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
Research has shown that obesity is a strong risk factor for adult-onset diabetes, but the link between obesity and cancer is generally less widely appreciated. Recent studies have confirmed that obesity may be associated with the incidence and mortality of a number of malignancies, including colon, pancreatic, and kidney, as well as aggressive prostate cancer in men and breast and endometrial cancer in women. An accumulating body of evidence suggests that the link between obesity and cancer may involve similar etiologic mechanisms that have been demonstrated to exist between obesity and diabetes.
Obesity is known to induce insulin resistance, a condition whereby some organs become resistant to the effect of insulin to shuttle glucose into cells, especially after a meal high in carbohydrates. To compensate for this resistance to insulin, the pancreas produces more insulin, which leads to an increase in circulating insulin levels. This compensation may continue for many years, but the pancreas cannot maintain this high insulin output indefinitely, especially in some susceptible individuals. 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.
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. That insulin is an important growth factor is not surprising because typically insulin increases when nutrients are plentiful, and drops dramatically during a fasting state. Insulin may signal cells to proliferate through a variety of mechanisms. Insulin could directly signal growth, or it could do this by increasing the levels of other more potent growth factors (insulin-like growth factors [IGF]), or it can 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 growth uncontrollably and to be less resistant to die. Thus, growth factors are critical to the initial development of cancers, and 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.
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 in insulin resistance. 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 currently 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. These include obesity, the tendency to carry extra body fat around the waist (male pattern or “apple-shape” obesity), physical inactivity, and a diet high in saturated fat, refined carbohydrates and sugars, and low in fiber. Indeed, diabetes itself has been found to be 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. It is not yet possible to prove that insulin itself is the culprit; however, the determinants, markers and consequences of insulin resistance are closely linked with colon cancer risk.
Although it is clear that obesity increases risk for cancers other than colon cancer, the evidence that insulin resistance is primarily responsible for this increased risk for other cancers is less consistent. For example, obesity increases risk of postmenopausal breast cancer, but some evidence indicates that the primary mechanism involves the increased amount of estrogens formed in fat tissue in overweight and obese women. Nonetheless, some evidence suggests that insulin resistance could 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 were to be related to high insulin levels, this would still be of major importance as colon cancer is the second leading cause of cancer incidence and mortality in men and women combined.
The insulin-cancer hypothesis not only may shed new light into the etiology of cancer, but may offer new opportunities for prevention and treatment. Preventing or reducing obesity, increasing physical activity, and improving diet is likely to lower risk of colon cancer and possibly other cancers, in addition to benefits on risk of 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 should reduce colon cancer risk, though this has not been directly studied to date. In contrast, one recent study has suggested that insulin treatment in diabetes may increase risk of colon cancer. 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.