Insulin resistance and cancer: Epidemiological
Shoichiro Tsugane1and Manami Inoue
Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
(Received November 24, 2009 ⁄Revised January 8, 2010 ⁄ Accepted January 28, 2010)
Over the last 60 years, Japanese people have experienced a rapid
and drastic change in lifestyle, including diet. Suspicions have
been raised that so-called ‘Westernization’, characterized by a
high-calorie diet and physical inactivity, is associated with increas-
ing trends in the incidence of cancer of the colon, liver, pancreas,
prostate, and breast, as well as type 2 diabetes. Epidemiological
evidence from our prospective study, the Japan Public Health Cen-
ter-based Prospective (JPHC) study, and systematic literature
reviews generally support the idea that factors related to diabetes
or insulin resistance are associated with an increased risk of colon
(mostly in men), liver, and pancreatic cancers. These cancers are
inversely associated with physical activity and coffee consump-
tion, which are known to decrease the risk of type 2 diabetes. The
suggested mechanism of these effects is that insulin resistance
and the resulting chronic hyperinsulinemia and increase in bio-
available insulin-like growth factor 1 (IGF1) stimulate tumor
growth. In contrast, associations with diabetes are less clear for
cancer of the colon in women, and breast and prostate, which are
known to be related to sex hormones. The effect of insulin resis-
tance or body fat on sex-hormone production and bioavailability
may modify their carcinogenic effect differently from cancers of
the colon in men, and liver and pancreas. In conclusion, there is
substantial evidence to show that cancers of the colon, liver, and
pancreas are associated with insulin resistance, and that these can-
cers can be prevented by increasing physical activity, and possibly
coffee consumption. (Cancer Sci 2010)
nomic growth occurring following World War II has been
accompanied by the so-called ‘Westernization’ of lifestyle, char-
acterized by a high-calorie diet and physical inactivity. Parallel-
ing this change, the mortality of infectious diseases has
decreased while that of lifestyle-related diseases such as cancer
and heart disease has increased. Cancer has been the leading
cause of death since 1981, and now accounts for 30% of all
deaths. Among various cancer sites, cancers of the colon, pan-
creas, breast, and prostate, which are known to be more common
in Western countries, have increased in Japan. Most but not all
of these cancers have been shown to be associated with greater
body (or abdominal) fatness and physical inactivity.
Here, we review the associations observed in our prospective
study, the Japan Public Health Center-based Prospective (JPHC)
study, between body fatness, diabetes, physical activity, coffee
consumption (which may affect diabetes), and the risk of cancer,
as well as the epidemiological literature on this topic. Evidence
is discussed with a special focus on the role of insulin resistance.
In brief, the JPHC study conducted a baseline survey of regis-
tered residents aged 40–69 years in 11 public health center areas
nationwide in 1990–1994. Approximately 110 000 subjects
apanese people have experienced a rapid and drastic change
in lifestyle, including diet. The industrialization and eco-
returned the questionnaire, giving a response rate of 81.0%, and
50 000 provided blood and health check-up data.(1)The subjects
have been followed for vital status and the occurrence of cancer
and other diseases, and 5- and 10-year follow-up surveys have
been conducted to update information on lifestyle and health
Time trend analysis
According to the annual National Nutrition Survey by the Minis-
try of Health, Labour and Welfare (MHLW) (Fig. 1), and allow-
ing for the lack of age-adjustment, total energy intake (per
capita per day) increased from 1903 kcal in 1946 to peak at
2287 kcal in 1971. It then followed a downward trend, decreas-
ing to 1891 kcal in 2006. The rapid increase in fat intake
(14.7 g in 1946 to 48.7 g in 1971) owed mainly to the increase
in total energy during the period of post-war reconstruction and
high economic growth. The constant decrease in carbohydrate
intake and leveling off of fat intake resulted in a decreasing
trend in total energy intake after the mid-1970s, probably when
physical activity decreased (due to the spread of electrification
and automobile use in daily life and at the workplace) and the
westernization of Japanese dietary habits plateaued.
