DIABETES AND CANCER: A CONNECT or DISCONNECT?

You probably have been hearing a lot about diabetes in the headlines. Is there a link between diabetes and cancer or not? Is the link actually between cancer and insulin level, which is elevated in many people with diabetes? Or is the link related to the medications used to treat diabetes, including insulin? Where is the link, if one does exist, and what do you need to know about it?

First, both diabetes and cancer are common diseases.

Worldwide, in 2008, there were an estimated 12.4 million new cancer cases diagnosed. The most commonly diagnosed cancers are those of the lung/bronchus, breast and colon/ rectum, while the most common causes of cancer deaths are from lung, stomach and liver cancer. Of the world population between the ages of 20 and 79 years, an estimated 285 million people had diabetes in 2007. In the United States, there are an estimated 1.6 million new cases reported each year. Type 2 diabetes is the most common form of diabetes, accounting for approximately 95 percent of cases. Both cancer and diabetes are common causes of death. In the United States, cancer is the second leading cause of death while diabetes is seventh, although diabetes is probably more often present than listed as a contributing medical condition.

Dr. Dace Trence is Director of the Diabetes Care Center and Associate Professor of Medicine at the University of Washington Medical Center in Seattle. She is also the University of Washington Endocrine Fellowship Program Director and Director of Endocrine Days, a medical education program for endocrinologists practicing in the Pacific Northwest. She is on the American College of Endocrinology Board of Trustees and chairs the CME Committee.

Dr. Tracy Tylee is a Clinical Assistant Professor at the University of Washington in Seattle, where she practices at the Diabetes Care Center. She is actively involved in the education of the endocrine fellows through the University of Washington fellowship program. Dr. Tylee is board-certified in endocrinology, diabetes and metabolism, and is interested in all aspects of clinical endocrinology, particularly the management of type 2 diabetes.

Does having diabetes increase the risk of developing cancer?

For over 50 years, physicians have noted that cancer and diabetes occur together more frequently than would be expected by chance. Multiple studies have found that certain cancers occur almost twice as frequently in patients with type 2 diabetes: liver, pancreas and, for women, the lining of the uterus. Other cancers are also increased, although to a lesser degree (1.2 to 1.5 times higher): colon, breast and bladder cancer. Fewer studies have looked at links with type 1 diabetes, but from a Swedish report, there appears to be a higher risk of developing stomach cancer, cervical cancer and cancer of the lining of the uterus in patients with type 1 diabetes.

Is there something specific about diabetes that could explain the increased cancer risk?

It is not known whether diabetes itself directly increases the risk of cancer or whether there is an indirect link. It is known that being overweight increases the risk for developing diabetes type 2, and being overweight is also associated with the risk of developing cancer, including those cancers linked to diabetes. Others have asked whether high glucose (sugar in the blood) might be a linking factor. Cancer cells have high energy needs, and the high blood sugars seen in poorly controlled type 2 diabetes might provide the energy needed for uncontrolled growth. However, this theory has not been proven in any studies to date.

Is diabetes simply a marker of underlying factors that increase the risk of cancer? Could insulin resistance and/or elevated insulin levels (the body’s attempt to compensate for insulin resistance) contribute to the apparent increase in cancer risk? Insulin is a growth factor, a hormone that stimulates cells in the body to grow. The majority of cancer cells have receptors for insulin, which allows them to grow and spread in response to high insulin levels. However, the recently completed ORIGIN (Outcome Reduction with Initial Glargine Intervention) study showed that insulin given by injection did not increase the risk in cancer. Over 12,500 individuals were followed for over six years, and there was no increase in cancer in those treated with insulin compared to those not treated with insulin. Thus, the possible link between diabetes and cancer remains unclear.

EXPERTS GATHER TO DISCUSS LINK BETWEEN DIABETES , CANCER

BY DONALD A .BERGMAN, MD, MACE

The American Association of Clinical Endocrinologists (AACE) recently held a conference in New York where experts from around the world gathered to discuss their work and answer this question: what is the relationship between diabetes and cancer?

