The Role of Obesity and Related Metabolic Disturbances in Cancers of

GASTROENTEROLOGY 2007;132:2208 –2225
The Role of Obesity and Related Metabolic Disturbances in Cancers of

the Colon, Prostate, and Pancreas
EDWARD GIOVANNUCCI,*,‡,§ and DOMINIQUE MICHAUD‡,§
*Department of Nutrition and ‡Department of Epidemiology, Harvard School of Public Health, Boston, and §Department of Medicine,
Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
Edward Giovannucci, MD
Recent evidence indicates that obesity and related met- able estradiol. The role of obesity for cancers of the colon,
abolic abnormalities are associated with increased inci- prostate, and pancreas will be addressed in this review.
dence or mortality for a number of cancers, including Specifically, this review will focus on how the major
those of the colon, prostate, and pancreas. Obesity, metabolic consequences of excess energy consumption
physical inactivity, visceral adiposity, hyperglycemia, and obesity may influence carcinogenesis at these sites.
and hyperinsulinemia are relatively consistent risk fac-
tors for colon cancer and adenoma. Also, patients with
type 2 diabetes mellitus have a higher risk of colon Colon Cancer
cancer. For prostate cancer, the relationship to obesity Obesity
appears more complex. Obesity seems to contribute to a The relationship between body mass index (BMI)
greater risk of aggressive or fatal prostate cancer but and increased risk of colon cancer has been well studied.
perhaps to a lower risk of nonaggressive prostate can- An association is quite consistent and is now generally
cer. Furthermore, men with type 2 diabetes mellitus are accepted.1 In most studies of men, obesity is associated
at lower risk of developing prostate cancer. Long-stand- with approximately a relative risk (RR) of 1.5 to 2.0
ing type 2 diabetes increases the risk of pancreatic can-
compared with a low or normal BMI. However, for un-
cer by approximately 50%. Furthermore, over the past 6
clear reasons, this association has been generally stronger
years, a large number of cohort studies have reported
for men than for women. This difference by sex was
positive associations between obesity and pancreatic
illustrated in the recent European Prospective Investiga-
cancer. Together with data from prediagnostic blood
tion Into Cancer and Nutrition (EPIC) study. Consistent
specimens showing positive associations between glu-
with other studies, in the EPIC, a 55% increased risk of
cose levels and pancreatic cancer up to 25 years later,
colon cancer was observed between high and low quin-
sufficient evidence now supports a strong role for dia-
tiles of BMI in men, but no significant association was
betes and obesity in pancreatic cancer etiology. The
mechanisms for these associations, however, remain observed in women.2 In most studies that have consid-
speculative and deserve further study. Hyperinsulin- ered anthropometric measures of adipose distribution in
emia may be important, but the role of oxidative stress addition to BMI, the association between waist circum-
initiated by hyperglycemia also deserves further atten- ference or waist-to-hip ratio and colon cancer risk has
tion. generally been more consistent than that for BMI.3–7 In
fact, unlike for BMI, clearer associations between waist
circumference and colon cancer risk have been observed
R ecent evidence has indicated that obesity is associ-
ated with an increased incidence or mortality rate
for a number of cancers. Of the top 5 causes of cancer
for women.2,5– 8 For example, in the aforementioned EPIC
study, higher waist-to-hip ratio was indeed associated
mortality in the United States, including those of the
lung, colon, breast, prostate, and pancreas, obesity is Abbreviations used in this paper: BMI, body mass index; GPx, glu-
likely to play an important role in all but lung cancer. tathione peroxidase; IGF, insulin-like growth factor; IGFBP, insulin-like
Obesity has a complex relationship with premenopausal growth factor binding protein; MnSOD, manganese superoxide dis-
mutase; PSA, prostate-speciﬁc antigen; RR, relative risk.
breast cancer, but it clearly increases the risk of post- © 2007 by the AGA Institute
menopausal breast cancer, which is most likely caused 0016-5085/07/$32.00
primarily by increasing serum concentrations of bioavail- doi:10.1053/j.gastro.2007.03.050
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May 2007 OBESITY, METABOLIC DISTURBANCES, AND CANCER RISK 2209
with an increased risk of colon cancer for women (RR, the etiology of the metabolic syndrome. Some studies
1.52) as well as for men (RR, 1.51).2 have examined the metabolic syndrome in relation to risk
Similarly, associations for circumference measures of colon neoplasia. The specific criteria (based on stan-
have been noted for large or advanced adenoma, the dard or modified definitions of obesity, high blood pres-
proximate precursor to most colon cancers.4,8,9 In one sure, high serum triglycerides, high blood glucose, and
study that directly measured visceral fat accumulation low serum high-density lipoprotein [HDL]-cholesterol)
through computerized tomography scanning, a strong have varied across the studies. Although the results were
association between visceral fat and colorectal ade- not always statistically significant among the studies,
noma was observed.10 However, no association was most found that individuals with the metabolic syn-
observed with recurrent adenomas in another study drome had an elevated risk of developing colon can-
using a similar approach.11 The lack of an association cer.18,20,22,23
with recurrent adenomas probably reflects that adipos- Hypertriglyceridemia is typically a component of the
ity promotes adenoma growth rather than increasing definition of metabolic syndrome24 and may be a partic-
occurrence of this lesion.12 Overall, the data strongly ularly important component of this syndrome. In fact, a
support that some metabolic characteristics associated recent alternative definition of the metabolic syndrome,
with central or abdominal adiposity increases risk of termed “the hypertriglyceridemic waist,” has been pro-
colon cancer. Correspondingly, consistent evidence in- posed for men based solely on waist circumference ⬎90
dicates that physical activity protects against colon cm and triglyceride levels ⬎2.0 nmol/L.25 The results for
cancer.8 Neither BMI nor physical activity has been studies that have examined hypertriglyceridemia in rela-
consistently associated with rectal cancer risk. tion to risk of colorectal or colon cancer have been
inconsistent and only suggestive at best,3,18,21,22,26 but
Diabetes Mellitus and Hyperglycemia these studies have been hindered by small sample sizes or
Obesity and physical inactivity are strong risk by long duration of follow-up after the blood assessment
factors for adult-onset or type 2 diabetes mellitus. Indi- was taken. A Japanese case-control study reported that
viduals with diabetes initially experience hyperglycemia hypertriglyceridemia was associated with a 3-fold higher
and hyperinsulinemia, but insulin concentrations wane risk of colorectal carcinoma in situ in multivariate anal-
eventually from pancreatic ␤-cell depletion. If type 2 ysis.27 Hypertriglyceridemia has also been associated with
diabetes is associated with increased risk of colon cancer, colorectal adenoma risk in studies conducted in diverse
this would provide some evidence that metabolic conse- populations, including in Germany,28 Korea,29 Japan,30
quences associated with obesity and diabetes may play a and China.31
role in colon cancer. Indeed, many studies have found
that individuals with adult-onset diabetes mellitus are at Hyperinsulinemia
increased risk of colon cancer. A recent metaanalysis of Hyperinsulinemia has been hypothesized to be an
studies published through July 31, 2005, demonstrated a underlying factor linking obesity, physical inactivity, type
highly significant summary RR of 1.43 for colon cancer 2 diabetes mellitus, and certain factors associated with a
among diabetic individuals, with no heterogeneity Western dietary pattern as risk factors for colon neopla-
among studies noted.13 This association was observed for sia (Figure 1).32 Obesity and physical inactivity are the
men and women and was consistent between case-control main determinants of insulin resistance and hyperinsu-
and cohort studies and between studies conducted in the linemia (in the nondiabetic state). Independent of its
United States and in Europe. A recent study confirmed influence on adiposity, physical activity increases insulin
this association in an Asian population, the Singapore sensitivity and lowers circulating insulin.33 Insulin has
Chinese.14 The association between type 2 diabetes and growth-promoting properties and increases free insulin-
risk of colon adenoma has not been as well studied, but like growth factor (IGF-I) levels,33 which is discussed
a recent study reported that diabetic individuals, espe- below.