In Japan, age-adjusted mortality rates of colon, liver, and pan-
creatic cancers steadily increased up to the mid-1990s, and then
flattened out or decreased. The exception to this trend was liver
cancer, which switched from a decrease to an increase around
the 1970s, probably due to endemic hepatitis virus infection
(Fig. 2). Cancer incidence rates for Japanese people are only
available for the years after 1975 and the quality of incidence
data is not considered high enough to allow comparison of long-
term trends.(2)However, allowing for this insufficient quality,
incidence rates of these cancers have fluctuated in parallel with
mortality rates. For cancer of the liver and pancreas in particu-
lar, mortality rate can be deemed as a substitute for incidence
rate due to their poor prognoses.
These trends in dietary and cancer mortality pattern appear to
be parallel with a lag time of approximately 20 years. Cancers
of the colon, liver, and pancreas might therefore be associated
with energy imbalance, with incubation periods of 20 years.
Cancers of the breast and prostate have shown different trends,
however, increasing even after the mid-1990s. The etiology of
these cancers may differ somewhat from those of the colon,
liver, and pancreas.
This parallel trend in suspected energy imbalance and cancers
of the colon, liver, and pancreas may indirectly support a
close link with insulin resistance, as characterized by energy
1To whom correspondence should be addressed. E-mail: email@example.com
ª ª 2010 Japanese Cancer Association
Body fatness, abdominal fatness, and cancer
In the JPHC study, overweight and obesity as measured by body
mass index (BMI) were associated with specific sites of cancer
such as male colorectum,(3)postmenopausal breast,(4)and liver
among subjects with hepatitis C virus (HCV) infection.(5)By
contrast, they had little impact on cancer of the pancreas(6)or
cancer at all sites.(7)
The World Cancer Research Fund and American Institute for
Cancer Research have evaluated causal relationships between
several factors and each cancer based on systematic reviews of
epidemiological evidence as well as mechanistic interpretations
and data from animal experimental models.(8)Greater body fat-
ness convincingly increased the risk of cancers of the esophagus
(adenocarcinoma only), colorectum, pancreas, postmenopausal
breast, endometrium, kidney, probably the gallbladder, and pos-
sibly the liver. In addition, greater abdominal fatness as mea-
sured by waist circumference or waist to hip ratio convincingly
increased the risk of colorectal cancer and probably cancers of
the pancreas, postmenopausal breast, and endometrium.
Based on a meta-analysis of 221 datasets (141 articles) report-
ing 282 000 incidence cases,(9)the magnitude of risk was
greaterforesophageal adenocarcinoma(relative risk
[RR] = 1.52, P < 0.0001, with a 5 kg⁄m2increase in BMI), thy-
roid (RR = 1.33, P < 0.0001), colon (RR = 1.24, P < 0.0001),
renal (RR = 1.24, P < 0.0001), and liver (RR = 1.24, P = 0.12)
cancers in men, and endometrial (RR = 1.59, P < 0.0001), gall-
bladder (RR = 1.59, P = 0.04), esophageal adenocarcinoma
(RR = 1.51, P < 0.0001), and renal (1.34, P < 0.0001) cancers
in women. The relative risk was 1.09 (P < 0.0001) for female
colon cancer, with this gender difference being highly statisti-
cally significant (P < 0.0001).
The proportions of all cancer deaths in the US population
attributable to overweight and obesity (BMI >25 kg⁄m2) have
been estimated at 4.2–14.2% in men and 14.3–19.8% in
women.(10)Incident cancer burden attributable to excess body
mass index across 30 European countries has been estimated at
2.5% (95% confidence interval [CI], 1.5–3.6%) in men and
4.1% (95% CI, 2.3–5.9%) in women.(11)In contrast, respective
figures in the JPHC study have been negligible, since no statisti-
cally significant increase in risk for cancer at any site has been
observed in overweight and obesity categories in either men or
Possible mechanisms of the effect of body fatness on cancer
risk are explained by increased bioavailable growth-factor pro-
duction (e.g. insulin, insulin-like growth factor [IGF] 1) due to
per day) in Japan. Data source: The National
Nutrition Survey by the Ministry of Health, Labour
and Welfare of Japan.
