Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms.
ABSTRACT Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.
Nutrition 12/1996; 13(1):65-65. · 3.03 Impact Factor
Article: Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.Diabetes 05/2009; 58(4):773-95. · 8.29 Impact Factor
Article: Insulin resistance syndrome.[show abstract] [hide abstract]
ABSTRACT: Insulin resistance can be linked to diabetes, hypertension, dyslipidemia, cardiovascular disease and other abnormalities. These abnormalities constitute the insulin resistance syndrome. Because resistance usually develops long before these diseases appear, identifying and treating insulin-resistant patients has potentially great preventive value. Insulin resistance should be suspected in patients with a history of diabetes in first-degree relatives; patients with a personal history of gestational diabetes, polycystic ovary syndrome or impaired glucose tolerance; and obese patients, particularly those with abdominal obesity. Present treatment consists of sensible lifestyle changes, including weight loss to attain healthy body weight, 30 minutes of accumulated moderate-intensity physical activity per day and increased dietary fiber intake. Pharmacotherapy is not currently recommended for patients with isolated insulin resistance.American family physician 04/2001; 63(6):1159-63, 1165-6. · 1.70 Impact Factor
Hindawi Publishing Corporation
Experimental Diabetes Research
Volume 2012, Article ID 789174, 12 pages
InsulinResistanceand CancerRisk: AnOverviewof the
KatiusciaPossidente,1MariaT. Nevolo,1Valeria Ventura,1DanielaFoti,1,2
1Department of Health Sciences, Magna Græcia University of Catanzaro, Viale Europa (Localit` a Germaneto), 88100 Catanzaro, Italy
2Clinical Pathology, Magna Græcia University of Catanzaro, Viale Europa (Localit` a Germaneto), 88100 Catanzaro, Italy
3Endocrinology, Magna Græcia University of Catanzaro, Viale Europa (Localit` a Germaneto), 88100 Catanzaro, Italy
Correspondence should be addressed to Antonio Brunetti, firstname.lastname@example.org
Received 29 January 2012; Accepted 10 April 2012
Academic Editor: Chien-Jen Chen
Copyright © 2012 Biagio Arcidiacono et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently
increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms
for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-
like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and
IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian
synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit
apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive
oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that
the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which
can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on
various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer
initiation and progression.
action is impaired in peripheral target tissues including
skeletal muscle, liver, and adipose tissue. Initially, in indi-
viduals destined to develop T2D, the pancreatic beta cells
increase insulin production to overcome insulin resistance
and maintain euglycemia. Frank T2D in insulin-resistant
Also, insulin resistance is a cardinal feature of the metabolic
syndrome, a quartet of vascular risk factors which include,
in addition to insulin resistance, central obesity, dyslipi-
demia, and systemic hypertension . With the exception
of rare, monogenic forms of insulin resistance, common
insulin resistance is a very heterogeneous disorder for which
both genetic and environmental factors jointly determine
susceptibility . The environmental component reflects
the unfavorable global shift toward a western lifestyle of
overeating and sedentary habits, with obesity as the outcome
[2, 5]. The genetic factor is linked to quantitative and/or
qualitative defects in the insulin receptor (INSR) signaling
pathway which regulates growth and metabolic responses
to insulin, in insulin target cells and tissues . Patients
with insulin resistance show an increased morbidity and
mortality, largely attributable to cardiovascular disease and
T2D [7, 8]. Moreover, a number of epidemiological studies
have consistently demonstrated that the risk for several types
of cancer (including that of the breast, colorectum, liver,
and pancreas) is higher in insulin-resistant patients .
As illustrated in Figure 1, various mechanisms have been
2 Experimental Diabetes Research
IGF-I, estradiol and testosterone
Figure 1: A multidimensional model of cancer development, which suggests insulin resistance and inflammation as driving forces behind
cancer. TG: triglycerides; FFA: free fatty acids; TNF-α: tumor necrosis factor α; IL-6: interleukin-6; ROS: reactive oxygen species; SHBG: sex-
hormone-binding globulin; IGF-I: insulin-like growth factor I; PAI-1: plasminogen activator inhibitor-1; IGFBPs IGF-I binding proteins;
VEGF, vascular endothelial growth factor.
proposed to explain this link, although a complete picture is
yet to emerge. The following is a summary of major specific
(1) Chronic hyperinsulinemia, in affected individuals,
may promote cancer, as insulin can exert its onco-
genic potential via abnormal stimulation of multiple
cellular signaling cascades, enhancing growth factor-
dependent cell proliferation and/or by directly affect-
ing cell metabolism.
(2) Insulin increases the bioactivity of IGF-I by enhanc-
ing hepatic IGF-I synthesis and by reducing hepatic
protein production of the insulin-like growth factor
binding proteins 1 (IGFBP-1) and 2 (IGFBP-2)
[10, 11]. Therefore, although insulin can directly
induce tumour growth, many of its mitogenic and
antiapoptotic effects are operating through the IGF-
I system, as reported in individuals with high levels
of circulating IGF-I, in which an increased risk of
developing certain types of tumours, in particular
breast and prostate cancers, has been documented
(3) Insulin, by reducing SHBG levels, exerts a positive
effect on estrogen bioavailability, therefore increasing
breast cancer risk.
(4) Obesity, the most common cause of insulin resis-
tance, is increasingly recognized as a low-grade
inflammatory state in which overproduction of cer-
tain molecules, such as free fatty acids, interleukin-
6 (IL-6), adiponectin, leptin, tumour necrosis factor
alpha (TNF-α), plasminogen activator inhibitor-1,
and monocyte chemoattractant protein (MCP-1),
can play a role in malignant transformation and/or
cancer progression . In this context, chronic
hyperglycemia and increased oxidative stress may
also contribute to increased cancer risk.
Therefore, many lines of evidence support the concept
that a relationship exists between insulin resistance and
cancer, although further studies must be done before this
relationship can be fully understood.
2.The INSR,Biological Function,
The first step in insulin action is its interaction with the
INSR, an integral membrane glycoprotein with intrinsic
enzymatic activity. The INSR belongs to the tyrosine kinase
growth factor receptor family and functions as an enzyme
that transfers phosphate groups from ATP to tyrosine
Experimental Diabetes Research3
residues on intracellular target proteins, thus playing a
critical role in both directing the hormone to a specific
target tissue and programming the biological response of the
tissue to the hormone. The INSR consists of two identical
domains and two transmembrane β subunits (95kDa) that
contain ligand-activated tyrosine kinase activity in their
intracellular domains [15–18]. Upon binding of insulin to
the α subunits, the receptor becomes activated by tyrosine
autophosphorylation, and then the INSR tyrosine kinase
phosphorylates various intracellular effector molecules (e.g.,
IRS proteins and Shc) which in turn alter their activity,
thereby generating a biological response [16–19]. The INSR
exists as two splice variant isoforms: the INSR-B isoform
that is responsible for signaling metabolic responses involved
mainly in the regulation of glucose uptake and metabolism
and the INSR-A isoform that is expressed in certain tumours
(such as mammary cancers), signals predominantly mito-
genic responses, and is capable of binding IGF-II with
high affinity [20, 21]. As a consequence of these cellular
activities, abnormalities of INSR expression and/or function
can facilitate the development of several metabolic and
neoplastic disorders. Abnormalities in the INSR signaling
pathway are implicated in certain common dysmetabolic
disorders, including obesity, T2D, the metabolic syndrome,
and the polycystic ovary syndrome [22–25]. Also, rare
clinical syndromes due to mutations in the INSR gene have
been identified in patients with monogenic forms of severe
insulin resistance [26, 27]. A relation between INSR and
cancer has been established following the observation that
overexpression of functional INSRs can occur in human
and colon cancer, in which the INSR may exert its oncogenic
potential via abnormal stimulation of multiple cellular
signaling cascades, enhancing growth factor-dependent pro-
liferation, and/or by directly affecting cell metabolism [28–
33]. On the other hand, epidemiological and clinical evi-
dence points to a link between insulin-resistant syndromes,
such as obesity and T2D, and cancer of the colon, liver,
pancreas, breast and endometrium. The mechanistic link
between insulin resistance and cancer is unknown, but
constitutive activation of the tyrosine kinase activity of
INSR and related downstream signaling pathways by chronic
sustained hyperinsulinemia, in these clinical syndromes,
appears to have a role in the neoplastic transformation
process [34–36]. Mechanisms due to hyperinsulinemia that
promote malignancy and neoplastic progression include the
increase in IGF-I and sex hormones bioavailability, the
increase in proinflammatory cytokines, and oxidative stress.