cially those who are obese, have an increased risk of A number of epidemiologic studies have now examined
prevalent colon adenoma and particularly for advanced hyperinsulinemia assessed in several ways (eg, fasting,
adenoma.15 Some studies have examined blood glucose nonfasting, postglucose load, and C-peptide, an indicator
levels in relation to colorectal cancer and adenoma in of insulin secretion) in relation to risk of colon cancer or
nondiabetic individuals. Most studies, although not all,16 adenoma. The first report was in a cohort study3 and
have found that hyperglycemia is associated with an found that fasting insulin was not related to an increased
increased risk of colon cancer.17–21 risk (RR, 1.2), but 2-hour insulin postglucose load level
was related to a significantly increased risk (RR, 2.0). In a
The Metabolic Syndrome and following prospective study of women in New York State,
Hypertriglyceridemia a 3-fold higher risk of colorectal cancer was observed in
Obesity, particularly visceral adiposity, physical those in the top quartile of C-peptide,34 and a 4-fold
inactivity, and insulin resistance are underlying factors in higher risk was seen for colon cancer alone.35 Another
2210 GIOVANNUCCI AND MICHAUD GASTROENTEROLOGY Vol. 132, No. 6
Because a number of metabolic consequences are as-

sociated with insulin resistance and hyperinsulinemia, it
is difficult to settle which is most critical based solely on
epidemiologic data. Of note, one rat model suggests that
hyperinsulinemia may be the most important factor. In
that study, insulin level, during a 10-hour euglycemic
clamp, correlated with colorectal epithelial proliferation
in a dose-dependent manner.42 Importantly, the addition
of hyperglycemia did not further increase proliferation,
and an intralipid infusion alone did not increase cell
proliferation. Based on this study, hyperinsulinemia,
rather than hyperglycemia or hypertriglyceridemia, was
the metabolic component primarily associated with pro-
liferation, a risk factor for enhanced carcinogenesis.
For humans, although such experimentation is not
feasible, the natural history of type 2 diabetes mellitus
can be exploited. The initial cause of type 2 diabetes is
insulin resistance, a condition for which higher levels of
insulin are required to achieve normal utilization of cir-
Figure 1. A model whereby nutritional factors affect colon cancer risk
through an influence on the insulin and IGF-I axis. In this model, factors
culating glucose. Initially, levels of glucose are stabilized
related to energy balance and diet influence growth hormone secretion, through increased circulating insulin levels. In the early
insulin resistance, and insulin secretion dependent on competent pan- stages of impaired glucose tolerance, glucose levels may
creatic ␤ cells. Either an increase in IGF-I, or the IGF-I/IGFBP-III ratio, or be not elevated or are only slightly increased. However,
insulin that decreases IGFBP-I and IGFBP-II could alter the levels of free
over many years or decades of this compensatory hyper-
or bioactive IGF-I, a stimulant of tumor growth.
insulinemia, pancreatic ␤-cell failure occurs in suscepti-
ble individuals, eventually leading to reduced secretion of
insulin. The hypoinsulinemia is most evident in the post-
study in northern Sweden did not find an appreciably prandial phase, when insulin demand is greatest.43 Thus,
elevated risk associated with fasting and nonfasting in- in the initial stages of impaired glucose tolerance, hyper-
sulin (RR, 1.2), although a suggestive association was insulinemia predominates, whereas, in later stages of
observed in analyses based on fasting (⬎4 hours) cases
diabetes, hypoinsulinemia occurs; in contrast, hypertri-
alone (RR, 1.68).36 In the CLUE II cohort, baseline insulin
glyceridemia and hyperglycemia tend to worsen over
levels (a mixture of fasting and nonfasting samples) were
time.
not related to risk of colorectal cancer.21 The 2 largest
Some observations concerning the natural history of
studies were the Physicians’ Health Study and the Nurses’
metabolic changes of impaired glucose tolerance and
Health Study. In the Physicians’ Health Study, men with
diabetes suggest that the hyperinsulinemia is the critical
C-peptide in the top vs the bottom quintile had a 2.7-fold
factor. First, in one study,19 patients with impaired glu-
significant increased risk of colorectal cancer, controlling
for BMI and exercise; this RR increased to 3.4 after cose tolerance but without diabetes (presumably hyper-
controlling for the indicators of the metabolic syn- insulinemic) had an excess of colon cancer deaths; in
drome.37 In the Nurses’ Health Study, women in the top contrast, diabetic patients had a higher rate of total
quartile of C-peptide had a borderline increased multi- mortality, mostly from cardiovascular disease but not
variate risk of colon cancer (RR, 1.76) compared with from cancer. Second, in an analysis from the Nurses’
women in the lowest quartile, also controlling for BMI Health Study, the risk of colon cancer was increased in
and physical activity.38 women recently diagnosed with diabetes, but this ele-
Three studies have considered insulin or C-peptide vated risk became attenuated 15 years after the diagno-
levels in relation to adenoma risk. In one study, fasting sis.44 Third, in the Physicians’ Health Study,37 C-peptide
plasma insulin was not related to an appreciably in- level, a robust measure of insulin secretion, was more
creased risk of adenomas.39 In contrast, in a study of strongly associated with colon cancer risk than was the
patients undergoing colonoscopy at the University of metabolic syndrome, defined on low plasma HDL cho-
Carolina hospitals, those in the highest quartile of insu- lesterol, high triglycerides, high BMI, and hypertension;
lin had a 2.2-fold significantly higher risk of adenoma.40 in fact, the association with C-peptide level became even
In the Nurses’ Health Study, high concentrations of C- stronger after controlling for metabolic syndrome. A
peptide were statistically significantly associated with risk fourth observation is that postprandial insulin3 and non-
of distal colorectal adenoma (RR, 1.63) controlling for fasting C-peptide,35,37 a measure of insulin secretion that
BMI and physical activity level.41 accounts for ␤-cell function as well as for the hyperinsu-
linemic effect of diet, predicted colon cancer risk more

strongly than did fasting insulin level.3,36
Another observation supportive of the direct role of
hyperinsulinemia is that, in a study of type 2 diabetes
patients, a 21% increase in colorectal risk was observed
with each incremental year of insulin therapy.45 Although
use of insulin therapy in type 2 diabetes patients may be
an indictor of severity of disease and thus waning endog-
enous insulin production, insulin therapy in these pa-
tients is associated with hyperinsulinemia because exog-
enous insulin is inefficient in maintaining glucose levels
in the presence of insulin resistance.46 Interestingly, in a
rodent azoxymethane model, insulin injections pro-
moted tumor growth.47 In total, these observations sup-
port the hypothesis that hyperinsulinemia may be the
essential consequence of obesity that increases risk of Figure 2. Colon cancer risk by level of IGF-I/IGFBP-III and IGFBP-I. In
colon cancer. the Nurses’ Health Study,38 risk of colon cancer increased with higher
levels of IGF-I/IGFBP-III ratio, or with decreasing IGFBP-I, which is
largely determined by hyperinsulinemia.
