REVIEW

CURRENT
OPINION Metabolic diseases and cancer risk
Malin H. Faulds and Karin Dahlman-Wright

Purpose of review
Metabolic disease and cancer are two of the leading causes of death worldwide. This review focuses on
the potential increased relative risk for the development of cancer in a population with a rapidly increasing
incidence of metabolic disturbances.
Recent findings
A large number of recent epidemiological and prospective studies link metabolic syndrome-associated
diseases to an increased risk for development of, as well as mortality from, several types of cancer. In
patients diagnosed with metabolic disorders, the incidence of gastrointestinal, glandular and reproductive
tract cancers is significantly higher compared to the general population. In line with that, hyperglycemia
has recently been shown to be an independent risk factor for overall cancer incidence.
Summary
Disorders connected to the metabolic syndrome have been shown to have profound impacts on the
incidence and progression of cancer. Continued efforts to make lifestyle interventions, such as weight loss
and increased physical activity in the general population, are clearly warranted as a contribution to efforts
aimed at decreasing the development of and mortality from cancer. Progression in this field requires a
better understanding of the underlying mechanisms behind the cancer-promoting effects associated with
disturbed energy balance.
Keywords
cancer, diabetes, hyperglycemia, insulin resistance, metabolic syndrome, obesity

INTRODUCTION Recent studies investigated the association

Metabolic diseases affect more than 230 million
people worldwide and are expected to almost double
in the coming 25 years. It is currently the fourth
leading cause of death by disease. The metabolic
syndrome refers to a group of inter-related meta-
bolic abnormalities that include hyperglycemia,
between postmenopausal breast cancer and the
metabolic syndrome based on two studies from
Italy and Switzerland. The metabolic syndrome
was defined as the presence of at least three meta-
bolic disturbances. Importantly, the risk of develop-
ing breast cancer was significantly higher for women
&

insulin resistance, hyperinsulinemia, obesity and
low-grade inflammation with an associated risk of
developing cardiovascular disease (CVD) and type 2
diabetes (T2D).
Cancer affects people of all ages but the overall
risk of developing cancer increases rapidly over a life
span. In 2007, cancer accounted for around 13% of
all human deaths worldwide.
with the metabolic syndrome (relative risk 1.75) [1 ].
The results also showed an increased incidence of
breast cancer for individual risk components, such
as T2D (relative risk 1.33), hypertension (relative risk
1.08) and hyperlipidemia (1.26).
INSULIN RESISTANCE AND CANCER RISK
Insulin resistance is a pathological condition in
which insulin is less effective in lowering glucose

METABOLIC DISEASE AND CANCER RISK

Metabolic diseases and cancer are influenced by
many factors including genetic and environmental
factors. Several epidemiological studies have shown
that certain types of cancer, especially cancer of the
gastrointestinal and urinary tracts and of the female
reproductive system, are more common in indi-
viduals with metabolic disorders.
Department of Biosciences and Nutrition, Novum, Karolinska Institutet,
Huddinge, Sweden
Correspondence to Karin Dahlman-Wright, Department of Biosciences
and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden.
Tel: +46 8 52481160; fax: +46 8 7745538; e-mail: Karin.Dahlman-
Wright@ki.se
Curr Opin Oncol 2012, 24:58–61
DOI:10.1097/CCO.0b013e32834e0582

