does give scientists a clue for future research on the role of diabetes and insulin in the development and growth of breast cancer.

What comes around, goes around (and around!)

As we’ve discussed many times on this site, diet and exercise appear to be one constant in the battle against breast cancer as well as diabetes. Obviously, we all long for the day when there are more definitive answers, but for the moment it appears our best recourse is to physically active, work on our weight to try to get it within normal ranges – and to continue to ask our doctors questions about what they feel will work best for us.

For anyone with diabetes, the message here is simple, do whatever is necessary to keep your disease under control. For those who have been warned they are pre-diabetic, it’s essential to buckle down right now and take the necessary steps to avoid full-blown diabetes. Although the information regarding a link between cancer and diabetes can be confusing, it is very clear that making healthy lifestyle changes now is a great step in the right direction.

 

December, 2012