Insulin and IGF Interactions
Although insulin may possibly have direct
growth-promoting properties, many of the growth-pro- genesis is also supported by the finding that acromegal-
moting actions of insulin are believed to operate through ics, who have abnormally elevated IGF-I from excessive
the IGF-I axis (Figure 1). When insulin levels are low, as growth hormone secretion, have an elevated risk of colo-
in a prolonged fasting state, the concentration of growth rectal cancer.55,56
hormone receptors in hepatocytes is lowered, which Very few studies have examined the interactive or
causes a reduction in IGF-I secretion.48 This specific ac- joint effects of insulin and IGF-I concentrations in
tion of insulin may be relevant in times of very low energy relation to colon neoplasia risk. In a Japanese study,
states (eg, prolonged fasting or starvation), but the rele- fasting and 2-hour postload glucose and BMI were
vancy of this effect in generally well-nourished popula- more strongly positively associated with risk of ad-
tions is unclear. Perhaps more important in well-nour- vanced colorectal adenomas than were total circulating
ished populations is insulin’s role in reducing levels of IGF-I and IGFBP-III; insulin and IGF-I appeared to
IGF binding proteins, specifically insulin-like growth fac- influence risk independently.57 In the Nurses’ Health
tor binding protein (IGFBP)-I and IGFBP-II.49 IGFBP-I Study, an association between total IGF-I and IGF-I/
binds IGF-I with high affinity and inhibits IGF-I action,50 IGFBP-III ratio and colon cancer risk was observed
which thereby increases free or bioactive IGF-I levels.51 primarily in women who were lean or who had low
Obesity is not an important determinant of circulating C-peptide levels but not in overweight women or those
levels of total IGF-I or IGFBP-III,52 but it influences the with high C-peptide levels.38 Figure 2 illustrates that
amount of free IGF-I available to cells.53 In support of the risk of colon cancer increases both with increasing
physiologic importance of the influence of insulin on IGF-I/IGFBP-III ratio and with decreasing IGFBP-I.
IGFBP-I levels, higher IGFBP-I is observed in various This pattern suggests that obesity and physical inac-
conditions associated with decreased insulin levels, in- tivity may influence cancer risk primarily through hy-
cluding fasting, exercise, and insulin-dependent (hypoin- perinsulinemia and resultant decreased IGFBP-I (and
sulinemic) diabetes mellitus.33 Thus, insulin is likely to possibly decreased IGFBP-II) level and that, in women
have a profound influence on the IGF axis, in part at high risk because of hyperinsulinemia, high total
through its direct effects on IGF-I levels but mostly IGF-I does not further increase risk. In contrast, lean
through its actions on the bioactivity of IGF-I. and physically active individuals without insulin resis-
Studies of circulating IGF-I in relation to risk of colon tance and hyperinsulinemia could still be at elevated
cancer or adenoma have generally found modest in- risk if they have high circulating IGF-I levels. In nono-
creases in risk of cancer or adenoma.33 However, in many bese individuals in adequately fed populations, genetic
studies, the associations were observed only after IGF-I determinants of total IGF-I appear to be quite
and IGFBP-III levels, which are correlated, were mutually strong,58 and even nonoverweight and active individu-
adjusted for in statistical analysis. Highest risk was gen- als could have relatively high circulating IGF-I concen-
erally observed in individuals who had relatively high trations. This finding, which requires confirmation,
IGF-I level in relation to their IGFBP-III level; those with suggests that insulin and total IGF-I levels influence
relatively low IGF-I and high IGFBP-III were at low risk.54 risk of colon cancer, and lowest risk is achieved by
The hypothesis that IGF-I enhances colorectal carcino- having low concentrations of both factors.
Table 1. Plausible Influences of Obesity on Prostate Cancer BMI.68 In a large Swedish retrospective cohort study of
Through Hormonal and Clinical Factors construction workers, BMI was a positive risk factor for
Influencesa on prostate cancer mortality.80
Recent studies have examined the association with
Changes associated with obesity Incidence Mortality BMI for high-grade and low-grade prostate cancers sep-
1 Insulin, bioavailable IGF-I 1 1 arately. An Australian cohort study reported a positive
1 Leptin 1 association between BMI and aggressive prostate cancer,
2 Testosterone, free testosterone 2 1 or 2 defined primarily by high-grade, but not with low-grade
Delayed diagnosis 2
Complicate treatment 1
prostate cancer.81 In the Prostate Cancer Prevention
Trial, higher BMI was associated with an increased risk of
a1, increased risk; 2, decreased risk. high-grade prostate cancer but a lower risk of low-grade
prostate cancer; these results are particularly interesting
because all of the men underwent biopsy, which reduces
Prostate Cancer the possibility of detection bias.82 The differential asso-
In animal studies, restriction of total energy re- ciation between obesity for high- and low-grade cancers is
duces tumor burden in a number of epithelial tumors, important because high-grade or poorly differentiated
including prostate cancer.59 However, epidemiologic cancers are more likely to progress than are low-grade
studies of obesity and body weight for prostate cancer cancers.
have been conflicting. Several factors may have contrib- Prostate-specific antigen (PSA) screening may be an-
uted to this apparent inconsistency. First, prostate cancer other modifying factor. In populations with wide-
is heterogeneous in regards to aggressive potential, and spread PSA screening, the vast majority of cases are
results may differ according to, for example, whether identified at early stages, and, furthermore, the cancers
incidence or mortality is studied. Second, results may are generally of lower aggressive potential. Thus, per-
differ according to the age group being studied. Third, haps it is not surprising that some recent United States
although obesity or high BMI is a surrogate of energy studies conducted during a time when PSA screening
balance, additional phenotypes related to energy metab- was widespread have suggested an inverse association
olism may be relevant for prostate cancer. Finally, mul- between BMI and total prostate cancer risk.83– 86 Inter-
tiple hormones may be associated with prostate cancer estingly, in a case-control study conducted in China,
risk, including androgens, IGFs, insulin, and leptin, and where cases were diagnosed in advanced stages because
these may have complex relationships with obesity and of very little screening, waist-to-hip ratio and hyperin-
with each other. We examine the evidence for obesity and sulinemia were positively associated with total prostate
related endocrinologic changes in relation to prostate cancer risk.87 This positive association with central
cancer (see summary in Table 1). adiposity was observed even though the vast majority
of men had a BMI ⬍25.