Although the molecular mechanisms that cause neoplastic
transformation, and sustain tumour progression in the
presence of INSR hyperexpression and/or hyperstimulation
are not fully understood, an explanation for increased INSR
expression in epithelial tumours has been recently provided
by our group in both breast cancer cell lines and human
breast cancer tissues, in which overexpression of the nuclear
transcription factor activator protein 2-α (AP2-α) accounted
for INSR overexpression  (Figure 2(a)). In these cases,
we demonstrated that transactivation of the INSR gene by
AP2-α represented a fundamental prerequisite to activate
a functional link between INSR and cyclin D1 has been
recently described in pancreatic cancer . Thiazolidine-
diones (TZDs), a class of commonly used antidiabetic
drugs that act as peroxisome proliferator-activated receptor
(PPARγ) agonists, have shown antiproliferative effects in
many studies in vitro and in vivo and have been there-
fore proposed as an auxiliary anticancer therapy in some
clinical trials . Recently, we showed that INSR gene
transcription and protein expression were reduced in cells
with forced expression of PPARγ or TZD-induced PPARγ
activation (Figure 2(b)). These findings were confirmed in
MCF-7 human breast cancer cells overexpressing PPARγ,
and 3T3-L1 adipocytes producing relatively high amounts
of endogenous PPARγ [40, 41]. Molecular biology studies
ity shift assay and chromatin immunoprecipitation, have
demonstrated that, in selected cell lines, PPARγ physically
interacts with Sp1, AP2-α, and C/EBPβ, preventing binding
of AP2-α to Sp1, as well as binding of Sp1 and C/EBPβ to
their DNA consensus sites within the INSR gene locus .
Therefore, it has been postulated that PPARγ may perturb
INSR gene expression by interfering with the transcriptional
initiation complex during activation of the INSR gene.
This observation might contribute to the identification of
new therapeutic targets for treatment of tumours in which
abnormal expression and/or function of INSR occur.
The INSR can be regulated by a wide variety of factors
and under different environmental conditions . For
example, glucocorticoids enhance transcription of the INSR
gene, whereas insulin downregulates its own receptor. As a
step toward understanding the molecular basis of regulation
of INSR gene expression, the promoter region of the human
INSR gene has been first identified and then analyzed by
several groups [44–46]. This region extends over 1800 bases
upstream from the INSR gene ATG codon and is extremely
GCrich, containing a series of GGGCGG repeats that are
putative binding sites for the mammalian transcription fac-
tor Sp1. It has neither a TATA box nor a CAAT box, reflecting
the common features for the promoters of constitutively
expressed genes (so-called housekeeping genes). The INSR
is expressed at higher levels in differentiated target tissues
such as muscle and fat. At these levels, tissue-specific and
ubiquitous nuclear transcription factors cooperate to induce
INSR gene transcription. We have previously identified two
distinct, functionally active DNA sequences, C2 and E3,
within the INSR gene promoter, which had a significant
ability to drive INSR gene transcription . The molecular
mechanisms regulating INSR gene expression have been
widely studied by our group and evidence has been provided
showing that the architectural transcription factor high-
mobility group A1 (HMGA1) is required for proper tran-
scription of the INSR gene. HMGA1 is a small basic protein
that binds to AT-rich regions of certain gene promoters and
functions mainly as a specific cofactor for gene activation
[47–49]. HMGA1 by itself has no intrinsic transcriptional
activity; rather, it has been shown to transactivate promoters
4 Experimental Diabetes Research
Figure 2: INSR gene expression in breast cancer. (a) AP2-α overexpression increases INSR expression in breast tumour . Transactivation
of the INSR gene by AP2-α occurs indirectly through physical and functional cooperation with HMGA1 and Sp1. (b) By binding to AP2-α
and Sp1, PPARγ and agonists may attenuate the stimulatory effect of AP2-α on INSR gene transcription in breast cancer.
of stereospecific DNA-protein complexes, “enhanceosomes,”
that drive gene transcription. HMGA1 performs this task
by modifying DNA conformation and by recruiting tran-
scription factors to the transcription start site, facilitating
DNA-protein and protein-protein interactions [47–49]. By
to the INSR promoter sequence, HMGA1 greatly enhances
the transcriptional activities of these factors in this gene
context [46, 50, 51]. Qualitative and/or quantitative defects
in these binding proteins and/or abnormalities in their
consensus sequences within the INSR gene may affect INSR
gene transcription, leading to abnormalities in INSR gene
and protein expression . Overexpression of INSR in cells
which normally express low levels of INSR, like epithelial
cells, may increase the biological responses to insulin and
studies have shown that INSRs are increased in most
transformation and increased cell growth occur in cultured
breast cells overexpressing the INSR [37, 52, 53]. Also,
overexpression of functional INSRs has been involved in
thyroid carcinogenesis . In all these cases, the INSR
can exert its oncogenic potential in malignant cells via
abnormal stimulation of multiple cellular signaling cascades,
enhancing growth factor-dependent proliferation and/or by
directly affecting cell metabolism.
Chronic hyperinsulinemia in insulin-resistant patients in-
creases bioavailability of IGF-I by reducing hepatic gene
expression and protein production of IGFBP-1and IGFBP-2.
Also, a decrease in circulating levels of SHBG, followed by an
increase in the bioavailability of estradiol and testosterone,
may occur in these patients, in whom the combined effect
of increased synthesis and bioavailability of estradiol and
testosterone can have an adverse impact on target cells
and tissues expressing estrogen and androgen receptors.
The effect of sex steroid binding to their specific receptors
can vary, depending on tissue type, but in some tissues
(e.g., breast epithelium and endometrium), this hormone-
receptor interaction results in abnormal cellular prolifera-
tion and inhibition of apoptosis. Of major importance in
hormone-mediated cancers is the IGF system. This system is
composed of at least three ligands (insulin, IGF-I, and IGF-
II), two receptors (IGF-IR and INSR) and six structurally
similar IGFBPs that have important influence over the
biological effectiveness of the IGFs, since they are able to
increase the half-lives of circulating IGFs, hence controlling
their availability for receptor binding . IGFBP-3 is the
predominant binding protein expressed in serum, and the
vast majority of circulating IGF-I and IGF-II are bound in
Experimental Diabetes Research5
a ternary complex with IGFBP-3 and a third component, the
acid-labile subunit. In addition, IGFBP-3 directly regulates
the interaction of IGF-I with its receptor and, through IGF-
independent mechanisms, is able to inhibit cell growth and
tion is in the liver, where its expression is upregulated by the
growth hormone (GH) and suppressed by insulin. Because
of the IGF-I’s mitotic properties, lower levels of IGFBP-
3, by increasing the IGF-I/IGFBP-3 ratio, may increase the
risk of developing cancer, with the opposite occurring when
tissue availability of IGF-I is reduced. Like IGFBP-3, the
biosynthesis of IGF-I occurs primarily in the liver, where
its production is GH dependent [56–58], and is increased
by insulin [56, 57]. Low insulin levels, as encountered in
individuals with type 1 diabetes, or following a prolonged
fasting state, by determining the reduction of GH receptor
expression, can contribute to lowering the hepatic IGF-I
protein synthesis, thus reducing circulating levels of IGF-I.