www.co-oncology.com Volume 24  Number 1  January 2012

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Metabolic diseases and cancer risk Faulds and Dahlman-Wright
KEY POINTS
 Several aspects of the metabolic syndrome are common
risk factors for developing cancer.
 Silencing of insulin signaling is a novel strategy for
cancer therapy.
 High levels of fasting glucose and T2D are independent
risk factors for cancer.
 Adipose tissue dysfunction and subsequent
inflammation are risk factors for several types of
cancer.
concentrations, which results in reduced glycogen
synthesis and storage and high levels of circulating
glucose. Metabolic pathways activated by insulin
signaling are involved in multiple cellular events
and are known to inhibit oxidation of fatty acids
and induce glucose expenditure in cancer cells.
Several studies have used silencing of insulin
signaling as a strategy for novel cancer therapy
[2]. High concentrations of insulin activate the
insulin receptor, which stimulates cell growth and
cell division.
Several in-vitro, animal and human epidemio-
logical studies demonstrate that cancer development
is promoted by high concentrations of insulin and
insulin-like growth factors (IGFs) acting through the
insulin/IGF axis [3]. For example, pancreatic cancer
strongly correlates with high postprandial insulin
levels. In observational studies of colorectal cancer
patients, high levels of the proinsulin C-peptide,
insulin, IGF-I and reduced levels of IGF-binding
protein-1 (IGFBP-1) have been reported [4]. Elevated
C-peptide levels and low IGFBP-1 levels have been
linked to a higher death risk after colorectal cancer
surgery [5].
The incidence of breast cancer in individuals
diagnosed with insulin resistance is also signifi-
cantly greater than in healthy women with a relative
risk of 3.6 for developing malignant tumors [6].
GLUCOSE METABOLISM AND CANCER
RISK
Large prospective studies show that high level of
fasting glucose is an independent risk factor for
cancer [7]. Cancer cells need increased energy due
to their substantial growth capacity and use various
substrates, such as glucose, for energy production.
Glucose concentrations in tumor cells are ensured
by increased levels of the membrane-bound glucose
transporters (GLUTs), especially the isoforms GLUT1,
GLUT3 and GLUT12. However, glucose metabolism
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in tumor cells is differently regulated compared to
normal cells. Normal cells convert glucose to
pyruvate and ATP is formed within the Krebs cycle
in the mitochondria. Tumor cells convert pyruvate
into lactic acid and instead utilize glucose for syn-
thesis of building blocks for cell construction. This
leads to an overproduction of lactic acid, despite
full accessibility to oxygen, a phenomenon called
the Warburg effect. The excess of lactic acid lowers
the pH of the extracellular matrix, which is a caus-
ative factor for death of surrounding tissues. The
activity of collagenases is known to increase with
lowered pH, which will, in turn, facilitate tumor cell
migration. The altered activity of several enzymes
involved in glucose metabolism is responsible for the
Warburg effect in neoplastic cells, like for example
hexokinase-2, which is the rate-limiting enzyme in
glycolysis and has been shown to have a 200 times
higher activity in proliferating tumor cells.
Another factor important for the increased
glucose metabolism in cancer cells is the occurrence
of the pyruvate kinase Tumor M2-PK, which is a
key enzyme in the altered metabolism observed
in tumor cells. Tumor M2-PK is present at high
concentrations in tissue, plasma and other body
fluids of individuals with malignant disease [8].
The M2-PK isoenzyme is specific for proliferating
cells, including cancer cells, fibroblasts, embryonic
cells and adult stem cells, and appears as either a
tetramer or a dimer. When M2-PK is in a tetrameric
state, glucose is used for energy production. How-
ever, M2-PK occurs mainly as a dimer in tumor
cells and, thus, energy is obtained from glutamine
breakdown. This will cause an excess of glucose
and will ultimately lead to cell damage via formation
and accumulation of glycation end-products. These
compounds can further trigger degenerative changes
in cells, change signaling pathways and lead to
additional carcinogenic mutations [9].
When glycation end-products are taken up into
the intracellular space, an inflammatory process is
started, which will stimulate neutrophils and, as a
consequence, increase production of oxygen free
radicals [10]. The processes initiated by the excess
of carbohydrates can cause chronic inflammatory
diseases and an increased risk of cancer mutations.
The glycation end-products are not only depending
on the excess glucose resulting from carbohydrate
metabolism disorders but are also a result of a high
sugar consumption [11], as well as other dietary
components [12].
The outcome of impaired glucose metabolism
on cancer mortality has recently been studied in
data from 17 European cohorts (DECODE, Diabetes
Epidemiology: Collaborative analysis of Diagnostic
criteria in Europe). The relative risk of death for
www.co-oncology.com 59
 Cancer biology
cancer patients in prediabetic and diabetic states was
1.13 and 1.71, respectively, for male patients and
1.11 and 1.43, respectively, for female patients.
Overall, mortality increased linearly with increasing
&
blood glucose concentration [13 ].
Another prospective study found a significant
role for glucose metabolism in breast cancer occur-
rence as high circulating glucose levels in women
increased the risk for breast tumors with 63% com-
&
pared to women with low circulating glucose [14 ].
DIABETES AND CANCER RISK
There is growing evidence that T2D is a risk factor
for the development of several types of cancer.
A primary care cohort from Germany concluded that
T2D and T2D medications were highly associated
& &
with risk for, as well as mortality from, cancer [15 ].