Obesity Case-only studies suggest that higher BMI is associated
BMI has been inconsistently associated with the with more aggressive prostate cancer in men who had
risk of total prostate cancer incidence.60 Prospective stud- apparently organ-confined disease.88,89 In a recent study,
ies have reported conflicting results, with some showing obesity was associated with higher grade tumors, a trend
a positive relation for BMI or body weight,61– 68 but many toward increased risk of positive surgical margins, and
not supporting an association.69 –78 In a recent meta- higher biochemical failure rates among men treated with
analysis of BMI and prostate cancer, based on 55,521 radical prostatectomy.90 Similar findings were observed
cases from cohort studies and 13,232 cases from case- in another study.91 One study found that obesity was
control studies, a very modest increase in risk of total associated with worse clinical and pathologic features of
prostate cancer was associated with increasing BMI (over- prostate cancer but not with worse prognosis.92 Thus,
all RR, 1.05, for a 5 kg/m2 increment in BMI).79 However, higher BMI, although not positively related to prostate
for studies that reported results by stage of disease, a cancer incidence, may be associated with advanced, high-
stronger association has been observed for advanced grade, or fatal prostate cancer or with worse prognostic
stage of prostate cancer, in contrast to localized disease, indicators. In contrast, for low aggressive, low-grade can-
at the time of diagnosis. In the aforementioned meta- cer, or primarily PSA-detected cancer, the association
analysis, a 5 kg/m2 increment of BMI was associated with with BMI may be inverse.
a RR of 0.96 for localized disease and a RR of 1.12 for
advanced disease (defined variably).79 When prostate can- Age Interaction
cer mortality is considered, the relative risks may be even Age may be an additional modifying factor when
stronger. The large prospective Cancer Prevention Study considering the role of obesity in prostate cancer risk.
II reported a 34% higher risk of prostate cancer death for Emerging evidence suggests a clearer positive association
a very high BMI (35⫹ kg/m2) compared with normal between obesity and advanced prostate cancer risk in
of energy intake, although the diminished sample size led

to wide confidence intervals. Also, the association of
energy intake with advanced prostate cancer was re-
stricted to men who were ⱕ65 years old. This pattern, if
confirmed, would contribute to weaker findings for obe-
sity because the comparison group is composed in part of
men with the phenotype of high energy intake but lean
body mass, who are at high risk. When compared with
men with low energy intake and lean body mass, the
increased risk associated with a higher BMI is stronger.
Figure 3. Multivariate RR of metastatic or fatal prostate cancer by Future studies need to confirm whether, indeed, this high
energy intake and BMI. In the Health Professionals Follow-Up Study,94 energy/low BMI phenotype is related to advanced pros-
highest risk of metastatic or fatal prostate cancer was observed in men tate cancer risk, and, if so, what is the mechanism.
with high energy intakes but low BMI, intermediate risk level was asso-
ciated with higher BMI, and lowest risk was observed in men with low Obesity and Sex Steroid Hormones
energy intakes and low BMI.
Androgens influence maturation of the prostate
and are believed to contribute to the development and
older individuals and a less clear, or perhaps even oppo- progression of prostate cancer. Several prospective stud-
site effect, in younger men. This pattern seems especially ies have assessed the association between circulating sex
notable in studies conducted in the PSA era. An age steroid hormone concentrations with prostate cancer
interaction was first reported in the Health Professionals risk, but only one study (the Physicians’ Health Study)
Follow-Up Study, in which among men under the age of observed that testosterone and androstanediol glucuro-
60 years, obesity was associated with about half the risk nide, a metabolite of dihydrotestosterone, were statisti-
of incident prostate cancer; the P value for interaction by cally significant positively associated with prostate cancer
age was highly significant (P ⬍ .0001).86 In the same and that estradiol and sex hormone binding globulin
cohort, obesity measures earlier in life (eg, age 10 or 20 were inversely associated with prostate cancer risk.95
years) had a strong inverse association with prostate These associations were apparent only after mutual ad-
cancer risk later in life. This latter finding was confirmed justment for these hormones. A metaanalysis of the pro-
in a population-based case-control study of African- spective studies did not find any associations with hor-
American and white men in California, in which obesity mones, except possibly for a slight positive association
at ages 20 –29 years was associated with approximately with androstanediol glucuronide.96 None of the studies
half the risk of prostate cancer in middle age or old age.84 included in the metaanalysis, except the Physicians’
A case-control study limited to a younger age-at-onset Health Study,95 adjusted for sex hormone binding glob-
prostate cancer found a significant inverse association ulin or mutually for the other hormones, which might
with BMI.85 In contrast, a Dutch study, where PSA contribute to the overall lack of case-control differences
screening was not a factor, found a positive association in hormone levels. However, mutual adjustment for tes-
between BMI at age 20 years and risk of prostate cancer.77 tosterone and estradiol in another study did not alter the
lack of associations of these hormones with prostate
Energy Intake cancer.97 The role of estrogen levels in prostate cancer
Energy intake has been evaluated in relation to risk remains quite unclear, although inverse associations
prostate cancer risk in more than 20 epidemiologic stud- with higher estrogens have been suggested in several
ies, but findings have been inconsistent.93 However, these studies.95,98
studies have not systematically considered the balance of The Prostate Cancer Prevention Trial recently showed
energy input with body size and physical activity. Also, that finasteride, which lowers dihydrotestosterone, de-
few of these studies have examined if the energy associ- creased risk of prostate cancer, but the effect may be
ation differs by whether the tumor was organ confined, primarily on well-differentiated prostate cancer; the risk
which may suggest an influence on the initial develop- of high-grade lesions was unaffected or perhaps even
ment of the tumor, or metastatic, which would suggest increased.99 A cross-sectional study100 and 2 prospective
an influence on the continued growth of the tumor. In studies101,102 found that low testosterone is associated
the Health Professionals Follow-Up Study cohort, a pos- with a higher risk of poorly differentiated prostate can-
itive association between energy intake and metastatic or cer. These studies suggest that androgens may have op-
fatal prostate cancer was observed, but this association posing effects on well- and poorly differentiated cancers
was seen primarily in nonoverweight men (BMI ⬍25) (see or that they may influence differentiation in prostate
Figure 3).94 With more extreme cut points for lower BMI cancer.
(eg, ⬍23 or 22), the RRs for advanced prostate cancer Obesity is associated with a reduction in the produc-
were even larger comparing the top to bottom quintiles tion of testosterone and an increased aromatization of
testosterone to estradiol.103 Obesity is also associated of obesity and physical inactivity, the main determinants
with an increase of leptin. Some perturbations associated of hyperinsulinemia.