The reduced bioavailability of IGF-I under these conditions
is accompanied by an increase in circulating levels of IGFBP-
1 and IGFBP-2, the expression of both of which is normally
suppressed by insulin. Consistently, higher expression of
GH receptors with increased IGF-I protein production can
be detected in patients with sustained hyperinsulinemia
and T2D . On the other hand, less IGFBP expression
following malignant transformation has been reported in
some tumour cell types in which the amount of free IGF-I
may, therefore, increase even if there is no change in the rate
of IGF-I production .
The IGF-IR is homologous to the INSR (sharing 84%
amino acid identity in the intracellular tyrosine kinase
domains). Because of their high sequence similarity [61,
62], an INSR hemireceptor may assemble with an IGF-
IR hemireceptor, forming INSR/IGF-IR hybrid receptors.
It has been demonstrated that signaling through these
receptors regulates cell survival and proliferation [63, 64].
Both insulin and IGF-I bind to the extracellular α sub-
units of their cognate receptors and induce conformational
changes that cause the activation of the tyrosine kinase
domain and self-phosphorylation of tyrosine residues of
the intracellular β subunit . The INSR, the IGF-IR,
as well as the hybrid receptors, are expressed at higher
levels in malignant cells . Functional activation of these
receptors results in the upregulation of the INSR substrate
1 (IRS1), that triggers signaling pathways downstream of
the mitogenic-activated protein (MAP) kinase pathway and
the phosphoinositide-3 kinase/Akt (PI3K/Akt), two of the
most important signaling cascades frequently dysregulated
in cancer (Figure 3). PI3K is recruited to the membrane
after being activated by growth factors and cytokines. At
this level, the enzyme is activated and transfers a phos-
phate group to its substrate, phosphatidylinositol [4, 5]-
bisphosphate [PtdIns(4,5)P2], forming PtdIns-(3,4,5)-P3
. The PtdIns(3,4,5)P3 recruits the protein kinase Akt,
facilitating its activation by the phosphoinositide-dependent
kinase-1, PDK1. Phosphorylation of Akt is critical for the
regulation of glucose metabolism, but also for the regulation
of cell size, proliferation, and cell survival. In addition, Akt
regulates gene transcription by direct phosphorylation of
some of the forkhead transcription factors of the FOXO
family which are involved in the control of fundamental
processes, including cell metabolism and differentiation,
apoptosis, cell cycle arrest, and DNA repair [68, 69]. Akt
also regulates mRNA translation through the raptor-mTOR
pathway, which plays a central role in metabolism and cell
growth [70, 71]. The mechanism how activation of the
INSR signaling pathway induces growth has been clarified
by demonstrating that Akt phosphorylates and inactivates
tuberin, an inhibitor of cell growth . It has been shown
that activation of PI3K by insulin relieves this inhibitory
function , resulting in activation of Rheb (Ras homolog
enriched in brain), leading to activation of the raptor-mTOR
complex. It is well known that PTEN, a lipid phosphatase
that dephosphorylates PtdIns(3,4,5)P3, negatively regulates
the PI3K/Akt signaling pathway, thus emphasizing the role
of PTEN as a tumour suppressor in multiple tumour types
and this emphasizes the role of the insulin/IGF-I-induced
PI3K/Akt/mTOR/S6K signaling in cancer  (Figure 3).
A second major intracellular signaling pathway involves
the Ras protein, a monomeric globular protein of 189
amino acids (21kDa) which is associated with the plasma
membrane and which binds either GDP or GTP. In response
to certain growth promoting stimuli, Ras is “switched on”
by exchanging its bound GDP for a GTP. Once activated,
Ras is able to interact with and activate other downstream
protein targets. Switching Ras off requires extrinsic proteins
termed GTPase-activating proteins (GAPs) that interact with
Ras leading to the conversion of GTP to GDP. Mutations in
Ras affecting its ability to interact with GAP, or to convert
GTP to GDP, will result in abnormal, prolonged activation
of this protein, thus in a sustained signal to the cell that
may result in uncontrolled proliferation and disorganized
growth of cells. In its active state, Ras binds Raf, a protein
kinase, and promotes the activation of a phosphorylation
cascade in which a series of serine/threonine protein kinases
(the MAP/ERK kinase cascade) are activated in sequence,
carrying the signal from the plasma membrane to the
nucleus. At the end of this signal cascade, the MAP/ERK-
kinase phosphorylates a number of substrates on serines
and threonines, including c-Jun, c-Fos, c-Myc, Elk-1, ATF-
2, NF-IL6, and TAL-1 p53, thereby modifying their ability to
regulate the transcription of genes potentially relevant to cell
survival, growth, and cell cycle, such as Sp1, E2F, Elk-1, and
AP-1 [76–79] (Figure 3).
On the whole, dysregulation of the IGF system is well
recognized as an important contributor to the progression
of multiple cancers, in which constitutive activation of
the PI3K/Akt/mTOR signaling and the MAP/ERK-kinase
pathway may play a role. Therefore, as underlined elsewhere
, consistently with these observations, the IGF system is
emerging as a promising new target in cancer therapy.
Many clinical and epidemiological lines of evidence prove
that excess body weight gain, associated with hyperinsuline-
mia, insulin resistance, and dyslipidemia, may be a major
6 Experimental Diabetes Research
Gene expression Gene expression
Inhibition of apoptosis
Inhibition of apoptosis
Figure 3: Schematic representation of the two major signaling cascades operating in cancer, following overactivation of the INSR/IGF-IR
signaling pathways. Binding of insulin, IGF-I (and IGF-II) triggers the intrinsic tyrosine kinase receptor domain, leading to activation of
the PI3K/Akt/mTOR signaling and the MAP/ERK-kinase pathway. HR: hybrid receptors; ERK: extracellular regulated kinase; IRS: INSR
substrate; MEK: mitogen-activated protein kinase kinase; mTOR: mammalian target of rapamycin; PI3K: Phosphoinositide-3 kinase; PIP2:
phosphatidylinositol [4,5]-bisphosphate; PIP3: phosphatidylinositol [3,4,5]-trisphosphate; PDK1: phosphoinositide-dependent kinase 1;
Raf: rapidly fibrosarcoma; Ras: rat sarcoma; Rheb: Ras homolog enriched in brain; TSC: tuberous sclerosis complex.
risk factor for certain types of tumours, including colon
and breast cancer (Table 1). As illustrated in Figure 1, in this
paper, besides its importance in storage and energy balance,
the adipose tissue is metabolically and immunologically
active, being able to produce many proteins and hormones
known as “adipokines” , which include adipocytokines
(leptin, adiponectin, and resistin), cytokines (TNF-α, IL-
1 and IL-6), and the chemokine MCP-1  that has
recently been identified as a potential factor contributing to
macrophage infiltration into adipose tissue . Adipokines
circulate in the plasma at concentrations that are positively
correlated with body mass index (BMI), with the exception
of adiponectin, that correlates inversely with BMI .