Time trends in nutrient intake (per capita
population in 1985). Data source: Vital Statistics
Reports by the Ministry of Health, Labour and
Welfare of Japan.
Trends in mortality rates of selected cancers
ª ª 2010 Japanese Cancer Association
insulin resistance, sex-hormone production (e.g. estrogen, testos-
terone), chronic local inflammation characterized by the creation
of reactive oxygen species and the induction of cell cycling for
tissue growth and repair, and chronic gastroesophageal reflux
(for adenocarcinoma of the esophagus).
Diabetes and cancer: Epidemiological evidence
In the JPHC study, a history of diabetes was associated with an
increased risk of several cancer sites after adjustment for poten-
tial confounding factors such as age, study area, history of cere-
brovascular disease, history of ischemic heart disease, smoking,
ethanol intake, body mass index, leisure-time physical activity,
green vegetable intake, and coffee intake (Fig. 3).(12)In men,
statistically significant increases were observed for cancers of
the colon, liver, pancreas, and kidney. Hazard ratios (HRs) were
almost double for cancers of the liver, pancreas, and kidney, and
remained so after the exclusion of cases occurring within
5 years of follow-up. In women, HRs were statistically signifi-
cant for cancers of the stomach and liver.
Although not statistically significant due to the small number
of cases, elevated HRs were also shown for cancers of the pan-
creas, endometrium, ovary, and kidney. In contrast, no associa-
tion was seen with colon and breast in women. These increases
in risk in several cancers resulted in a 27% increase in total can-
cer in men and a 21% increase in women.
In Japan, only a few cohort studies have evaluated the associa-
tion between diabetes and total cancer risk. A report from the
Takayama study on the history of diabetes and mortality risk
also showed an increased risk of cancer mortality with a history
of diabetes (HR = 1.88; 95% CI, 1.16–3.05) among women.(13)
However, the Japan Collaborative Cohort (JACC) study on the
association between a history of diabetes and cancer mortality
showed no significant impact of a history on total cancer risk
in either men (HR = 0.98) or women (HR = 0.83), although an
increased risk was observed for liver cancer in both sexes
(HR = 2.30; 95% CI, 1.47–3.59 in men and HR = 2.70 95%
CI, 1.20–6.05 in women) and non-Hodgkin lymphoma in men
(HR = 2.77; 95% CI, 1.04–7.38), while a decreased risk was seen
for stomach cancer in both sexes (HR = 0.67; 95% CI, 0.46–0.99
in men and HR = 0.49; 95% CI, 0.23–1.04 in women).(14)
Findings similar to those of the JPHC study were seen in a
10-year prospective cohort study of 1.3 million Koreans aged
30 to 95 years.(15)Elevated fasting serum glucose levels
(‡140 mg⁄dL) were associated with higher death rates for all
cancers combined (HR = 1.29; 95% CI, 1.22–1.37 in men and
HR = 1.23; 95% CI, 1.09–1.39 in women) compared with sub-
jects with the lowest level (<90 mg⁄dL). By cancer site, the
association was strongest for pancreatic cancer (HR = 1.91;
95% CI, 1.52–2.41 in men and HR = 2.05; 95% CI, 1.43–2.93
in women). Significant associations were also found for cancers
of the esophagus (1.44), liver (1.57), and colorectum (1.31) in
men and liver (1.33) in women. In contrast, the HR of colorectal
cancer mortality was 0.85 in women.