with obesity are predicted to increase risk of prostate As discussed above, hyperinsulinemia, and thus obesity
cancer (eg, high leptin and insulin), whereas some may and physical inactivity, may increase IGF-I bioactivity in
decrease risk (eg, high circulating estrogen, reduced tes- various tissues.33 These effects may be important because
tosterone, perhaps lower total IGF-I); however, as dis- IGF-I promotes proliferation and inhibits apoptosis, includ-
cussed above, testosterone may influence low-grade and ing normal prostate and tumor cells in vitro115; and IGF-I
high-grade cancers differentially. Furthermore, complex levels in most although not all studies are associated with
interrelationships exist among hormones, partly because an increased risk of prostate cancer, particularly advanced
of their associations with body mass. These were illus- cancer. A metaanalysis reported a summary odds ratio of
trated in a recent study of men.104 Testosterone corre- prostate cancer of 1.47 comparing high with low IGF-I.116
lated inversely with IGF-I, IGFBP-III, insulin, leptin, and
BMI. Free testosterone was inversely correlated with lep- Leptin
tin. However, the causal direction of these relationships is Leptin, a peptide hormone that belongs to the
unclear. In another study, men with free testosterone cytokine family, controls body weight by modulating
levels in the lowest third were 2.7 times more likely to energy utilization. In obesity, individuals become leptin
have the metabolic syndrome in age-adjusted analyses resistant and exhibit elevated plasma leptin.117 Leptin
and 1.7 times more likely even after further adjusting for levels largely reflect the amount of adiposity tissue; in
BMI.105 Even after adjusting for BMI (and age), total and fact, the two are so highly correlated that they are diffi-
free testosterone were inversely associated with concen- cult to separate from each other from an epidemiologic
trations of insulin, glucose, and triglycerides. These hor- perspective. Leptin also plays a role in immune response
monal interrelationships may not just be related to severe by enhancing adipocyte secretion of interleukin 6 and
obesity but appear to span across the range of body mass. tumor necrosis factor ␣.118 Higher circulating leptin con-
centrations were associated with prostate cancer in a
Circulating Insulin, Glucose, and IGF-I cohort study119 and with prostate cancer that was of a
Insulin and glucose levels have been examined in higher volume compared with low volume on prostatec-
relation to prostate cancer risk in several studies. A case- tomy.120 A small study suggested that higher leptin level
control study conducted in China found a 2.6-fold higher is associated with a higher Gleason grade.121 However, no
risk of prostate cancer comparing the top with the bot- association was observed in a Chinese case-control study
tom tertiles of fasting plasma insulin.106 Also, in that after adjusting for BMI, waist-to-hip ratio, and insulin106;
study, higher fasting plasma glucose was positively and in a small case-control study in Greece122 or in a Swedish
higher insulin sensitivity was inversely related to prostate cohort study.123 A recent in vitro study found that leptin
cancer risk.107 Hyperglycemia, a correlate of hyperinsu- stimulated cell proliferation specifically in androgen-in-
linemia, was associated with a nonstatistically significant dependent prostate cancer cells but not in androgen-
increased risk of prostate cancer in the Chicago Heart dependent cells.124 The suggestion that leptin is a novel
Association Detection Project in Industry cohort.78 In a growth factor in androgen-independent prostate cancer
cohort study in Norway, combination of any 2 (RR, 1.23) cell growth is consistent with a role of obesity at late
or any 3 (RR, 1.56) factors of the metabolic syndrome stages.
predicted risk of prostate cancer.108 Another cohort study
in Finland found that the metabolic syndrome was asso- Type 2 Diabetes Mellitus
ciated with an increased risk of prostate cancer, especially Obesity and physical inactivity are strong risk
among overweight men.109 factors for type 2 diabetes, and diabetic individuals ini-
However, not all studies have been supportive. No tially have hyperglycemia and hyperinsulinemia, with
association between insulin and prostate cancer was ob- waning insulin concentrations over decades with pancre-
served in a prospective study in Sweden.110 In a study in atic ␤-cell depletion.43 Hyperinsulinemia might be pre-
Sweden, high insulin levels were associated with a poorer dicted to increase the risk of epithelial cancers through
prognosis from prostate cancer.111 In contrast, in a growth promotion, and, in fact, diabetes has been related
United States study, the metabolic syndrome was associ- to a higher risk of some epithelial cancers, including
ated with a lower risk of primarily PSA-detected prostate colon and pancreatic cancers.33 However, contrary to this
cancer.112 Also, no association between glucose concen- hypothesis, a number of studies have noted a reduction
tration and prostate cancer was seen in a cohort study in in prostate cancer risk among diabetic individ-
Norway.65,113 One study found that increased serum in- uals.63,125–129 Although not all studies have shown an
sulin was associated with increased risk of prostate can- association, a recent meta-analysis of studies up to 2005
cer recurrence.114 Although not entirely consistent, evi- confirmed a lower risk of prostate cancer among diabetic
dence suggests that high insulin may increase risk of individuals.130 An inverse association was also observed
prostate cancer progression, consistent with the studies in the Prostate Cancer Prevention Trial cohort; in this
study, all men underwent biopsy, which precluded the

possibility of detection bias.82 Interestingly, some studies
suggested a trend of decreasing risk of prostate cancer
from time of diagnosis of diabetes.125,126,131,132 In addi-
tion, one study observed that this risk reduction was
more pronounced among patients who have been hospi-
talized for diabetic complications.129 The associations
with time and with hospitalization suggest that some
aspect of worsening diabetes over time may decrease risk
of prostate cancer.
Men with severe type 2 diabetes mellitus manifest
lower androgen levels,133 possibly resulting from the det-
rimental effect of hyperglycemia on the Leydig cells,
which produce testosterone. Type 2 diabetes, even
though associated with obesity, is likely to be related to
reductions in leptin, especially when glucose control is
poor and hypoinsulinemia predominates.134 Thus, the
lack of an association in some studies and the reduced
risk of prostate cancer in other studies may reflect the
balance or imbalance of the beneficial effects of reduced
androgenicity against the adverse effects of hyperinsulin-
emia or hyperglycemia on growth promotion. The risk of
prostate cancer may decrease with increasing time since
diagnosis of diabetes, possibly because androgen aberra-
tions may increase with worsening of diabetes and insulin
levels may lower. Based on a metaanalysis, low testosterone
may also be a risk factor for diabetes mellitus in men, and
diabetes is associated with increased estrogen levels.135
Figure 4. Summary of association between obesity and pancreatic
cancer in cohort studies. Cohort studies were not included in this Figure
Pancreatic Cancer if the top BMI category did not consist of exclusively obese individuals
(ie, BMI ⱖ30). Three studies (Moller, Wolk, Samanic) were cohorts of
Over 85% of pancreatic cancers develop in the clinically obese (compared with the general population). Remaining
exocrine portions of the pancreas as adenocarcinoma studies were prospective cohort studies. Cut points for Calle were
and are named pancreatic ductal adenocarcinoma given higher than other studies (BMI ⱖ 35 for men and BMI ⱖ 40 for women).