It has been demonstrated that adipocyte-secreted factors
can directly promote mammary tumorigenesis through
induction of antiapoptotic transcriptional programs and
protooncogene stabilization . Also, evidence has been
provided indicating that adipocytes in obesity, by the action
of adipokines, participate in a highly complex cross-talk
with the surrounding tumour cells, promoting tumour
progression . Biosynthesis of leptin in adipose tissue
is influenced by insulin , and this may explain the
high leptin levels observed in obesity. Studies have been
provided indicating that higher leptin concentrations may
constitute a possible link relating obesity and cancer, par-
ticularly colorectal cancer. Also, it has been demonstrated
that, by influencing specific second intracellular messengers,
such as signal transducers and activators of transcription 3
cancer cell proliferation and survival. On the other hand,
greater adiposity in obese or overweight persons down-
regulates secretion of adiponectin, an adipokine with anti-
inflammatory and insulin-sensitizing properties . Low
blood concentrations of adiponectin have been associated
with high incidence and poor prognosis of breast cancer,
independently from the hormone receptor status .
Adiponectin and adiponectin receptors have been found to
play a role in the activation of the PPARγ pathway, which,
in turn, induces the transcription of several genes involved
in the regulation of cell proliferation and differentiation.
Experimental Diabetes Research7
Table 1: Relative risk of association between T2D and cancer, as reported by meta-analysis studies.
CancerNumber (n) of examined studies
Case control (n = 13)
Cohort (n = 7)
Cohort (n = 18)
Case-control (n = 13)
Cohort (n = 3)
Case-control (n = 17)
Cohort (n = 19)
Case-control (n = 3)
Cohort (n = 35)
Cohort (n = 9)
Case-control (n = 8) and cohort (n = 13)
Case-control (n = 10) and cohort (n = 5)
Case-control (n = 7)
Cohort (n = 3)
Case-control (n = 6)
Cohort (n = 9)
Case-control + cohort (n = 14)
Case-control (n = 6) and cohort (n = 11)
Case-control (n = 5)
Cohort (n = 11)
Case-control (n = 10)
Cohort (n = 3)
Case-control (n = 5)
Cohort (n = 15)
Relative risk (CI 95%)
Enhancement of BRCA1 expression by PPARγ has been
reported in MCF-7 breast cancer cells . Thus, an
explanation for the association of adiponectin with breast
cancer is that functional reduction of PPARγ signalling,
leading to reduced levels of BRCA1, may impair the DNA
oxidative stress . However, the functional role of
oxidative stress in cancer has long been a hotly debated topic.
Recent findings in this context indicate that oxidative stress
may directly contribute to tumour progression and metasta-
sis . As recapitulated in Figure 1, one possibility is that
ROS overproduction, by triggering the P13K/Akt signaling,
could lead to adverse genetic modifications and DNA dam-
age followed by tumour formation and progression .
NFκB is a central coordinator of immunity, inflammation,
and cell survival. Mutual cross-talk between ROS and NFκB
has been identified . For example, fibroblasts harboring
activated NFκB are able to promote tumour growth .
Activation of NFκB in fibroblasts leads to a loss of Cav-1
which drives onset of “The Reverse Warburg Effect,” due
to the autophagic destruction of mitochondria (mitophagy)
in these cells, resulting in aerobic glycolysis and lactate
production . Thus, by using oxidative stress, cancer
cells induce the activation of the autophagic program to
promote aerobic glycolysis under conditions of normoxia
. Therefore, treatment with antioxidants (such as N-
acetyl-cysteine, metformin, quercetin, vitamins A, C, and
E, selenium and perhaps others) or nitric oxide inhibitors
may be beneficial to reverse many of the cancer-associated
fibroblast phenotypes .
and cancer, particularly in the obese, in which visceral fat
is infiltrated by macrophages which constitute an important
source of proinflammatory mediators [113, 114]. Moreover,
macrophage accumulation in adipose tissue is associated
with local hypoxia in fat . It has been postulated
that hypoxia in the fat tissue of the obese plays a role
in the activation of inflammatory macrophages. Colocal-
ization/coordination between macrophages/adipocytes and
other cells of the immune system in white fat tissue leads
to a low-grade, chronic inflammation that produces many
cytokines able to initiate, promote, and sustain tumour
progression either directly , or indirectly, by causing
(via inhibition of the INSR signaling) insulin resistance,
which leads to the activation of protumorigenic pathways
(see Figure 1). For example, TNF-α, a cytokine involved
in systemic inflammation, blocks insulin signaling by pre-
venting serine phosphorylation of IRS-1 . Increased
expression of TNF-α has been observed in both acute and
chronic inflammatory states, including the chronic inflam-
matory response associated with cancer, obesity, and dia-
the inflammatory process leading to insulin resistance .
8Experimental Diabetes Research
TNF-α may activate both proapoptotic and antiapoptotic
pathways. Under certain circumstances TNF-α may act as
a tumour promoter by activating signaling pathways that
are critical for life/death decisions, such as MAPKs and
the antiapoptotic NFκB pathway. Thus, increased levels of
Another well-characterized inflammatory cytokine, IL-
6, has also been involved in various metabolic, endocrine,
and neoplastic disorders. Activation of STAT signaling, via
IL-6, is known to induce cancer cell proliferation, survival,
and invasion, while suppressing host antitumour immunity
. It has been documented that the expression of IL-
6 in adipose tissue and its serum concentrations positively
correlate with obesity, insulin resistance, and T2D, even
with insulin resistance in cancer patients [97, 120]. In
one study with breast cancer patients, IL-6 and estrogen
levels were found to be higher in the insulin-resistant
breast cancer patients without treatment compared to the
ones without insulin resistance . Similarly, in prostate
cancer, serum levels of IL-6 were higher in patients with
obesity/insulin resistance and clinically evident hormone-
resistant prostate cancer, compared to those with hormone-
shift the cell’s response to the inflammatory activating NFκB,
which is strongly associated with abdominal obesity and
insulin resistance. As stated above, this transcription factor
is involved in cytokine signaling and in cell survival, and its
stimuli, including chemotherapeutics, stress stimuli, and
involved in cellular proliferation and cell migration, anti-
apoptosis, and angiogenesis. Functional reduction of NFκB
correlates with decreased breast tumour cell proliferation.
Another mechanism that fuel cancer growth and tumour
progression in low-grade chronic inflammation and insulin
resistance is the accumulation of damaged DNA [123, 124].
Hyperglycemia in insulin resistance increases advanced gly-
cation end-product (AGE) formation . The production
of intracellular AGE precursors damages target cells by
modifying proteins and altering their function. It has been
reported that plasma proteins modified by AGE precursors
bind to AGE receptors on endothelial and mesangial cells
and macrophages, inducing receptor-mediated production
of ROS. Also, AGE receptor ligation, by activating NFκB, can
induce adverse changes in gene expression .
The last decades of medical research examining the patho-
genesis of common tumours have provided compelling
evidence for the involvement of insulin resistance in cancer.
