Insulin resistance and cancer: the role of insulin and IGFs

TL;DR: Evidence highlighting recent advances in understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity are discussed, as well as those areas where there remains a paucity of data.

Abstract: Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

Full text

Insulin resistance and cancer:
the role of insulin and IGFs
Sefirin Djiogue
1
, Armel Herve
´
Nwabo Kamdje
2,3
, Lorella Vecchio
4
,
Maulilio John Kipanyula
5
, Mohammed Farahna
6
, Yousef Aldebasi
7
and
Paul Faustin Seke Etet
6
1
Department of Animal Biology and Physiology, University of Yaounde
´
1, PO Box 812, Yaounde
´
, Cameroon
2
Biomedical Research Center, University of British Columbia, 2222 Health Science Mall, Vancouver, British Columbia,
Canada V6T 1Z3
3
Department of Biomedical Sciences, University of Ngaounde
´
re
´
, PO Box 454, Ngaounde
´
re
´
, Cameroon
4
Laboratory of Cytometry, University of Pavia, via Ferrata 1, 27100 Pavia, Italy
5
Department of Veterinary Anatomy, Sokoine University of Agriculture, PO Box 3016, Chuo Kikuu, Morogoro,
Tanzania
Departments of
6
Basic Health Sciences
7
Optometry, College of Applied Medical Sciences, Qassim University,
Buraydah, 51452 Al-Qaseem, Saudi Arabia
Correspondence
should be addressed to
P F Seke Etet
Email
paul.seke@gmail.com
Abstract
Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary
conserved factors well known as key regulators of energy metabolism and growth, with crucial
roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2
diabetes mellitus, as well as associated immune deregulations. A growing body of evidence
suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation,
differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream
through insulin receptor substrate molecules and thus play a pivotal role in cell fate
determination. Despite the emerging evidence from epidemiological studies on the possible
relationship between insulin resistance and cancer, our understanding on the cellular and
molecular mechanisms that might account for this relationship remains incompletely
understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high
energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which
has been proposed as the key mechanism bridging insulin resistance and cancer. The present
review summarizes and discusses evidence highlighting recent advances in our understanding
on the role of ILPs as the link between insulin resistance and cancer and between immune
deregulation and cancer in obesity, as well as those areas where there remains a paucity of data.
It is anticipated that issues discussed in this paper will also recover new therapeutic targets that
can assist in diagnostic screening and novel approaches to controlling tumor development.
Endocrine-Related Cancer
(2013) 20, R1–R17
Introduction
Insulin resistance is a pathological condition characterized
by a decrease in efficiency of insulin signaling for blood
sugar regulation. Insulin resistance is a major component
of metabolic syndrome, i.e. a group of risk factors that
generally occur together and increase the risk for various
diseases, including type 2 diabetes mellitus and several
other metabolic diseases (Campbell 2011, Karagiannis
et al. 2012), cerebrovascular and coronary artery diseases
(Hadaegh et al. 2012, Vykoukal & Davies 2012), neuro-
degenerative disorders (Kaidanovich-Beilin et al. 2012,
Endocrine-Related Cancer
Review
S Djiogue et al. Insulin resistance and cancer
20:1 R1–R17
http://erc.endocrinology-journals.org q 2013 Society for Endocrinology
DOI: 10.1530/ERC-12-0324 Printed in Great Britain
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Talbot et al. 2012), infectious diseases (Jeon et al.
2012, Witso 2012), and cancer (Byers & Sedjo 2011,
Spyridopoulos et al. 2012). Due to the ongoing worldwide
epidemic of obesity and other insulin resistance-related
disorders (Campbell 2011), insulin-like peptides (ILPs), i.e.
evolutionary conserved and ubiquitous factors historically
involved in the regulation of energy metabolism, have
been the subject of thorough investigations. In humans,
ILPs include insulin, IGF1, IGF2, and seven relaxin-related
peptides, which share the same basic fold (Sajid et al.
2011). In the present review, the term ‘ILP’ will be used to
indicate insulin and IGFs, whereas relaxin-related peptides
will not be discussed.
Insulin signal transduction occurs through two
insulin receptor (IR) isoforms resulting from transcrip-
tional alternative splicing: the ‘A’ isoform (IR-A) that
recognizes insulin and IGFs, with a greater affinity for IGF2
than IGF1, and the IR ‘B’ isoform (IR-B), which is insulin
specific and mainly involved in glucose homeostasis
(Zhang & Roth 1991, Artim et al. 2012). In healthy
individuals, blood glucose concentrations are maintained
within narrow physiological range by a state of balance
between insulin production by specialized pancreatic
b-cells and insulin-mediated glucose uptake in target
tissues, which is further determined by the translocation
of glucose transporters, of which GLUT-4 is the most
abundant, to the cell surface (Kern et al. 1990). Evidence
that insulin resistance in classic insulin-target organs,
together with the associated hyperglycemia and hyper-
insulinemia (followed by hypoinsulinemia) are the patho-
logical hallmark of metabolic disorders such as obesity and
type 2 diabetes is compelling (Ricketts 1947, Berry &
Helwig 1948, Ahmed et al. 2012, Aldhafiri et al. 2012).