Recent epidemiological investigations show
that carcinomas frequently appear in patients diag-
nosed with T2D, including cancer in the pancreas,
liver, bile ducts, colon, endometrium and breast.
An Israeli study involving T2D patients and
healthy controls showed increased risk of cancer
of the reproductive system (relative risk 1.96) and
digestive system (1.41) in women. Male diabetic
patients did not have increased cancer risks; instead
a 47% decrease of prostate cancer was found [16].
A Swedish epidemiological study examined
the risk of overall cancer among hospitalized T2D
patients compared to the general population. A risk
increase was found for a plethora of malignant
cancers; gastrointestinal tract cancers, endometrial,
cervical, ovarian, lung, kidney, pancreas and hep-
&
atocellular carcinoma [17 ].
Studies of a large cohort of US Army veterans with
diabetes, however, show a slightly different result.
The overall cancer risk was slightly lower than in the
control group except for liver, pancreatic, bile ducts,
colon, rectal and kidney cancer. Leukemia and mel-
anoma risks were also somewhat enhanced [18].
The relationship between T2D and pancreatic
cancer has been widely confirmed. A novel study
analyzed 35 cohort studies and concluded that
T2D is associated with a significantly increased
risk of developing pancreatic cancer in both
males and females (summary of relative risks 1.94)
and that diabetes is both an early manifestation, as
&
well as a causative factor, of pancreatic cancer [19 ]. It
has also very recently been shown that 70% of newly
diagnosed pancreatic cancer patients had T2D [20].
Epidemiological studies have also shown
a connection between T2D and breast cancer.
A retrospective cohort study recently showed that
diabetic patients with estrogen receptor negative
breast cancer had a more than two-fold higher risk
60 www.co-oncology.com
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for metastasis than nondiabetic patients. T2D was
also associated with a two-fold increase in mortality
within a 5-year period [21]. There have also been
several reports on the increased incidence of endo-
metrial cancer in T2D patients. A case-control
study from Italy displayed an odds ratio (OR) of
2.18 for development of cancer in the endometrium
&
in diabetic patients [22 ].
Diabetic patients may also have an increased risk
for cancer in the urinary tract but evidence from
prospective studies is scarce. A multiethnic cohort
study with a 10-year follow-up in the USA showed
that individuals with T2D display a relative risk of
1.25 for developing urothelial cancer [23] and
another American study showed a 2.2 relative blad-
der cancer risk for diabetic patients, a risk that was
significantly higher in patients that had been diag-
nosed with diabetes for the longest duration [24 ].
ADIPOSE TISSUE DYSFUNCTION AND
CANCER RISK
The relationship between obesity, especially visceral
obesity, and many cancer types has been confirmed
in several epidemiological studies. However, the
conclusions derived from these studies remain
controversial [25]. In studies using the combined
evaluations of body mass index (BMI) and waist-to-
hip circumference ratio with cancer incidence,
the responsible mechanisms seem to be mainly
those of metabolic disorders, resulting from obesity
[26]. Another study shows that obese, postmeno-
pausal women have a 50% higher risk of breast
cancer than their leaner counterparts. This has also
been confirmed using an animal model that mimics
postmenopausal obesity in combination with breast
cancer progression, when obesity significantly
&
increased tumor weight and angiogenesis [27 ].
Excess adipose tissue and its dysfunction lead to a
range of related syndromes, like insulin resistance
with associated hyperinsulinemia [28]. Obesity is
strongly linked to chronic inflammation within adi-
pose tissue. The normal processes in adipose tissues
are usually disturbed in the great majority of obese
people, in whom the fat accumulation and tissue size
enlargement will cause enhanced protein synthesis
and disturbed post-translational processing within
the endoplasmic reticulum. This could, in turn, cause
abnormal intracellular signaling, insulin resistance,
free radical production and activate the adipocytes to
secrete adipokines, which trigger inflammation and
enhance production of inflammatory cytokines and
chemokines [29]. The adipose tissue infiltration is
further increased by macrophages.
A link between inflammation and cancer
development was found by Rudolf Virchow already
Volume 24  Number 1  January 2012
 Metabolic diseases and cancer risk Faulds and Dahlman-Wright
in 1863 upon discovery of leukocytes in neoplastic
cells. Many epidemiological studies have correlated
infections or chronic inflammatory diseases with
tumor development. The mechanisms behind this
association are currently not fully elucidated but
include healing and reconstruction processes within
inflamed tissues, stimulated angiogenesis and pro-
motion of cancer cell development and oncogene
activation by pro-inflammatory cytokines. Studies
also show that direct impairment of DNA by reactive
oxygen and nitrogen leads to genome instability
and carcinogenic mutations [30,31].
CONCLUSION
The number of people with excess body weight
is rapidly increasing worldwide. Overweight and
obesity with associated metabolic abnormalities
and diseases, such as T2D, constitute in addition
risk factors for a broad spectrum of cancers.
Recent epidemiological studies show associ-
ations between obesity/T2D and an increased tumor
incidence. The increased levels of circulating glucose
and triglycerides also contribute to sustaining tumor
growth. Thus, combating obesity is a priority in
society for reducing the incidence of, and reducing
the mortality from, various kinds of cancer.
Acknowledgements
None.
Conflicts of interest
This work was supported with grants from the Center for
Biosciences.
None declared.
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