Consequently, many research articles have been published
in the literature which give support to the hypothesis that
patients with insulin-resistant syndromes, such as obesity
and T2D, might be at higher risk for developing cancer
than the general population. The molecular mechanisms
for this association are unknown, but chronic sustained
hyperinsulinaemia in these insulin-resistant patients appears
to play a role in the neoplastic transformation process. As
underlined in this paper, several explanations have been pro-
posed for this association; however the precise mechanisms
that link insulin resistance and cancer have not yet been
fully understood and a more detailed molecular and mech-
anistic understanding is required to interpret the existing
data, together with more thorough preclinical and clinical
studies. Understanding these mechanisms may lead to novel
diagnostic and therapeutic strategies in these patients in
which measures to decrease chronic hyperinsulinemia and
insulin resistance may offer a general approach to prevention
C/EBPβ: CCAAT/enhancer binding protein beta
ERK: Extracellular regulated kinase
HMGA1: High-mobility group A1
IGF-I:Insulin-like growth factor-I
IGFBP:Insulin-like growth factor binding
IRS-1:Insulin receptor substrate-1
MAP:Mitogenic activated protein
MCP-1:Monocyte chemoattractant protein-1
MEK:Mitogen-activated protein kinase kinase
mTOR:Mammalian target of rapamycin
NFκB:Nuclear factor kappa B
PDK1: Phosphoinositide-dependent kinase 1
PTEN: Phosphatase and tensin homolog
Ras: Rat sarcoma
Rheb:Ras homolog enriched in brain
ROS: Reactive oxygen species
SHBG: Sex-hormone-binding globulin
Sp1: Specificity protein 1 transcription factor
STAT: Signal transducer and activator of
T2D: Type 2 diabetes mellitus
TAL-1:T-cell acute lymphocytic leukemia
TNF-α:Tumour necrosis factor-alpha
TSC: Tuberous sclerosis complex.
Advanced glycation end-product
Activator protein 2-alpha
Activating transcription factor-2
Conflict of Interests
The authors declare that there is no conflict of interests.
Experimental Diabetes Research9
Research support has been received from MIUR (Protocol
2004062059-002 Italy) to A. Brunetti The authors acknowl-
edge financial support from Dr. Belcastro, Mrs Baffa, and
Mrs Tiano (Cotronei, Italy) and from Associazione “`E
Solidariet` a” (Crotone, Italy).
 G. M. Reaven, “Role of insulin resistance in human disease,”
Diabetes, vol. 37, no. 12, pp. 1595–1607, 1988.
 R. A. Defronzo, “From the triumvirate to the ominous octet:
Diabetes, vol. 58, no. 4, pp. 773–795, 2009.
 G. Rao, “Insulin resistance syndrome,” American Family
Physician, vol. 63, no. 6, pp. 1159–1163, 2001.
 E. J. Mayer, B. Newman, M. A. Austin et al., “Genetic and
environmental influences on insulin levels and the insulin
resistance syndrome: an analysis of women twins,” The
American Journal of Epidemiology, vol. 143, no. 4, pp. 323–
 R. H. Unger, “Reinventing type 2 diabetes: pathogenesis,
treatment, and prevention,” Journal of the American Medical
Association, vol. 299, no. 10, pp. 1185–1187, 2008.
 R. K. Semple, D. B. Savage, E. K. Cochran, P. Gorden, and S.
O’Rahilly, “Genetic syndromes of severe insulin resistance,”
Endocrine Reviews, vol. 32, no. 4, pp. 498–514, 2011.
 H. E. Resnick, K. Jones, G. Ruotolo et al., “Insulin resistance,
the metabolic syndrome, and risk of incident cardiovascular
disease in nondiabetic American Indians: The Strong Heart
Study,” Diabetes Care, vol. 26, no. 3, pp. 861–867, 2003.
 R. L. Hanson, G. Imperatore, P. H. Bennett, and W. C.
Knowler, “Components of the “metabolic syndrome” and
incidence of type 2 diabetes,” Diabetes, vol. 51, no. 10, pp.
riskstateforcancer?” AmericanJournalofPathology, vol.169,
no. 5, pp. 1505–1522, 2006.
 R. Kaaks and A. Lukanova, “Energy balance and cancer: the
role of insulin and insulin-like growth factor-I,” Proceedings
of the Nutrition Society, vol. 60, no. 1, pp. 91–106, 2001.
 M. Pollak, “Insulin and insulin-like growth factor signalling
in neoplasia,” Nature Reviews Cancer, vol. 8, no. 12, pp. 915–
A, a newly recognized, high-affinity insulin- like growth
factor II receptor in fetal and cancer cells,” Molecular and
Cellular Biology, vol. 19, no. 5, pp. 3278–3288, 1999.
 P. Vigneri, F. Frasca, L. Sciacca, G. Pandini, and R. Vigneri,
“Diabetes and cancer,” Endocrine-Related Cancer, vol. 16, no.
4, pp. 1103–1123, 2009.
 E. Giovannucci, D. M. Harlan, M. C. Archer et al., “Diabetes
and cancer: a consensus report,” Diabetes Care, vol. 33, no. 7,
pp. 1674–1685, 2010.
 I. D. Goldfine, “The insulin receptor: molecular biology and
transmembrane signaling,” Endocrine Reviews, vol. 8, no. 3,
pp. 235–255, 1987.
 A. Ullrich, J. R. Bell, E. Y. Chen et al., “Human insulin
receptor and its relationship to the tyrosine kinase family of
oncogenes,” Nature, vol. 313, no. 6005, pp. 756–761, 1985.
 M. F. White and C. R. Kahn, “The insulin signaling system,”
The Journal of Biological Chemistry, vol. 269, no. 1, pp. 1–4,
 O. M. Rosen, “Structure and function of insulin receptors,”
Diabetes, vol. 38, no. 12, pp. 1508–1511, 1989.
 A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt, “The role
of the IGF system in cancer growth and metastasis: overview
 S.K.Singh,C.Brito,Q.W.Tan,M.DeLe´ on,andD.DeLe´ on,
“Differential expression and signaling activation of insulin
receptor isoforms A and B: a link between breast cancer and
diabetes?” Growth Factors, vol. 29, no. 6, pp. 278–289, 2011.
insulin receptor isoform exon 11- (IR-A) in cancer and other
diseases: a review,” Hormone and Metabolic Research, vol. 35,
no. 11-12, pp. 778–785, 2003.
 S. I. Taylor, “Deconstructing type 2 diabetes,” Cell, vol. 97,
no. 1, pp. 9–12, 1999.
 R. A. DeFronzo, D. Simonson, and E. Ferrannini, “Hepatic
and peripheral insulin resistance: a common feature of type
2 (non-insulin-dependent) and type 1 (insulin-dependent)
diabetes mellitus,” Diabetologia, vol. 23, no. 4, pp. 313–319,
 C. B. Hollenbeck, Y. D. Chen, and G. M. Reaven, “A
comparison of the relative effects of obesity and non-insulin-
dependent diabetes mellitus on in vivo insulin-stimulated
glucose utilization,” Diabetes, vol. 33, no. 7, pp. 622–626,
 S. B. Biddinger and C. R. Kahn, “From mice to men: insights
into the insulin resistance syndromes,” Annual Review of
Physiology, vol. 68, pp. 123–158, 2006.
factor HMGA1 causes insulin resistance and diabetes in
humans and mice,” Nature Medicine, vol. 11, no. 7, pp. 765–
 E. Chiefari, S. Tanyolac ¸, F. Paonessa et al., “Functional
variants of the HMGA1 gene and type 2 diabetes mellitus,”
Journal of the American Medical Association, vol. 305, no. 9,
pp. 903–912, 2011.
 P. Massoner, M. Ladurner-Rennau, I. E. Eder, and H.
Klocker, “Insulin-like growth factors and insulin control a
multifunctional signalling network of significant importance
in cancer,” British Journal of Cancer, vol. 103, no. 10, pp.
 F. Frasca, G. Pandini, L. Sciacca et al., “The role of insulin
receptors and IGF-I receptors in cancer and other diseases,”
Archives of Physiology and Biochemistry, vol. 114, no. 1, pp.
 V. Papa, V. Pezzino, A. Costantino et al., “Elevated insulin
receptor content in human breast cancer,” Journal of Clinical
Investigation, vol. 86, no. 5, pp. 1503–1510, 1990.