their histologic resemblance to ductal cells.136 Despite
the resemblance to ductal cells, the cell of origin in
pancreatic adenocarcinoma is not known. Islet tumors and height, obtained from next of kin (ie, proxies), and
of the endocrine pancreas and other nonadenocarci- low participation rates. To date, 10 prospective cohort
noma tumors account for less than 15% of pancreatic studies, with a total of over 10,000 pancreatic cancer
cancers.136 In most epidemiological studies, pancreatic cases, have reported elevated risks of pancreatic cancer
cancer is used synonymously with exocrine pancreatic for obese individuals (BMI ⱖ30), compared with individ-
cancer because endocrine cancers are usually excluded uals of healthy weight (BMI ⬍25), with RR ranging
from the analyses or represent only a small fraction of between 1.2 and 3.0.68,140 –148 Seven prospective studies
the total cases. did not detect associations with recent BMI149 –155; but, of
these, 3 did not include a category of exclusively obese
Obesity individuals,149,151,152 2 reported statistically significant
The availability and publication of data from large positive associations with other measures of obesity
cohort studies over the past several years has changed the (weight gain of 12 or more kilograms as adults,150 waist-
totality of evidence on obesity and pancreatic cancer. to-hip ratio [RR per 0.1 increment, 1.23; 95% CI: 1.04 –
Whereas several case-control studies conducted in the 1.48]),155 and 1 reported a statistically significant associ-
1990s reported no associations between BMI and pancre- ation with BMI at age 40 years.154 In addition, elevated
atic cancer,137–139 numerous cohort studies have now risks of pancreatic cancer have also been reported among
reported positive associations (Figure 4). In light of re- overweight and obese men and women in 4 recent case-
cent cohort study data, results from earlier case-control control studies in which only direct interviews were
studies are now believed to be biased; limitations from used.156 –159
those studies, which could largely be faulted to high case A metaanalysis of 14 studies on obesity and pancreatic
fatality, included imprecise exposure data, such as weight cancer risk estimated a 19% increase in risk among obese
individuals compared with those with a normal body than in women in the Chicago study (men: multivariable
weight (RR, 1.19; 95% CI: 1.10 –1.29, for BMI 30 vs 22, RR, 2.39; 95% CI: 1.20 – 4.79; women: multivariable RR,
respectively).160 However, the results from this meta- 1.68; 95% CI: 0.57– 4.89 for ⱖ11.1 mmol/L compared
analysis included all studies, regardless of study design, with ⱕ6.6 mmol/L postload glucose level) and were un-
and, therefore, the overall effect is likely to be underesti- changed after excluding deaths in the first 5 years of
mated. The RR estimates were higher when the authors follow-up.148
excluded case-control studies with proxy data or those In 2 other studies, the Korean Cancer Prevention Study
studies that had not adjusted for smoking in their anal- and the Alpha-Tocopherol Beta-Carotene (ATBC) Cancer
yses. Prevention Study, fasting serum glucose levels were mea-
sured. In the Korean study, fasting serum glucose levels
Diabetes Mellitus were measured on all participants at baseline, and par-
Pancreatic cancer patients are often diagnosed ticipants were followed for 10 years; both men and
with type 2 diabetes several months to several years prior women considered to have diabetes (fasting blood glu-
to being diagnosed with cancer; in these patients, unde- cose of at least 7.0 mmol/L or medication) had a higher
tected pancreatic cancer is likely the cause of the recent risk of pancreatic cancer death (men: age-adjusted RR,
onset of diabetes. Because diabetes is a manifestation of 1.71; 95% CI: 1.42–2.06; women: age-adjusted RR, 1.71;
pancreatic cancer, a long-standing controversy exists over 95% CI: 1.25–2.34).164 Removing the first 5 years of fol-
the role of type 2 diabetes in the etiology of pancreatic low-up in the Korean study only attenuated the associa-
cancer. Despite numerous epidemiologic studies report- tion slightly (men: age-adjusted RR, 1.5; 95% CI: 1.2–1.9).
ing positive associations between diabetes and pancreatic In the ATBC study, serum glucose levels were measured
cancer, reverse causation could not be ruled out as an in stored blood samples in all 169 incident pancreatic
explanation for the earlier findings. Examining the dura- cancer cases that were diagnosed between 5 and 16.7
tion of diabetes prior to cancer was critical to under- years of follow-up and in a subset of the cohort (400
standing whether diabetes is a risk factor, in addition to controls); a 2-fold increase in risk was observed for dia-
being a consequence, of pancreatic cancer. A metaanalysis betic individuals (multivariable RR, 2.13; 95% CI: 1.04 –
published in 1995 of 20 studies estimated that long- 4.35, for ⱖ7 mmol/L vs ⬍7 mmol/L).165
standing diabetes (5 years or more) increased pancreatic In all 4 of these studies, statistically significant dose-
cancer risk 2-fold (RR, 2.0; 95% CI: 1.2–3.2).161 In an response associations were observed between glucose lev-
updated metaanalysis based on 50 studies, the associa- els and pancreatic cancer. In the Korean study, even
tion between established diabetes and pancreatic cancer relatively low glucose levels (between 90 and 109 mg/dL)
was slightly weaker than in the earlier metaanalysis but were associated with a significant elevated risk of pancre-
remained statistically significant (compared with nondi- atic cancer mortality in women (compared with ⬍90
abetic individuals: RR, 1.5; 95% CI: 1.3–1.8 and RR, 1.5; mg/dL: RR, 1.45; 95% CI: 1.16 –1.81).
95% CI: 1.2–2.0, for 5–9 years and 10⫹ years of existing The results from these studies and those that have
diabetes prior to cancer, respectively).162 When analyzed examined the association between diabetes and pancre-
separately, results from cohort and case-control studies atic cancer risk strongly support a causal role for type 2
were similar,162 suggesting that bias is unlikely to explain diabetes in pancreatic cancer etiology. At this time, the
the excess risk observed in these studies. causal factors related to diabetes are unknown, but insu-
lin has been a primary candidate, given the existing ex-
Studies with Blood Glucose Measures perimental data on the role of insulin in other cancers (as
The direct relation between blood glucose levels discussed in the section on colon cancer).
and pancreatic cancer risk has been examined in prospec-
tive studies in which measurements were obtained from Role of Insulin
healthy individuals. In 2 studies, the Whitehall study and The ATBC study is the only study to date that has
the Chicago Heart Association Detection Project, individ- directly examined the relation between prediagnostic se-
uals participated in a postload test at baseline; blood was rum insulin levels and pancreatic cancer risk. In this
drawn 1 hour148 or 2 hours163 after administering a 50-g study, a 2-fold increase in risk was observed after exclud-
oral glucose load for measurement of plasma glucose. In ing cases in the first 5 years of follow-up (RR, 2.01; 95%
these 2 studies, a postload glucose level of ⱖ11.1 CI: 1.03–3.93, for the highest vs lowest quartile of insulin
mmol/L, a standard cut point used to define diabetes, level).165
was associated with 2- to 4-fold elevation in risk of Animal data are not entirely supportive of a direct role
pancreatic cancer death over the follow-up period of 25 for insulin in pancreatic carcinogenesis. Although insulin
years.148,163 In the Whitehall study, the 4-fold increase in promotes growth of hamster and human pancreatic cell
risk was only modestly attenuated when conducting the lines in vitro,166,167 administration of exogenous insulin
same analyses removing deaths occurring in the first 10 in the hamster pancreatic cancer model inhibits tumor
years of follow-up.163 Associations were stronger in men induction.168 Although pancreatic cancer in the hamster
model resembles human pancreatic ductal adenocarci- dial glucose response of individual food items compared
noma, new transgenic mouse models169 may provide new with a reference food; refined grains, such as white bread
insights into the role of insulin. or white rice, produce a larger increase in postprandial
Although insulin per se may not be directly carcinogenic glucose levels than foods such as whole grain foods.
to the pancreas, considerable evidence suggests that the Glycemic load reflects both the quality (ie, glycemic in-
complex processes that can lead to a diabetic state, includ- dex) and the quantity of the carbohydrates that are con-
ing peripheral insulin resistance and impaired glucose tol- sumed by individuals. Glycemic load has been related to
erance, are likely to play a role in pancreatic carcinogenesis. risk of diabetes in several large studies180,181 and there-
Animal studies suggest that islet cell turnover, associated fore may also be relevant in pancreatic carcinogenesis.
