AICR ScienceNow
Volume 25, Summer 2008

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The Diabetes-Cancer Connection

Evidence linking diabetes and high insulin levels to certain cancers has grown stronger over the past several years, leading scientists to investigate potential mechanisms.

Insulin vialsA growing body of evidence is finding that having diabetes or signs of insulin resistance may lead to an increased risk of certain cancers. The connection is strongest among certain types of cancers, including kidney, pancreatic and colorectal.

“The trend emerging [in this area] 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.

The Insulin-Cancer Connection

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.

Hyperinsulinemia, type 2 diabetes and cancer all share a major risk factor: high body fat. AICR’s second expert report found that high body fat is convincingly linked to increased risk of several cancers, including pancreatic and colorectal.

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.

High levels of insulin, independent of body fat, are linked to increased production of insulin-like growth factor 1 (IGF-1). And IGF-1, which shares a similar structure to insulin, plays a key role in cell growth, proliferation and inhibiting apoptosis.

A Complex Link

Some of the strongest findings relating to diabetes, hyperinsulinemia and cancer risk relate to colorectal cancer, but – as in other cancers – there are no clear answers. In one recent study, researchers from the University of Minnesota found that women diagnosed with diabetes had a 50 percent higher chance of developing colorectal cancer than women without the disease. The researchers drew upon data from approximately 45,000 participants of a large screening study that began in the 1970s. The study analyzed data on women with no history of colorectal cancer or self-reported diabetes for eight years, who later developed colorectal cancer.

“We didn’t have information on insulin level, so we used diabetes as a proxy,” said lead study author Andrew Flood, Ph.D., Assistant Professor in the Division of Epidemiology and Community Health and the Masonic Cancer Center at the University of Minnesota School of Public Health. “But a lot of people have undiagnosed diabetes,” said Dr. Flood. “If insulin is the problem, then we thought people who were prediabetic would have elevated levels of insulin.”

To test this hypothesis, the researchers included women who were likely prediabetic at the beginning of the follow-up period (they were later diagnosed with diabetes). It is likely these women had hyperinsulinemia. Surprisingly, the link to cancer was lower – although still significant -- with the addition of the hyperinsulinemia group. “It could be that the people diagnosed with diabetes during follow-up hadn’t been hyperinsulinemic long enough to increase risk, or that people need to be hyperinsulinemic to a greater degree to see an effect.”

Responding to Insulin

After eating carbohydrates, the pancreas responds by producing enough insulin to transport the glucose from the bloodstream into the cells. Glucose is the cells’ energy source and without it, cells cannot function. If the cells do not respond to insulin (insulin-resistant), the pancreas pumps out more. Over time, it can take ever-increasing amounts of insulin for the cells to take in enough glucose. People with prediabetes and type 2 diabetes can have both high glucose and insulin levels. In some cases, blood can measure a normal glucose level but insulin levels are still elevated.

Recurrence and Outcome

In some cases where there is only a moderate link between insulin resistance and cancer risk, there is a strong relationship to cancer behaving aggressively and recurrence. In a preliminary finding, Dr. Pollak and his colleagues examined data from a trial involving approximately 600 post-menopausal breast cancer patients. Along with other hormones, insulin was measured at time of diagnosis and ten years later. The researchers found that obese participants who had the highest insulin levels at diagnosis showed significantly increased risk of disease recurrence.

Dr. Pollak’s results mirror studies in prostate and other cancers that show high levels of insulin or blood glucose are linked to advanced adenomas, recurrence or mortality. A study by Dr. Flood, for example, found that patients who recently had potentially precancerous polyps removed from their colon or rectum and who had elevated insulin and glucose levels were at higher risk of recurrence compared to those with the lowest levels. And patients having the highest glucose levels had especially elevated risk for recurrence of advanced adenoma.

Next Steps

Laboratory studies are investigating how insulin and IGF may affect chronic inflammation, which is associated with cancer incidence and growth. Scientists are working on teasing apart the roles of obesity and hyperinsulinemia in cancer risk. Ongoing research is also looking at people’s genetic susceptibility.

For now, researchers know that obesity is tied to hyperinsulinemia and type 2 diabetes. The National Diabetes Information Clearinghouse states that losing at least 5 to 10 percent of a person’s starting weight can prevent or delay diabetes or even reverse prediabetes.

“This is tied in to bad nutritional habits, excess energy intake and a sedentary lifestyle,” said Dr. Pollak. The work in progress is exciting, he says, but “there’s something people can do about their risk now.”

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