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.

Full text

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Hindawi Publishing Corporation
Experimental Diabetes Research
Volume 2012, Article ID 789174, 12 pages
doi:10.1155/2012/789174
Review Article
InsulinResistanceand CancerRisk: AnOverviewof the
Pathogenetic Mechanisms
Biagio Arcidiacono,1StefaniaIiritano,1AuroraNocera,1
KatiusciaPossidente,1MariaT. Nevolo,1Valeria Ventura,1DanielaFoti,1,2
EusebioChiefari,1andAntonio Brunetti1,3
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, brunetti@unicz.it
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
cited.
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.
1.Introduction/GeneralOverview
Insulinresistanceisapathologicalconditioninwhichinsulin
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
individualsdevelopswhenbetacellsfailtocompensate[1,2].
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 [3]. 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 [4]. 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 [6]. 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 [9].
As illustrated in Figure 1, various mechanisms have been

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2 Experimental Diabetes Research
Environmental
factors
Genetic
susceptibility
Gluconeogenesis
FFA
TG
PAI-1
VEGF
Leptin
Adiponectin
IL-6
Hyperinsulinemia
Hyperglycemia
SHBG
IGFBPs
IGF-I
ROS
IGF-I, estradiol and testosterone
bioactivity
Estradiol
Cancer
AngiogenesisMitosisMigrationDNA damageAnti-apoptosis
resistance
Obesity
Inflammation
Insulin
TNF-α
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
issuescurrentlyunderdebate,relatedtothisareaofresearch.
(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
[12, 13].
(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 [14]. 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,
andIts ClinicalSignificanceinCancer
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

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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
extracellularαsubunits(130kDa)thathouseinsulinbinding
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
breastcancerandotherepithelialtumours,includingovarian
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 [37] (Figure 2(a)). In these cases,
we demonstrated that transactivation of the INSR gene by
AP2-α represented a fundamental prerequisite to activate
INSRgenetranscription inneoplasticbreasttissue.Similarly,
a functional link between INSR and cyclin D1 has been
recently described in pancreatic cancer [38]. 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 [39]. 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
usingGSTpull-down,combinedwithelectrophoresismobil-
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 [42].
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 [43]. 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 [46]. 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
throughmechanismsthatfacilitatetheassemblyandstability

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4 Experimental Diabetes Research
HMGA1
HMGA1
Sp1
Sp1
INSR mRNA
Transcription
CEBP/β
AP2-α
AP2-α
AP2-α
AP2-α
(a)
HMGA1
HMGA1
Sp1
Sp1
INSR mRNA
Transcription
CEBP/β
AP2-α
AP2-α
AP2-α
PPARγ
PPARγ
(b)
Figure 2: INSR gene expression in breast cancer. (a) AP2-α overexpression increases INSR expression in breast tumour [37]. 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
potentiatingtherecruitmentandbindingofSp1andC/EBPβ
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 [26]. Overexpression of INSR in cells
which normally express low levels of INSR, like epithelial
cells, may increase the biological responses to insulin and
triggeraligand-mediatedneoplastic transformation.Various
studies have shown that INSRs are increased in most
humanbreastcancers,andbothligand-dependentmalignant
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 [54]. 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.
3.Proposed Mechanismsfor
Hormone-MediatedTumorigenesis
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 [55]. IGFBP-3 is the
predominant binding protein expressed in serum, and the
vast majority of circulating IGF-I and IGF-II are bound in

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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
induceapoptosis.TheprimarylocationforIGFBP-3produc-
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 [59]. 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 [60].
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 [65]. The INSR, the IGF-IR,
as well as the hybrid receptors, are expressed at higher
levels in malignant cells [66]. 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
[67]. 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 [72]. It has been shown
that activation of PI3K by insulin relieves this inhibitory
function [73], 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
[74].Inthisrespect,PTENisoftendisruptedintumourcells,
and this emphasizes the role of the insulin/IGF-I-induced
PI3K/Akt/mTOR/S6K signaling in cancer [75] (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
[80], consistently with these observations, the IGF system is
emerging as a promising new target in cancer therapy.
4.Obesity,Diabetes,andCancer
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