 J. H. Law, G. Habibi, K. Hu et al., “Phosphorylated insulin-
like growth factor-I/insulin receptor is present in all breast
cancer subtypes and is related to poor survival,” Cancer
Research, vol. 68, no. 24, pp. 10238–10246, 2008.
 K. R. Kalli, O. I. Falowo, L. K. Bale, M. A. Zschunke, P. C.
Roche, and C. A. Conover, “Functional insulin receptors on
human epithelial ovarian carcinoma cells: implications for
IGF-II mitogenic signaling,” Endocrinology, vol. 143, no. 9,
pp. 3259–3267, 2002.
 M. E. Cox, M. E. Gleave, M. Zakikhani et al., “Insulin
69, no. 1, pp. 33–40, 2009.
10 Experimental Diabetes Research
 R. Schiel, W. Beltschikow, T. Steiner, and G. Stein, “Diabetes,
insulin, and risk of cancer,” Methods and Findings in Experi-
 E. Giovannucci and D. Michaud, “The role of obesity and
related metabolic disturbances in cancers of the colon,
prostate, and pancreas,” Gastroenterology, vol. 132, no. 6, pp.
 C. K. Osborne, G. Bolan, M. E. Monaco, and M. E. Lippman,
“Hormone responsive human breast cancer in long term
tissue culture: effect of insulin,” Proceedings of the National
Academy of Sciences of the United States of America, vol. 73,
no. 12, pp. 4536–4540, 1976.
 F. Paonessa, D. Foti, V. Costa et al., “Activator protein-
2 overexpression accounts for increased insulin receptor
expression in human breast cancer,” Cancer Research, vol. 66,
no. 10, pp. 5085–5093, 2006.
 S. Kolb, R. Fritsch, D. Saur, M. Reichert, R. M. Schmid,
and G. Schneider, “HMGA1 controls transcription of insulin
cells,” Cancer Research, vol. 67, no. 10, pp. 4679–4686, 2007.
 D. P. Foti, F. Paonessa, E. Chiefari, and A. Brunetti, “New tar-
get genes for the peroxisome proliferator-activated receptor-
(PPAR ) antitumour activity: perspectives from the insulin
receptor,” PPAR Research, Article ID 571365, 2009.
 P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation
of adipogenesis in fibroblasts by PPARγ2, a lipid-activated
 E. Mueller, P. Sarraf, P. Tontonoz et al., “Terminal differentia-
tion ofhuman breast cancer through PPARγ,” Molecular Cell,
vol. 1, no. 3, pp. 465–470, 1998.
 V. Costa, D. Foti, F. Paonessa et al., “The insulin receptor:
a new anticancer target for peroxisome proliferator-activated
receptor-γ (PPARγ)andthiazolidinedione-PPARγ agonists,”
Endocrine-Related Cancer, vol. 15, no. 1, pp. 325–335, 2008.
 P. W. Mamula, A. R. McDonald, A. Brunetti et al., “Regulat-
ing insulin-receptor-gene expression by differentiation and
hormones,” Diabetes Care, vol. 13, no. 3, pp. 288–301, 1990.
 E. Araki, F. Shimada, H. Uzawa, M. Mori, and Y. Ebina,
“Characterization of the promoter region of the human
insulin receptor gene: evidence for promoter activity,” The
Journal of Biological Chemistry, vol. 262, no. 33, pp. 16186–
 S. Seino, M. Seino, S. Nishi, and G. I. Bell, “Structure of
the human insulin receptor gene and characterization of its
promoter,” Proceedings of the National Academy of Sciences of
 A. Brunetti, D. Foti, and I. D. Goldfine, “Identification of
unique nuclear regulatory proteins for the insulin receptor
gene, which appear during myocyte and adipocyte differen-
tiation,” Journal of Clinical Investigation, vol. 92, no. 3, pp.
 M. Bustin and R. Reeves, “High-mobility-group chromo-
somal proteins: architectural components that facilitate
chromatin function,” Progress in Nucleic Acid research and
Molecular Biology, vol. 54, pp. 35–100, 1996.
 R. Reeves and L. Beckerbauer, “HMGI/Y proteins: flexi-
ble regulators of transcription and chromatin structure,”
Biochimica et Biophysica Acta, vol. 1519, no. 1-2, pp. 13–29,
 M. Merika and D. Thanos, “Enhanceosomes,” Current Opin-
ion in Genetics and Development, vol. 11, no. 2, pp. 205–208,
 A. Brunetti, G. Manfioletti, E. Chiefari, I. D. Goldfine, and D.
Foti, “Transcriptional regulation of human insulin receptor
gene by the high-mobility group protein HMGI(Y),” The
FASEB Journal, vol. 15, no. 2, pp. 492–500, 2001.
human insulin receptor gene transcription,” Molecular and
Cellular Biology, vol. 23, no. 8, pp. 2720–2732, 2003.
 C. K. Osborne, M. E. Monaco, M. E. Lippman, and C. R.
Kahn, “Correlation among insulin binding, degradation, and
biological activity in human breast cancer cells in long term
tissue culture,” Cancer Research, vol. 38, no. 1, pp. 94–102,
 G. Milazzo, F. Giorgino, G. Damante et al., “Insulin receptor
expression and function in human breast cancer cell lines,”
Cancer Research, vol. 52, no. 14, pp. 3924–3930, 1992.
 N. R. Farid, Y. Shi, and M. Zou, “Molecular basis of thyroid
cancer,” Endocrine Reviews, vol. 15, no. 2, pp. 202–232, 1994.
 J. I. Jones and D. R. Clemmons, “Insulin-like growth factors
and their binding proteins: biological actions,” Endocrine
Reviews, vol. 16, no. 1, pp. 3–34, 1995.
 D. R. Clemmons and L. E. Underwood, “Nutritional regula-
tion of IGF-I and IGF binding proteins,” Annual Review of
Nutrition, vol. 11, pp. 393–412, 1991.
factors that control mammalian growth,”The FASEB Journal,
vol. 8, no. 1, pp. 6–12, 1994.
 J. P. Thissen, J. M. Ketelslegers, and L. E. Underwood,
“Nutritional regulation of the insulin-like growth factors,”
Endocrine Reviews, vol. 15, no. 1, pp. 80–101, 1994.
 E. E. Calle and R. Kaaks, “Overweight, obesity and can-
cer: epidemiological evidence and proposed mechanisms,”
Nature Reviews Cancer, vol. 4, no. 8, pp. 579–591, 2004.
 D. R. Clemmons, “Modifying IGF1 activity: an approach to
treatendocrinedisorders,atherosclerosis andcancer,” Nature
Reviews Drug Discovery, vol. 6, no. 10, pp. 821–833, 2007.
 M. A. Soos, J. Whittaker, R. Lammers, A. Ullrich, and K.
in transfected cells,” The Biochemical Journal, vol. 270, no. 2,
pp. 383–390, 1990.
 A. Ullrich, A. Gray, A. W. Tam et al., “Insulin-like growth
factor I receptor primary structure: comparison with insulin
receptor suggests structural determinants that define func-
tional specificity,” The EMBO Journal, vol. 5, no. 10, pp.
phosphorylation of upstream binding factor 1 by nuclear
phosphatidylinositol 3-kinase,” Proceedings of the National
Academy of Sciences of the United States of America, vol. 101,
no. 25, pp. 9272–9276, 2004.
 C. R. Kahn, “The Gordon Wilson Lecture. Lessons about
the control of glucose homeostasis and the pathogenesis of
diabetes from knockout mice,” Transactions of the American
 F. P. Ottensmeyer, D. R. Beniac, R. Z.-T. Luo, and C. C. Yip,
“Mechanism of transmembrane signaling: insulin binding
and the insulin receptor,” Biochemistry, vol. 39, no. 40, pp.