Several population-based studies revealed a decrease in
cancer risk in diabetic patients assuming antidiabetic
agents of the biguanide family such as metformin (Pezzino
et al. 1982, Suissa 2008, Kiri & Mackenzie 2009). On the
other hand, a growing body of evidence indicates an
association between type 2 diabetes and an increase in risk
of developing breast, prostate, colon, endometrial, and
ovarian cancers (Alvino et al. 2011, Tan et al. 2011, Tzivion
et al. 2011, Mu et al. 2012).
Data obtained from independent studies involving
Drosophila model show that ILPs have specialized
functions including regulating cell proliferation, differen-
tiation, survival, and apoptosis, thus playing a pivotal role
in cell fate determination and life span control (Bai et al.
2012, Bolukbasi et al. 2012). Such functions are evolution-
arily conserved (Duckworth et al. 1989, Klusza & Deng
2011), and accordingly, the stimulation of IGF1 axis may
represent a common medium for both cancer and
diabetes pathogenic processes, together with systemic
inflammation and the associated increase in cytokine
production (Nunez et al. 2006, Dool et al. 2011, Faria &
Almeida 2012, Ferguson et al. 2012, Fernandez-Real &
Pickup 2012, Ga llagher et al. 2012). Except for the
IGF2 receptor (IGF 2R), following ligand binding, the
kinase activity of ILP receptors is activated, leading to
the phosphorylation of IR substrates in the cell membrane,
which in turn i) ac tivates phosphoinositide 3-kinase
(PI3K)/protein kinase B (Akt)/mammalian target of
rapamycin (mTOR), PI3K/Akt/forkhead box O (FoxO),
and Ras/MAPK/extracellular signal-related kinase 1/2
(ERK-1/2) pathways, whose important roles in cancer
cell growth and carcinogenesis have been reported
(Alvino et al. 2011, Tzivion et al. 2011); and ii) inactivates
glycogen synthase kinase 3b (GSK3b), the inhibitor of the
oncogenic b -catenin signaling, through PI3K/Akt signal-
ing pathway, resulting in b-catenin signaling activation
that has been associated with cancer stemness and
chemoresistance (Fleming et al. 2008, Ashihara et al.
2009; see Fig. 1). Other ILP receptors include the IGF1
receptor (IGF1R) that recognizes both IGF1 and IGF2;
holoreceptors made up of combinations of half IGF1R
and IR isoforms or other tyrosine kinases; and finally
the IGF2R that recognizes only IGF2 (Rinderknecht &
Humbel 1978) and attenuates IGF2 signaling by clearing
the ligand from cell surface without signal transduction
(Artim et al. 2012). IGFs also bind to carrier proteins
named ‘IGF-binding proteins’ (IGFBP).
Contrary to insulin, IGFs are produced by many cell
types, although the liver is their main site of production.
IGF1 production in the liver is stimulated by GH (Blethen
et al. 1981, Madsen et al. 1983). IGFs have characteristics of
both hormones and tissue growth factors, and conse-
quently, they can induce both local and systemic
responses (Blundell et al. 1978, Sajid et al. 2011). Tissues
that classically respond to IGFs preferentially express the
IGF1R, and nonclassic target tissues including cancer cells
express both the latter receptor and IR-A genes and may
display hybrid receptors as well, which probably account
in carcinogenesis and chemoresistance (Artim et al. 2012,
Pierre-Eugene et al. 2012).
In the present review, we critically summarize recent
reports indicating a crucial role of insulin, IGFs, and
their receptors in cancer development and maintenance.
A unifying model for the high cancer risks and chemo-
resistance associated with insulin resistance, in obesity
and type 2 diabetes cases, will also be discussed.
Endocrine-Related Cancer
Review
S Djiogue et al. Insulin resistance and cancer
20:1 R2
http://erc.endocrinology-journals.org q 2013 Society for Endocrinology
DOI: 10.1530/ERC-12-0324 Printed in Great Britain
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ILPs, insulin resistance, and cancer risk
ILP molecules and cancer risk
Data sustaining an association between IGF1 and cancer
risk include recent studies from Mora et al. (2011) in
elderly, which have suggested that genetic variations in
the insulin/IGF1 pathway genes are associated with
longevity, dementi a, metabolic diseases, and cancer.