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IRS IRS
PI3K
PI3K
Ras
Ras
PIP2 PIP2
PIP3
PIP3
PDK1
PDK1
TSC 1-2
TSC 1-2
Raf Raf
ERK
ERK
MEK
MEK
AKTAKT
Insulin
Insulin
IGF-I
IGF-I
GTP GTP
Rheb
Rheb
Raptor
mTOR
mTOR
Gene expression Gene expression
Proliferation
Proliferation
Migration
Migration
Differentiation
Differentiation
Inhibition of apoptosis
Inhibition of apoptosis
INSR
IGF-IR
HR
HR
Raptor
INSR
IGF-IR
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” [97], which include adipocytokines
(leptin, adiponectin, and resistin), cytokines (TNF-α, IL-
1 and IL-6), and the chemokine MCP-1 [98] that has
recently been identified as a potential factor contributing to
macrophage infiltration into adipose tissue [99]. 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 [100].
It has been demonstrated that adipocyte-secreted factors
can directly promote mammary tumorigenesis through
induction of antiapoptotic transcriptional programs and
protooncogene stabilization [101]. 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 [102]. Biosynthesis of leptin in adipose tissue
is influenced by insulin [103], 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
(STAT3),AP-1,ERK2,andMAPK,leptinisinvolvedinbreast
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 [104]. Low
blood concentrations of adiponectin have been associated
with high incidence and poor prognosis of breast cancer,
independently from the hormone receptor status [105].
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.

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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%)
2.50 (1.80–3.50)
2.51 (1.90–3.20)
2.01 (1.61–2.51)
2.22 (1.80–2.74)
1.62 (1.21–2.16)
1.94 (1.53–2.36)
1.73 (1.59–1.88)
1.80 (1.50–2.10
1.94 (1.66–2.27)
1.42 (1.06–1.91)
1.43 (1.18–1.72)
1.60 (1.38–1.87)
1.37 (1.04–1.80)
1.43 (1.18–1.74)
1.36 (1.23–1.50)
1.29 (1.16–1.43)
1.38 (1.26–1.51)
1.30 (1.12–1.50)
1.12 (0.95–1.31)
1.41 (1.07–1.88)
1.18 (0.99–1.42)
1.79 (1.30–2.47)
1.18 (1.05–1.32)
1.20 (1.11–1.30)
Reference number
[81]
[81]
[82]
[83]
[83]
[84]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[90]
[91]
[91]
[92]
[93]
[94]
[94]
[95]
[95]
[96]
[96]
Liver
Endometrium
Pancreas
Kidney
Biliary tract
Bladder
Colon-rectum
Esophagus
N-H lymphoma∗
Breast
∗Non-Hodgkin’s lymphoma.
Enhancement of BRCA1 expression by PPARγ has been
reported in MCF-7 breast cancer cells [106]. 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
repair mechanisms.
ObesityandT2Darefrequentlyassociatedwithincreased
oxidative stress [107]. 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 [108]. 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 [109].
NFκB is a central coordinator of immunity, inflammation,
and cell survival. Mutual cross-talk between ROS and NFκB
has been identified [110]. For example, fibroblasts harboring
activated NFκB are able to promote tumour growth [111].
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 [111]. Thus, by using oxidative stress, cancer
cells induce the activation of the autophagic program to
promote aerobic glycolysis under conditions of normoxia
[111]. 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 [112].
5.Inflammatory Cytokines,Diabetes,and
CancerRisk
Chronicinflammationmayrepresentalinkbetweendiabetes
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 [115]. 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 [116], 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 [117]. 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-
betes.OverproductionofTNF-αsupportsandevenamplifies
the inflammatory process leading to insulin resistance [118].

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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
circulatingTNF-αmaypromotetumorigenesisinoverweight
insulin-resistant patients.
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
[119]. 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 [121]. 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-
dependentcancer[122].Inflammationandinsulinresistance
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
expressionisinducedbyamultitudeofdifferentextracellular
stimuli, including chemotherapeutics, stress stimuli, and
growthfactors.NFκBpromotestheexpressionoftargetgenes
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 [125]. 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 [126].
6.Conclusions
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
of cancer.
Abbreviations
AGE:
AP2-α:
ATF-2:
C/EBPβ: CCAAT/enhancer binding protein beta
Cav-1: Caveolin-1
ERK: Extracellular regulated kinase
GAP:GTPase-activating protein
HMGA1: High-mobility group A1
IGF-I:Insulin-like growth factor-I
IGF-IR:IGF-I receptor
IGFBP:Insulin-like growth factor binding
protein
INSR:Insulin receptor
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
PI3K:Phosphoinositide-3 kinase
PPAR:Peroxisome proliferator-activated
receptor
PTEN: Phosphatase and tensin homolog
Raf:Rapidly fibrosarcoma
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
transcription
T2D: Type 2 diabetes mellitus
TAL-1:T-cell acute lymphocytic leukemia
protein-1
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.

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Experimental Diabetes Research9
Acknowledgments
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).
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