Several cancers were discussed, but the evidence presented was most compelling for breast cancer. The experts showed that high levels of insulin can lead to a change in the way breast cells behave and cause malignant change. High insulin levels are seen in individuals who are obese and also those who have type 2 diabetes (many of whom are overweight).

Obesity is associated with increased inflammation in breast fat and this inflammation is also associated with malignant change in the breast cells.

Research is now focused on whether losing weight, improving blood sugar control and lowering insulin levels can correct the faulty metabolism in the breast cells and prevent cancer from occurring or, if it has already occurred, then at least prevent spread of the cancer. The excess insulin-obesity-inflammation connection is being studied in other cancers as well.

Data was also presented about whether drugs can cause or can prevent certain cancers by affecting insulin levels and correcting the faulty cell metabolism that leads to certain cancers, but more evidence is needed.

Convening basic researchers and clinicians together to share information and develop new ideas is something that AACE does well. Efforts such as this conference move us one step closer to the goal of staying healthy and free of disease as we get older.

Are there diabetes medicines, other than insulin, that could increase risk of cancer?

The pill used most frequently throughout the world for blood sugar lowering is metformin [met-FAWR-min], which has been shown to actually be protective against the development of cancer. It can inhibit an increase in cell number, inhibit cell groups from forming and even partially stop cell growth in some cancer cell studies. Studies have suggested that metformin may add to the effectiveness of breast cancer treatment regimens. The potential effect of metformin on breast cancer cells is currently being evaluated in clinical trials, even in women without diabetes.

A small number of studies have found a trend of higher risk of cancer or cancer death among individuals with diabetes treated with sulfonylureas [sul·fo·nyl·u·re·a ] (examples of these would be glyburide, glimepiride) compared with those treated with metformin or other diabetes medications. However, the majority of these studies had very few cancer cases among users of sulfonylureas, so the ability of the studies to make any definite conclusions (referred to as “power of a study”) was limited.

Pioglitazone [PYE-oh-GLI-ta-zone] has been associated with an increased risk of bladder cancer, prompting the FDA to advise against the use of this drug in those with bladder cancer or a prior history of the cancer. This was based on a 40 percent increased risk of developing bladder cancer after more than one year’s use in a review of over 190,000 patients. Another medication, liraglutide [LIR-a-GLOO-tide] (a drug that decreases appetite and inhibits glucagon, a hormone that acts against insulin) was found to increase the risk of medullary thyroid cancer in rats and mice. However, receptors (attachment points on cells for a chemical) for liraglutide are present on rat and mice thyroid cells, but are not present on monkey or human thyroid cells. This is a very important difference!

What should you take home as a message?

Although there is an association between diabetes and cancer, it is by no means clear what this link is. Both diabetes and cancer are very common in the human population, and both share common risk factors which could explain some of the apparent links between the two. In addition, the high glucose levels or high insulin levels seen in diabetes could increase the risk of cancer, but studies to date have not shown conclusively that this is the case. Some diabetes treatment drugs have been associated with increased specific cancer risk, and one has been found to decrease risk. Subcutaneous injection of insulin just recently was not found to be associated with increased risk of cancer, when started, as compared to those not starting insulin.

The link between diabetes and cancer remains unclear. What is clear is that physical activity, maintaining a stable weight and consuming a healthful diet will prevent both diabetes and cancer. Until more is known about the possible link between diabetes and cancer, the best approach we can take is to strive to follow a healthy lifestyle. The American Association of Clinical Endocrinologists hosted a conference this fall to further look into the issue of diabetes and cancer. See the accompanying article on this page for news about the conference’s proceedings.

Dr. Donald Bergman is in private practice in New York City and is board certified in internal medicine and endocrinology and metabolism. He is Clinical Professor of Medicine at Mount Sinai School of Medicine in New York City. Dr. Bergman is past president of AACE and ACE. In 2003,during his AACE presidency, Dr. Bergman founded EmPower, previously known as “Power of Prevention,” a program that encourages people to partner with their physicians in establishing healthy lifestyles and demonstrating the importance of primary and secondary prevention. He serves as Executive Editor of EmPower Magazine.