Meta-analyses, derived mainly from Western populations,
support the idea that diabetes (e.g. self-report, or elevated
blood glucose level in fasting or after glucose load) was
associated with an increased risk of cancers of the liver
(summary HR = 2.5; 95% CI, 1.8–2.9 among 13 case-control
and 12 cohort studies),(16)pancreas (HR = 1.82; 95% CI,
1.66–1.99 among 17 case-control and 19 cohort studies),(17)
colorectum (HR = 1.30; 95% CI, 1.20–1.40 among six case-
control and nine cohort studies),(18)breast (HR = 1.20; 95%
CI, 1.12–1.29 among five case-control and 15 cohort stud-
ies),(19)and endometrium (HR = 2.10; 95% CI, 1.75–2.53
among 13 case-control and three cohort studies).(20)In con-
trast, diabetes was inversely associated with the risk of pros-
tate cancer (HR = 0.84; 95% CI, 0.76–0.93 among seven
case-control and 12 cohort studies).(21)
Possible mechanisms relating diabetes to cancer risk
The findings of a nested case-control study within the JPHC
study showed that plasma levels of C-peptide, a marker of insu-
lin resistance, were strongly associated with the risk of colorec-
tal cancer in men, specifically colon cancer, but not in women
(Fig. 4).(22)Similar findings were observed in two nested case-
control studies within cohort studies in the USA: C-peptide was
strongly associated with the risk of colorectal cancer in the Phy-
sicians’ Health Study (men),(23)but not in the Nurses’ Health
These data support the ideas that insulin resistance and the
chronic hyperinsulinemia which results may increase the risk of
colon cancer, and that this carcinogenic effect may be modified
by hormone production and bioavailability in women. The
mechanisms of insulin resistance and cancer risk were first
proposed with regard to the pathogenesis of colon cancer, and
subsequently expanded to include those of breast, pancreas, and
endometrium. They have been reviewed in detail.(25)
In brief, an increase in insulin levels leads to a decrease in the
liver synthesis and blood levels of insulin-like growth factor
binding protein 1 (IGFBP1), and is associated with a decrease in
IGFBP2 in the blood. These effects in turn result in an increase
in bioavailable IGF1. Insulin and IGF1 signal through insulin
receptors and IGF1 receptors, respectively, to promote cellular
proliferation and inhibit apoptosis in many tissue types. These
effects might contribute to tumorigenesis. Insulin resistance also
causes a decrease in circulating levels of sex-hormone-binding
(JPHC) study. Adjusted for age, study area, history
of cerebrovascular disease, history of ischemic heart
disease, smoking, ethanol intake, body mass index,
intake, and coffee intake. Data source: Inoue
History of diabetes and risk of cancer: the
Tsugane and InoueCancer Sci|
ª ª 2010 Japanese Cancer Association
globulin (SHBG) and an increase in the bioavailability of estra-
diol and testosterone. In parallel, adipose tissue produces the
enzymes aromatase and 17b-hydroxysteroid dehydrogenase and
increases estradiol production. Estradiol production is accord-
ingly higher in obese individuals, who are characterized by insu-
lin resistance. The combined effect of increased bioavailability
and formation of estradiol and testosterone can impact target
cells where these hormones bind to estrogen and androgen
receptors. The effect of sex steroid binding with receptors can
vary, depending on tissue type, but in some tissues (e.g. breast
epithelium and endometrium), binding promotes cellular prolif-
eration and inhibits apoptosis.
However, the magnitude of associations between diabetes and
typical sex hormone-related cancers such as breast and prostate
are less clear (summary HR by meta-analysis = 1.20 for
breast(19)and 0.84 for prostate(21)) than those for other diabetes-
related cancers(summary HR
pancreas,(17)and endometrium(20)). The pathway of insulin
resistance to carcinogenesis in sex hormone-related cancers
therefore appears complicated. Although endometrial cancer is
known to be hormone-related, the effects of combined estrogen-
progestagen oral contraceptives and tamoxifen, a selective
estrogen-receptor modulator, act in opposing directions in the
endometrium and breast(26)and are more closely associated with
body fatness. For colon cancer, the association with diabetes
and body fatness is less clear in women, because female sex
hormones may modify the effect of insulin resistance in colon
epithelium. A randomized controlled trial showed that the use of
estrogen plus progestin was associated with a decreased risk of
colorectal cancer in women.(27)
Physical activity and cancer
Physical activity is well known to reduce the risk of type 2
diabetes,(28)as well as colon and female hormone-related
cancers, such as postmenopausal breast and endometrium,
independently of other factors such as body fatness. Due to
the small number of studies, however, evidence suggesting
that physical activity protects against cancers of the liver and
pancreas is limited.