 J. B. Carvalheira, H. G. Zecchin, and M. J. Saad, “Vias de
sinalizac ¸˜ ao da insulina,” Arquivos Brasileiros de Endocrinolo-
gia & Metabologia, vol. 46, no. 4, pp. 419–425, 2002.
Experimental Diabetes Research 11
 L. C. Cantley, “The phosphoinositide 3-kinase pathway,”
Science, vol. 296, no. 5573, pp. 1655–1657, 2002.
 A. Barthel, D. Schmoll, and T. G. Unterman, “FoxO proteins
in insulin action and metabolism,” Trends in Endocrinology
and Metabolism, vol. 16, no. 4, pp. 183–189, 2005.
 Y. Zou, W. B. Tsai, C. J. Cheng et al., “Forkhead box
transcription factor FOXO3a suppresses estrogen-dependent
breast cancer cell proliferation and tumorigenesis,” Breast
Cancer Research, vol. 10, no. 1, article R21, 2008.
 N. Hay and N. Sonenberg, “Upstream and downstream of
mTOR,” Genes and Development, vol. 18, no. 16, pp. 1926–
for the mTOR pathway,” Current Opinion in Cell Biology, vol.
17, no. 6, pp. 596–603, 2005.
 K. Inoki, Y. Li, T. Zhu, J. Wu, and K. L. Guan, “TSC2 is
phosphorylated and inhibited by Akt and suppresses mTOR
signalling,” Nature Cell Biology, vol. 4, no. 9, pp. 648–657,
 F. Os´ orio-Costa, G. Z. Rocha, M. M. Dias, and J. B. C.
Carvalheira, “Epidemiological and molecular mechanisms
aspects linking obesity and cancer,” Arquivos Brasileiros de
Endocrinologia e Metabologia, vol. 53, no. 2, pp. 213–226,
 V. Stambolic, A. Suzuki, J. L. de la Pompa et al., “Negative
regulation of PKB/Akt-dependent cell survival by the tumor
suppressor PTEN,” Cell, vol. 95, no. 1, pp. 29–39, 1998.
 L. Simpson and R. Parsons, “PTEN: life as a tumor suppres-
sor,” Experimental Cell Research, vol. 264, no. 1, pp. 29–41,
 B. P. Ceresa and J. E. Pessin, “Insulin regulation of the
Ras activation/inactivation cycle,” Molecular and Cellular
Biochemistry, vol. 182, no. 1-2, pp. 23–29, 1998.
 A. Brunet, D. Roux, P. Lenormand, S. Dowd, S. Keyse, and
J. Pouyss´ egur, “Nuclear translocation of p42/p44 mitogen-
activated protein kinase is required for growth factor-
induced gene expression and cell cycle entry,” The EMBO
Journal, vol. 18, no. 3, pp. 664–674, 1999.
 P. P. Roux and J. Blenis, “ERK and p38 MAPK-activated
protein kinases: a family of protein kinases with diverse
biological functions,” Microbiology and Molecular Biology
Reviews, vol. 68, no. 2, pp. 320–344, 2004.
 L. O. Murphy and J. Blenis, “MAPK signal specificity: the
right place at the right time,” Trends in Biochemical Sciences,
vol. 31, no. 5, pp. 268–275, 2006.
 P. D. Ryan and P. E. Goss, “The emerging role of the insulin-
like growth factor pathway as a therapeutic target in cancer,”
Oncologist, vol. 13, no. 1, pp. 16–24, 2008.
 H. B. El-Serag, H. Hampel, and F. Javadi, “The association
between diabetes and hepatocellular carcinoma: a systematic
review of epidemiologic evidence,” Clinical Gastroenterology
and Hepatology, vol. 4, no. 3, pp. 369–380, 2006.
 C. Wang, X. Wang, G. Gong et al., “Increased risk of
hepatocellular carcinoma in patients with diabetes mellitus:
a systematic review and meta-analysis of cohort studies,”
International Journal of Cancer, vol. 7, no. 6, pp. 1639–1648,
 E. Friberg, N. Orsini, C. S. Mantzoros, and A. Wolk,
“Diabetes mellitus and risk of endometrial cancer: a meta-
analysis,” Diabetologia, vol. 50, no. 7, pp. 1365–1374, 2007.
 R. Huxley, A. Ansary-Moghaddam, A. Berrington de
Gonz´ alez, F. Barzi, and M. Woodward, “Type-II diabetes
and pancreatic cancer: a meta-analysis of 36 studies,” British
Journal of Cancer, vol. 92, no. 11, pp. 2076–2083, 2005.
 D. Li, H. Tang, M. M. Hassan, E. A. Holly, P. M. Bracci, and
D. T. Silverman, “Diabetes and risk of pancreatic cancer: a
pooled analysis of three large case-control studies,” Cancer
Causes and Control, vol. 22, no. 2, pp. 189–197, 2011.
 Q. Ben, M. Xu, X. Ning et al., “Diabetes mellitus and risk
of pancreatic cancer: a meta-analysis of cohort studies,”
European Journal of Cancer, vol. 47, no. 13, pp. 1928–1937,
 S. C. Larsson and A. Wolk, “Diabetes mellitus and incidence
of kidney cancer: a meta-analysis of cohort studies,” Dia-
betologia, vol. 54, no. 5, pp. 1013–1018, 2011.
 H. B. Ren, T. Yu, C. Liu, and Y. Q. Li, “Diabetes mellitus and
increased risk of biliary tract cancer: systematic review and
meta-analysis,” Cancer Causes and Control, vol. 22, no. 6, pp.
 W. Jing, G. Jin, and X. Zhou, “Diabetes mellitus and
increased risk of cholangiocarcinoma: a meta-analysis,”
European Journal of Cancer Prevention, vol. 21, no. 1, pp. 24–
 S. C. Larsson, N. Orsini, K. Brismar, and A. Wolk, “Diabetes
mellitus and risk of bladder cancer: a meta-analysis,” Dia-
betologia, vol. 49, no. 12, pp. 2819–2823, 2006.
 S. C. Larsson, N. Orsini, and A. Wolk, “Diabetes mellitus
and risk of colorectal cancer: a meta-analysis,” Journal of the
National Cancer Institute, vol. 97, no. 22, pp. 1679–1687,
 H. Yuhara, C. Steinmaus, S. E. Cohen, D. A. Corley, Y. Tei,
and P. A. Buffler, “Is diabetes mellitus an independent risk
factor for colon cancer and rectal cancer?” The American
Journal of Gastroenterology, vol. 106, no. 11, pp. 1911–1921,
 W. Huang, H. Ren, Q. Ben, Q. Cai, W. Zhu, and Z. Li, “Risk
of esophageal cancer in diabetes mellitus: a meta-analysis of
observational studies,” Cancer Causes and Control, vol. 18,
pp. 263–272, 2011.
 J. Mitri, J. Castillo, and A. G. Pittas, “Diabetes and risk of
non-hodgkin’s lymphoma: a meta-analysis of observational
studies,” Diabetes Care, vol. 31, no. 12, pp. 2391–2397, 2008.
 C. Chao and J. H. Page, “Type 2 diabetes mellitus and risk
of non-hodgkin lymphoma: a systematic review and meta-
analysis,” The American Journal of Epidemiology, vol. 168, no.
5, pp. 471–480, 2008.
 S. C. Larsson, C. S. Mantzoros, and A. Wolk, “Diabetes mel-
litus and risk of breast cancer: a meta-analysis,” International
Journal of Cancer, vol. 121, no. 4, pp. 856–862, 2007.
