Edward L. Giovannucci, MD, ScD
Professor of Nutrition and Epidemiology
Departments of Nutrition and Epidemiology
Harvard School of Public Health
Department of Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
Although research has shown that obesity is a strong risk factor for adult-onset diabetes, the link between obesity and cancer is generally less widely appreciated. But that is changing. Recent studies have confirmed that obesity may be associated with the incidence and mortality of a number of cancers, such as those of the colon, pancreas, and kidney, in addition to aggressive prostate cancer in men and breast cancer and endometrial cancer in women. The evidence suggests that the link between obesity and cancer may involve similar causes as the link between obesity and diabetes.
Insulin Resistance
Obesity induces insulin resistance, a condition whereby some organs become resistant to insulin’s ability to shuttle glucose into cells, especially after eating a meal high in carbohydrates. To compensate for this resistance to insulin, the pancreas produces more insulin, which leads to an increase in blood insulin levels. Although this compensation may continue for many years, the pancreas cannot maintain this high insulin output indefinitely. It is then that insulin levels begin to decrease and blood sugar levels increase. When the blood sugar rise is severe enough, diabetes is diagnosed.
Insulin Resistance and Cancer
The link between insulin resistance and cancer may be related to the compensatory high levels of insulin. Insulin is an important growth factor for body tissues. Typically, insulin increases when nutrients are plentiful, and drops dramatically during a fasting state. Insulin may signal cells to increase rapidly in number through a variety of mechanisms. Insulin could directly signal growth, or it could do this by increasing the levels of other potent growth factors (insulin-like growth factors [IGF]), or it could make cells more sensitive to other growth factors. Although cancer is a complex, multifactorial disease, one of the consistent characteristics of cancer cells is their ability to grow uncontrollably and to be resistant to programmed death. Thus, growth factors are critical to the initial development of cancers, as well as to their progression. A number of studies now show that individuals with higher levels of circulating IGFs are at increased risk for developing colon, premenopausal breast, and aggressive prostate cancers than are individuals with lower levels.
Obesity + Insulin Resistance = Cancer?
Although insulin resistance is characterized by cells becoming less sensitive to the effects of insulin to transport glucose into cells, insulin insensitivity does not seem to lower the growth promoting properties of insulin. Only the glucose transporting properties are affected. Thus, in an insulin resistant state, such as induced by obesity, the higher circulating levels of insulin may have a cancer-promoting influence for at least some tissues. As long as the pancreas can continue to produce large amounts of insulin in the face of insulin resistance, some individuals may avoid diabetes; however, these individuals may be the ones most susceptible to cancer because they have the highest circulating insulin concentrations.
Some tissues appear to be more susceptible to these adverse consequences of high insulin levels, for reasons as yet unknown. The organ that seems to be most susceptible is the colon. In fact, the risk factors for colon cancer are remarkably similar to those for diabetes, including obesity, the tendency to carry extra body fat around the waist (male pattern or “apple-shape” obesity), physical inactivity, and a diet that is high in saturated fat, refined carbohydrates, and sugars, and low in fiber. Indeed, diabetes itself is a risk factor for colon cancer. In addition, a number of studies have found that individuals with various abnormalities associated with the insulin resistance syndrome, including hypertriglyceridemia, hyperglycemia, low HDL-cholesterol, and high insulin levels are at increased risk of colon cancer. Although it is not yet possible to prove that insulin itself is the culprit, the determinants, markers, and consequences of insulin resistance are closely linked with colon cancer risk.
Studies have shown that obesity increases risk for cancers other than colon cancer, but the evidence that insulin resistance is primarily responsible for this is less consistent. For example, obesity increases the risk of postmenopausal breast cancer, but some evidence indicates that the primary mechanism may actually involves the increased amount of estrogens formed in the fat tissues of overweight and obese women. Nonetheless, some evidence does suggest that insulin resistance might very well play a role in many of the cancers associated with obesity, particularly pancreatic, kidney, and endometrial cancers. Even if it turns out that only colon cancer is related to high insulin levels, this would still be of major importance because colon cancer is the second leading cause of cancer incidence and mortality in men and women combined.
Possibilities for Prevention and Treatment
The insulin-cancer hypothesis not only may shed new light onto cancer development, but may offer new opportunities for prevention and treatment. Preventing or reducing obesity, increasing physical activity, and improving diet are likely to lower the risk of colon cancer and possibly other cancers. In addition, these efforts have significant protective effects on for cardiovascular disease, diabetes, and many other conditions. Furthermore, establishing insulin resistance may help identify high-risk individuals who may warrant more intensive screening with colonoscopy. For diabetics, treatment approaches also may influence colon cancer risk. For example, treatments to improve insulin resistance may reduce colon cancer risk, though this has not been directly studied to date. Thus, this insulin-cancer link may have implications for primary prevention through diet and lifestyle, secondary prevention through screening, and for treatment options for various diseases.