In the JPHC study, physical activity (calculated as metabolic
equivalents (METs) score) showed a statistically significant
inverse trend for colon and pancreatic cancers in men and for
stomach cancer in women (Fig. 5).(29)A similar tendency was
seen for liver cancer in both men and women. Among other sites,
a statistically significant decrease was seen for stomach cancer
in women, whereas no decreasing trend was seen for breast can-
cer. The decreases in these cancers led to a statistically signifi-
cant inverse trend for cancer as a whole in both men and women.
Physical activity may reduce the risk of colon, liver, and
pancreatic cancers, which are diabetes-related, by inhibiting
insulin resistance and hyperinsulinemia.
P trend = 0.025
P trend = 0.54
Lowest SecondThird Highest
a nested case control study within the Japan Public
Matched by sex, age, date of blood drawn, time
since last meal, and study area. Adjusted for
smoking, ethanol intake, body mass index, leisure-
colorectal cancer. Data source: Otani et al.(22)
Plasma C-peptide and risk of colon cancer:
liver, and pancreas: the Japan Public Health Center-
based Prospective (JPHC) study. HR, hazard ratio.
Data source: Inoue et al.(29)
Physical activity and cancers of the colon,
ª ª 2010 Japanese Cancer Association
Coffee consumption and cancer
Many recent reports have provided evidence of an inverse asso-
ciation between coffee consumption and diabetes(30)and several
sites of cancer.
In the JPHC study, coffee consumption was inversely associ-
ated with diabetes(31)and several cancer sites such as liver,(32)
colon (women),(33)pancreas (men) (Fig. 6),(34)and endome-
trium.(35)For liver cancer, a similar risk tendency was observed
in those with either or both HCV and hepatitis B virus (HBV)
A meta-analysis has supported the association of coffee con-
sumption with a decreased risk of cancers of the liver(37)(sum-
mary HR = 0.45; 95%CI,
consumption category and HR = 0.70; 95% CI, 0.57–0.85 for
moderate consumption against lowest consumption among seven
case-control and five cohort studies) and endometrium(38)
(HR = 0.64; 95% CI, 0.48–0.86 for the highest consumption cat-
egory and HR = 0.87; 95% CI, 0.78–0.97 for moderate con-
sumption against lowest consumption among six case-control
and two cohort studies). The association was less clear for colon
cancer,(39)particularly in men (HR = 1.00; 95% CI, 0.81–1.24
in men and HR = 0.79; 95% CI, 0.60–1.04 in women among six
Biologically, the beneficial effects of coffee on carcinogenesis
are thought to derive from three major components of coffee:
chlorogenic acids, caffeine, and the coffee diterpenes cafestol
and kahweol. Because diterpene content is negligible in instant,
drip-filtered, and percolated brews, the preparation methods
most commonly used in Japan, the main putative candidates in
our population are chlorogenic acids and caffeine.
Chlorogenic acid has relatively strong antioxidant effects and
improves insulin resistance by increasing insulin sensitivity or
inhibiting glucose absorption in the intestine. The latter effect
may explain the observation that higher coffee consumption was
associated with lower postload, rather than fasting, glucose
Several short-term studies have shown that acute caffeine
ingestion can decrease glucose disposal.(42–44)In US studies,
however, decaffeinated coffee consumption was inversely asso-
ciated with the risk of type 2 diabetes, and our cross-sectional
study showed that the inverse association with hyperglycemia
was stronger for coffee than for caffeine.(45)These observations
suggest that coffee components other than caffeine may have
beneficial effects on the risk of type 2 diabetes. Coffee also con-
tains substantial amounts of magnesium, which has been linked
to better insulin sensitivity and insulin secretion.
0.38–0.53 forthe highest
Based on substantial evidence and biological plausibility, cof-
fee consumption is considered to have a favorable effect on
insulin resistance, and may thereby reduce the risk of diabetes-
related cancers such as colon, liver, pancreas, and endometrium.