with insulin resistance, is critical to pancreatic carcinogen- Two studies have examined the relation between gly-
esis. In hamsters, the stimulation of islet cell proliferation cemic index and load and pancreatic cancer risk. In one
enhances pancreatic ductal carcinogenesis,170 and the de- prospective study of women, an increase in risk was
struction of islet cells by streptozotocin or alloxan inhibits observed with higher intakes of glycemic load.174 The
cancer induction.171 Furthermore, development of chemi- association was stronger among women who were either
cally induced ductal-type pancreatic cancer in hamsters was overweight or sedentary, 2 physiologic states that are
completely inhibited by the addition of the drug metformin associated with greater insulin resistance.174 In contrast,
to the diet of hamsters with peripheral insulin resistance. no associations were reported for glycemic index or load
Because metformin normalizes the rate of islet cell turnover, and pancreatic cancer risk in another prospective
the study lends support to the role of islet cell proliferation, study.176
stimulated by insulin resistance, in ductal pancreatic can-
cer.172 Mechanisms for Obesity and Pancreatic
Cancer
Carbohydrate, Sugar, and Glycemic Index In addition to insulin and insulin resistance, other
A number of observational studies have examined mechanisms may explain the relation between obesity
the relation between carbohydrate intake and pancreatic and pancreatic cancer; these include a role for IGFs and
cancer risk, but findings have been inconsistent. Al- oxidative stress.
though a number of case-control studies reported higher IGF. Insulin and the IGF-I axis function in an
risk of pancreatic cancer with elevated carbohydrate in- integrated fashion to promote cell growth and survival.
take,138,173 several cohort studies, which are less prone to IGF-I and IGF-I receptors are highly expressed in pancre-
recall and selection bias, did not observe positive associ- atic cancer cell lines,182 and initiation of intracellular
ations for total carbohydrate intake.152,174 –176 signaling through the IGF-I receptor leads to an increase
Refined sugar, added sugar, and fructose intake have in proliferation, invasion, and expression of mediators of
been positively associated with pancreatic cancer in 4 angiogenesis and a decrease in apoptosis in pancreatic
studies. In a case-control study, sugar added to coffee, tumor cell lines.183 Blocking the IGF-I receptor decreases
cereal, fruit, and other foods was associated with a greater human pancreatic cancer growth and up-regulates stres-
than 3-fold risk among women (top to bottom tertile sor-induced apoptosis.184
comparison: RR, 3.7; 95% CI: 1.5–9.1).173 A 2-fold increase Two retrospective studies have examined the associ-
in risk was observed for the intake of refined sugar in ation between IGFs and pancreatic cancer risk. In one
another case-control study.177 In a United States prospec- study, elevated levels of serum IGF-I, IGFBP-III, and
tive study, fructose (from high-fructose syrup) was asso- IGFBP-I were measured in patients with pancreatic
ciated with a nonsignificant increase in risk (RR, 1.57; cancer compared with controls.185 No association was
95% CI: 0.95–2.57),174 and an increased risk was also observed for serum IGF-I, IGF-II, or IGFBP-III and
observed with sweetened soda.178 Soft drink consump- pancreatic cancer in a case-control study of 20 patients
tion and added sugar (to coffee, tea, cereals, and others) and 20 controls.186 Because plasma samples were col-
were also related to elevated pancreatic cancer risk in a lected after cancer diagnosis and cancer can influence
different cohort study conducted in Sweden (association the levels of these hormones, these studies are of lim-
after removing first 2 years of follow-up: RR, 2.30; 95% ited use in determining whether IGF plays a role in the
CI: 1.35–3.92, for ⱖ2 servings/day vs never for soda etiology of pancreatic cancer.
consumption; RR, 1.95; 95% CI: 1.10 –3.46, for 5 servings/ To date, only 2 prospective studies with each fewer
day vs never adding sugar).179 than 100 cases have examined the relation between IGF-I
Total carbohydrate, however, combines refined and and IGFBP-III levels and pancreatic cancer risk.187,188 In
whole grains and therefore may not represent the intake the ATBC study, no association was observed for plasma
of interest with respect to glucose and insulin response. IGF-I, IGFBP-III, or IGF-I/IGFBP-III ratio and pancreatic
Research on diabetes and cardiovascular disease has fo- cancer risk.187 In the other study conducted in Japan, a
cused on glycemic index when evaluating the effect of slightly higher risk of pancreatic cancer was observed
diet on risk. The glycemic index represents the postpran- with elevated plasma IGF-I or IGFBP-III (highest vs low-
est quartile comparison, IGF-I: RR, 2.31; 95% CI: 0.70 –

7.64; IGFBP-III: RR, 2.53; 95% CI: 0.93– 6.85, P trend ⫽
.03).188
There is currently insufficient data on IGFs and pan-
creatic cancer to determine whether these hormones are
involved in pancreatic carcinogenesis. Future studies,
based on animal and human analyses, should shed light
on the relation between IGFs and pancreatic cancer.
Hyperglycemia and oxidative stress. Mechanisms
that underlie and explain complications that result from
diabetes are being unraveled, and recent discoveries have
unified many of the pathways known to be involved with
different complications.189 In diabetic individuals, hyper-
glycemia in susceptible cells results in the overproduction
of superoxide by the mitochondrial electron-transport
chain, and this process is the key to initiating all dam-
aging pathways related to diabetes.189 In the pancreatic
duct adenocarcinoma cell line Capan-1, hyperglycemia
specifically activates the polyol pathway through in-
creased expression and activity of aldose reductase.190
Busik et al hypothesized that the hyperglycemia-induced Figure 5. Proposed model of mechanisms through which diabetes
can increase risk of pancreatic cancer (See text for details.)
activation of polyol metabolism may explain the de-
creased pancreatic secretion observed in insulin-depen-
dent diabetes mellitus patients.190 In vascular epithelial
cells, glucose-induced activation of sorbitol accumula- Elevated fructose concentrations may directly contrib-
tion and nuclear factor-␬B activation can be prevented by ute to oxidative stress in pancreatic cancer cells by inac-
normalizing levels of mitochondrial reactive oxygen spe- tivating cellular antioxidants. In a study of hamster islet
cies.191 The levels of reactive oxygen species can be de- tumor cells, GPx was inactivated by fructose, and mes-
creased by an inhibitor of electron transport chain com- senger RNA GPx expression was suppressed by fruc-
plex II, by an uncoupler of oxidative phosphorylation, by tose.194 Whether the effects of hyperglycemia-induced
uncoupling protein-1, and by manganese superoxide dis- oxidative stress or elevated fructose levels are sufficient to
mutase (MnSOD).191 These findings suggest that hyper- cause DNA damage in pancreatic tissue and contribute to
glycemia may be directly contributing to oxidative stress pancreatic carcinogenesis remain to be determined.