 E. E. Kershaw and J. S. Flier, “Adipose tissue as an endocrine
89, no. 6, pp. 2548–2556, 2004.
 H. Tilg and A. R. Moschen, “Adipocytokines: mediators
linking adipose tissue, inflammation and immunity,” Nature
Reviews Immunology, vol. 6, no. 10, pp. 772–783, 2006.
 H. Kanda, S. Tateya, Y. Tamori et al., “MCP-1 contributes
to macrophage infiltration into adipose tissue, insulin resis-
tance, and hepatic steatosis in obesity,” Journal of Clinical
Investigation, vol. 116, no. 6, pp. 1494–1505, 2006.
 L. Vona-Davis and D. P. Rose, “Adipokines as endocrine,
paracrine, and autocrine factors in breast cancer risk and
progression,” Endocrine-Related Cancer, vol. 14, no. 2, pp.
 P. Iyengar, T. P. Combs, S. J. Shah et al., “Adipocyte-
secreted factors synergistically promote mammary tumori-
genesis through induction of anti-apoptotic transcriptional
programs and proto-oncogene stabilization,” Oncogene, vol.
22, no. 41, pp. 6408–6423, 2003.
12Experimental Diabetes Research
 A. Macci` o and C. Madeddu, “Obesity, inflammation, and
postmenopausal breast cancer: therapeutic implications,”
The Scientific World Journal, vol. 11, pp. 2020–2036, 2011.
 G. Fantuzzi, “Adipose tissue, adipokines, and inflammation,”
Journal of Allergy and Clinical Immunology, vol. 115, no. 5,
pp. 911–919, 2005.
levels and risk of type 2 diabetes: a systematic review and
meta-analysis,” Journal of the American Medical Association,
vol. 302, no. 2, pp. 179–188, 2009.
 A. Sch¨ affler, J. Sch¨ olmerich, and C. Buechler, “Mechanisms
of disease: adipokines and breast cancer—endocrine and
cer,” Nature Clinical Practice Endocrinology and Metabolism,
vol. 3, no. 4, pp. 345–354, 2007.
 M. Pignatelli, C. Cocca, A. Santos, and A. Perez-Castillo,
“Enhancement of BRCA1 gene expression by the peroxisome
proliferator-activated receptor γ in the MCF-7 breast cancer
cell line,” Oncogene, vol. 22, no. 35, pp. 5446–5450, 2003.
 S. Furukawa, T. Fujita, M. Shimabukuro et al., “Increased
oxidative stress in obesity and its impact on metabolic
syndrome,” Journal of Clinical Investigation, vol. 114, no. 12,
pp. 1752–1761, 2004.
 F. Sotgia, U. E. Martinez-Outschoorn, and M. P. Lisanti,
“Mitochondrial oxidative stress drives tumor progression
and metastasis: should we use antioxidants as a key compo-
nent of cancer treatment and prevention?” BMC Medicine,
vol. 9, article 62, 2011.
 S. D. Hursting and N. A. Berger, “Energy balance, host-
related factors, and cancer progression,” Journal of Clinical
Oncology, vol. 28, no. 26, pp. 4058–4065, 2010.
 C. Bubici, S. Papa, K. Dean, and G. Franzoso, “Mutual
cross-talk between reactive oxygen species and nuclear
factor-kappa B: molecular basis and biological significance,”
Oncogene, vol. 25, no. 51, pp. 6731–6748, 2006.
 B. Chiavarina, D. Whitaker-Menezes, G. Migneco et al.,
“HIF1-alpha functions as a tumor promoter in cancer asso-
ciated fibroblasts, and as a tumor suppressor in breast cancer
cells: autophagy drives compartment-specific oncogenesis,”
Cell Cycle, vol. 9, no. 17, pp. 3534–3551, 2010.
 U. E. Martinez-Outschoorn, R. M. Balliet, D. B. Rivadeneira
et al., “Oxidative stress in cancer associated fibroblasts drives
tumor-stroma co-evolution: a new paradigm for under-
standing tumor metabolism, the field effect and genomic
instability in cancer cells,” Cell Cycle, vol. 9, no. 16, pp. 3256–
 G. Tuncman, J. Hirosumi, G. Solinas, L. Chang, M. Karin,
and G. S. Hotamisligil, “Functional in vivo interactions
between JNK1 and JNK2 isoforms in obesity and insulin
resistance,” Proceedings of the National Academy of Sciences
of the United States of America, vol. 103, no. 28, pp. 10741–
 C. A. Curat, A. Miranville, C. Sengen` es et al., “From blood
monocytes to adipose tissue-resident macrophages: induc-
tion of diapedesis by human mature adipocytes,” Diabetes,
vol. 53, no. 5, pp. 1285–1292, 2004.
 J. Aron-Wisnewsky, C. Minville, J. Tordjman et al., “Chronic
liver disease in morbid obese,” Journal of Hepatology, vol. 56,
no. 1, pp. 225–233, 2012.
 S. I. Grivennikov, F. R. Greten, and M. Karin, “Immunity,
inflammation, and cancer,” Cell, vol. 140, no. 6, pp. 883–899,
 G. S. Hotamisligil, P. Peraldi, A. Budavari, R. Ellis, M. F.
White, and B. M. Spiegelman, “IRS-1-mediated inhibition
of insulin receptor tyrosine kinase activity in TNF-α- and
obesity-induced insulin resistance,” Science, vol. 271, no.
5249, pp. 665–668, 1996.
 G. S. Hotamisligil, N. S. Shargill, and B. M. Spiegelman,
“Adipose expression of tumor necrosis factor-α: direct role in
obesity-linked insulin resistance,” Science, vol. 259, no. 5091,
pp. 87–91, 1993.
and immunity: a leading role for STAT3,” Nature Reviews
Cancer, vol. 9, no. 11, pp. 798–809, 2009.
 B. Vozarova, C. Weyer, K. Hanson, P. A. Tataranni, C.
Bogardus, and R. E. Pratley, “Circulating interleukin-6 in
relation to adiposity, insulin action, and insulin secretion,”
Obesity Research, vol. 9, no. 7, pp. 414–417, 2001.
 G. Gonullu, C. Ersoy, A. Ersoy et al., “Relation between
insulin resistance and serum concentrations of IL-6 and
TNF-α in overweight or obese women with early stage breast
cancer,” Cytokine, vol. 31, no. 4, pp. 264–269, 2005.
 M. J. Khandekar, P. Cohen, and B. M. Spiegelman, “Molec-
ular mechanisms of cancer development in obesity,” Nature
Reviews Cancer, vol. 11, pp. 886–895, 2011.
 L. Zheng, H. Dai, M. Zhou et al., “Fen1 mutations result in
autoimmunity, chronic inflammation and cancers,” Nature
Medicine, vol. 13, no. 7, pp. 812–819, 2007.
 J. Vakkila and M. T. Lotze, “Inflammation and necrosis
promote tumour growth,” Nature Reviews Immunology, vol.
4, no. 8, pp. 641–648, 2004.
 H. P. Hammes, S. Martin, K. Federlin, K. Geisen, and M.
Brownlee, “Aminoguanidine treatment inhibits the develop-
National Academy of Sciences of the United States of America,
vol. 88, no. 24, pp. 11555–11558, 1991.
 I. Giardino, D. Edelstein, and M. Brownlee, “Nonenzymatic
glycosylation in vitro and in bovine endothelial cells alters
lar glycosylation in diabetes,” Journal of Clinical Investigation,
vol. 94, no. 1, pp. 110–117, 1994.