Metabolic factors, their aggregate, and cancer
The MHLW has repeatedly warned about a rapid increase in
type 2 diabetes, which is also caused by energy imbalance. The
2007 National Health and Nutrition survey estimated that a total
of 22 million people possibly had diabetes, nearly twofold the
14 million estimated in 1997. In 2008, the MHLW implemented
a policy against metabolic syndrome, which is defined by the
presence of increased waist circumference (necessary factor)
and at least two of the following metabolic factors: lipid abnor-
mality (elevated triglyceride levels or low high density lipopro-
tein (HDL) cholesterol), elevated blood pressure, and elevated
fasting glucose level. It is expected that the control of abdominal
fatness as indicated by waist circumference would result in a
decrease in risk factors, and thereby prevent future ischemic car-
diovascular diseases (CVD) such as ischemic heart disease as
well as ischemic stroke.
This now-implemented policy against metabolic syndrome
may also influences cancer control. Estimating its impact on
cancer requires the elucidation of how the respective metabolic
factors, both individually and in the aggregate, namely meta-
bolic syndrome are related to not only CVD but also cancer, the
leading cause of death in Japan.
Using data from approximately 30 000 subjects who provided
health check-up data at baseline or in a 5-year follow-up survey,
we tested the association between these metabolic factors, both
individually and in the aggregate, and the risk of cancer.(46)
Each metabolic factor increased the risk of specific sites of can-
cer with statistical significance, albeit that statistical power was
not strong enough due to the relatively small number of subjects
and cancer cases. For liver cancer, high glucose (HR = 1.76;
95% CI, 1.07–2.89), low HDL (HR = 2.25; 95% CI, 1.34–3.79)
and overweight (HR = 2.18; 95% CI, 1.33–3.58) were associ-
ated with an increased risk in men, and overweight was also
associated in women (HR = 1.95; 95% CI, 1.03–3.69). In addi-
tion, high triglyceride (HR = 1.71; 95% CI, 1.11–2.62) was
associated with the risk of colon cancer in men and overweight
(HR = 1.75; 95% CI, 1.21–2.55) with the risk of breast cancer.
However, the presence of metabolic factors in the aggregate
(two or more factors in addition to overweight) was shown to be
a statistically significant risk only for male liver (HR = 1.99;
95% CI, 1.11–3.58) and female pancreatic cancer (HR = 1.99;
colon, liver, and pancreas: the Japan Public Health
Center-based Prospective (JPHC) study. HR, hazard
ratio. Data sources: colon;(33)liver;(32)pancreas.(34)
Coffee consumption and cancers of the
Tsugane and InoueCancer Sci|
ª ª 2010 Japanese Cancer Association
95% CI, 1.00–3.96). The observed HR was not as high as those
observed for each factor individually, nor did the individual fac-
tors or their aggregate predict the subsequent occurrence of can-
cer as a whole.
These studies on the association between metabolic syn-
drome and cancer have focused mainly on specific sites of
cancer, including colon, prostate, breast, and endometrium,
which are common in Western populations and are consid-
ered to have an etiologic link with the respective metabolic
factors or their aggregate. Among them, two large prospec-
tive studies, in Italy(47)and the USA, showed that the cluster-
ing of metabolic factors increased the risk of colorectal
cancer mortality compared with the individual factors alone
The only study focusing on the impact of metabolic factors
in the aggregate on total cancer risk to date, in Italy, reported
a null association for total cancer incidence,(49)which accords
with our result. Although the extent to which the grand sum
of the effect on these sites affects total cancer incidence has
yet to be clarified, it appears that metabolic factors in the
aggregate have little impact on the risk of cancer as a
whole in Japan. The association between specific components
of metabolic syndrome and specific cancers suggests the
presence of an etiologic link.
Descriptive (time-trend) and analytic (cohort and case-control
studies) evidence obtained to date suggest that cancers of the
colon, liver, and pancreas may be associated with insulin resis-
tance or energy imbalance. These cancers may be preventable
by increasing physical activity, and possibly also coffee
consumption, as well as by maintaining energy balance. Insulin
resistance may be a stronger predictor of these cancers than
body fatness itself. Metabolic factors in the aggregate appear to
have little impact on the risk of cancer as a whole in Japan.
We sincerely thank the members and coworkers of the Japan Public
Health Center-Based Prospective Study Group. This work was supported
by Grants-in-Aid for Cancer Research and for the Third-Term Compre-
hensive Ten-Year Strategy for Cancer Control from the Ministry of
Health, Labour, and Welfare of Japan.
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