in pancreatic ductal cells. Figure 5 is a simplified sche-
matic diagram of the proposed mechanisms through Discussion
which hyperglycemia could directly contribute to pancre- High BMI, physical inactivity, and visceral adipos-
atic cancer. ity as assessed by circumference measures or scanning
Several animal studies indicate that oxidative stress is techniques are consistent risk factors for colon cancer
important in pancreatic cancer. MnSOD prevents the and adenoma. These factors are the major modifiable
formation of superoxide in the mitochondria and can determinants of insulin resistance and hyperinsulinemia
inhibit 3 pathways of hyperglycemia damage.191 In pri- and of the metabolic syndrome. In addition, patients
mary pancreatic cancer cell lines, MnSOD activity was with type 2 diabetes mellitus, one of the major conse-
decreased when compared with normal human pancreas quences of long-standing insulin resistance, and of the
and activity correlated with pancreatic tumor cell dou- metabolic syndrome for which insulin resistance is a key
bling time. Furthermore, enforced expression of MnSOD etiologic factor, have a higher risk of colon cancer. Most
using adenovirus gene transfection increased MnSOD studies show that elevated fasting or 2-hour glucose
activity and decreased growth rate of the rapid growing levels increase risk of colon cancer or adenoma. In addi-
cell line MIA PaCa-2.192 Additional studies have also tion, most studies of 2-hour insulin or C-peptide levels,
reported lower levels of other cellular antioxidants, markers of hyperinsulinemia, have found an association
namely copper/zinc superoxide dismutase, catalase, and with colon cancer or adenoma risk.
glutathione peroxidase (GPx), in human pancreatic can- Hyperinsulinemia appears to be a consistent marker of
cer specimens compared with normal pancreatic speci- enhanced colon cancer risk. It remains unclear whether
mens.193 These findings suggest that cellular antioxidants this is due to direct effects of insulin on tumor growth or
may play a role in regulating pancreatic tumor growth, to closely related hormonal changes, such as an increase
although these mechanisms still need to be examined in in bioavailable IGF-I. Furthermore, other hormones as-
vivo. sociated with insulin resistance, such as leptin and adi-
ponectin, have been associated with colon cancer risk in plausible biologic and nonbiologic influences of obesity
limited studies to date.195–197 However, one study did not on prostate cancer incidence and mortality are displayed
support an association with adiponectin.198 Future stud- in Table 1.
ies examining multiple hormones simultaneously will be Although type 2 diabetes is associated with obesity,
required to attain a better understanding of their role in with worsening disease, several hormonal disturbances
colon carcinogenesis. occur that could reduce risk of prostate cancer: (1) hy-
For obesity and prostate cancer, various factors appear poinsulinemia, which also may reduce leptin levels and
to contribute to a complex epidemiologic pattern. Obe- decrease free IGF-I, (2) reduction of testosterone, and (3)
sity seems to contribute to a greater risk of aggressive or higher estrogen levels. These hormonal characteristics
fatal prostate cancer but perhaps to a lower risk of non- could account for the lower risk of prostate cancer in
aggressive prostate cancer, particularly for well-differen- diabetic individuals. Understanding why type 2 diabetes
tiated cancers diagnosed in the PSA era. The protective is associated with a lower risk of prostate cancer may
aspects of obesity may possibly be stronger for obesity provide some insight into the hormonal etiologies of
earlier in life and for younger age-at-onset prostate can- prostate cancer.
cers, but this finding requires confirmation. Another Over the past decade, the role of diabetes in pancreatic
complexity that requires further study is that, although cancer etiology has been clarified; long-standing type 2
obesity increases risk of aggressive prostate cancer, men diabetes increases the risk of pancreatic cancer by approx-
who have high energy intake but have a metabolic phe- imately 50%. Diabetes also manifests as a consequence of
notype such that they remain lean may also be at high pancreatic cancer, and removal of the tumor often im-
risk. proves impaired glucose tolerance, but this fact does not
The mechanisms whereby obesity may contribute to invalidate the association between long-standing diabetes
increased risk of prostate cancer progression are unclear, and pancreatic cancer risk. Furthermore, over the past 6
but several hormonal factors could contribute: increased years, a large number of cohort studies, which are not
insulin, increased free IGF-I, and increased leptin. In
prone to recall or selection bias, have reported positive
addition, obesity is associated with decreased testoster-
associations between obesity and pancreatic cancer. To-
one, which may decrease differentiation in existing tu-
gether with data from prediagnostic blood specimens
mors. At the low end of energy balance, for example in a
showing positive associations between glucose levels and
traditional agrarian population with few overweight in-
pancreatic cancer up to 25 years later, sufficient evidence
dividuals, a positive association between BMI and pros-
now supports a strong role for diabetes and obesity in
tate cancer may be clear because levels of essentially all
pancreatic cancer etiology.
relevant hormones will be in the direction of higher risk
The mechanisms for these associations, however, re-
(ie, high IGF-I, insulin, leptin, testosterone) with increas-
main speculative and deserve further study. The role of
ing BMI. However, with increasing levels of adiposity (eg,
insulin appears to be indirect, through stimulation of
beyond BMI of 25 or 30), the association between BMI
and prostate cancer risk is attenuated or may be even islet cell proliferation and turnover. These mechanisms
inverse because of disturbances in hormones such as have been examined in hamster models, in which insulin
testosterone. resistance appears to play a key role; in these models,
Beyond the complexities of hormonal changes associ- inhibition of insulin resistance prevents tumor develop-
ated with obesity that could either increase or decrease ment. Alternatively, IGFs have been proposed as respon-
prostate cancer incidence, and influence prognosis simi- sible hormones because insulin and IGF are tightly inte-
larly or differently, nonbiologic factors related to treat- grated; the observational data so far on IGF-I, however,
ment may also be relevant. In regards to diagnosis in the do not support this mechanism. The role of oxidative
obese, digital rectal examinations may be impaired, PSA stress initiated by hyperglycemia also deserves further
may be reduced because of lower androgenicity,199 non- attention.
cancerous prostate volume may be increased, and physi- Future research on pancreatic cancer should include
cians could be less aggressive in performing tests for new animal studies aimed at elucidating the mechanisms
screening and diagnosis. In addition, treatment could be that are responsible for the diabetes and obesity associ-
delayed because of later diagnosis for the above reasons. ations. Understanding the underlying pathways will pro-
Furthermore, it is possible that effective treatments, such vide new opportunities for early detection and treatment.
as prostatectomy, could be avoided because of technical Observational studies can also provide some answers on
difficulties or comorbidities. If prostatectomy is per- questions that remain: Is there a period during life when
formed, surgery may be more difficult, which could result weight gain is particularly detrimental to pancreatic can-
in higher rates of positive margin.200 The overall influ- cer risk? Is BMI an adequate measure for this disease, or
ences of obesity on diagnosis and treatment would gen- would waist-to-hip ratio (reflecting abdominal adiposity)
erally be in the direction of reducing apparent incidence provide a clearer association? Can diet modifications re-
and increasing mortality. A summary of the direction of duce risk? Does genetic susceptibility play a role?
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GASTROENTEROLOGY 2007;132:2208 –2225

The Role of Obesity and Related Metabolic Disturbances in Cancers of

Because a number of metabolic consequences are as-

linemic effect of diet, predicted colon cancer risk more

of energy intake, although the diminished sample size led

study, all men underwent biopsy, which precluded the

est quartile comparison, IGF-I: RR, 2.31; 95% CI: 0.70 –

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