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
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.
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