However, ILP association with cancer risk is still debated,
as controversial data have been reported. In a study
assessing the link between overall cancer mortality and
circulating IGF1 or IGFBP3 levels, no significant associ-
ation was found (Kaplan et al. 2012). However, another
recent clinical study has indicated that IGF1 is positively
associated and IGFBP3 is inversely associated with all-
cause mortality in men with advanced prostate cancer
(Rowlands et al. 2012), indicating that levels of IGF1 and
IGFBP3 may have potential as prognostic markers in
predicting risk of death in men with advanced prostate
cancer. A comparable study has revealed a correlation
between zinc, IGF1, and IGFBP3 concentrations, and
prostate-specific antigen in prostate cancer, and findings
have indicated that zinc, IGF1, and IGFBP3 can be useful
in early diagnosis of prostate cancer (Darago et al. 2011). In
addition, other investigators reported that IGFBP3 gene
polymorphism would be associated with the susceptibility
to develop prostate cancer (Safarinejad et al. 2011a).
A report from Price et al. (2012) indicates that increases
in circulating IGF1 levels are associated with a signi-
ficantly increased risk for prostate cancer development.
Interestingly, t his positive associ ation did not d iffer
depending on the duration of follow-up for cancers
diagnosed more than 7 years after blood collection, or by
stage, grade, and age at diagnosis or age at blood
collection, and raise up the question whether reducing
circulating IGF1 levels may affect prostate cancer risk.
Moreover, IGF1 serum levels are increased in patients with
locally advanced colorectal cancer (pT3 and pT4), in
comparison to less advanced (pT2); a higher serum level
of IGF1 is observed in patients with poorly differentiated
cancers (G3) than in modera tely differentiated, and
similarly, higher serum levels of IGF1 are found in male
IGF1, IGF2
IGFBP 1 to 6
Involved in chemoresistance
Overexpressed in
cancer tissues
Downregulated in
cancer tissues
Insulin,
IGF1, IGF2
Insulin,
IGF2
IGF1, IGF2
IGF2
IGF2R
IGF1R
Hybrid
IR-A
IR-B
Insulin
Ras
PI3K
Akt
FoxO
mTOR
Internalization
and
degradation
MAPK
Erk-1/2
Glucose
homeostasis
Proliferation, tumorigenesis, self-renewal
β-Catenin
GSK3β
Figure 1
ILP signaling and cancer. ILP receptors are structurally related tyrosine
kinase receptors. Canonical insulin receptor isoform ‘A’ (IR-A), isoform
‘B’ (IR-B), IGF1 receptor (IGF1R), and hybrid receptor (holoreceptors
made of combinations of half IGF1R and IR isoforms or other tyrosine
kinases) signaling are mediated through downstream pathways like
phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian
target of rapamycin (mTOR), PI3K/Akt/forkhead box O (FoxO), Ras/MAPK/
extracellular signal-related kinase 1/2 (ERK-1/2) pathways, or through
PI3K/Akt-mediated inactivation of glycogen synthase kinase 3b (GSK3b)
that results in the accumulation of b-catenin and in the activation of its
downstream targets. The IGF2 receptor (IGF2R) attenuates IGF2 signaling
by clearing that molecule from the cell surface without signal transduction.
Overexpression of IGF1R signaling and downregulation of IGF2R are
commonly reported in cancer, as well as the overexpression of IR-A and
hybrid receptor signaling in the presence of abnormally high levels of
insulin and IGFs.
Endocrine-Related Cancer
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20:1 R3
http://erc.endocrinology-journals.org q 2013 Society for Endocrinology
DOI: 10.1530/ERC-12-0324 Printed in Great Britain
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patients older than 60 years and in mucigenous colorectal
cancers (Kuklinski et al. 2011). The risk of colorectal cancer
would also be associated with higher IGF1/IGFBP3 ratio
or C-peptide levels (Wu et al. 2011).
A possible explanation for the differences between the
observations of the first investigators and the following
ones has been provided by studies of Henningson et al.
(2011) and Masago et al. (2011). Both studies reported
experimental and clinical data suggesting a correlation
between interpersonal variability in IGF1 levels and cancer
risk. These findings indicate that according to the type of
cancer considered and at an individual basis, the import-
ance of ILP molecules for cancer risk evaluation can
change. Another illustration can be provided by recent
studies in colorectal adenoma. In a first clinical study, only
the increases in circulating IGF1 and IGF1/IGFBP3 ratio
have been reported to represent a disturbed GH/IGF1
homeostasis, which could favor the development of
precancerous lesions such as colorectal adenoma, and to
be, therefore, an indicator of the risk of cancer develop-
ment (Soubry et al. 2012), suggesting that IGF1 is
associated with the pivotal precursor to colorectal cancer.
On the other hand, in another clinical study, although a
positive association between circulating IGF1 levels and
the risk of advanced colorectal adenoma was observed as
wel l, IGFBP3 levels and IGF1/IGFBP3 ratio were not
indicative of cancer risk, whereas elevated IGF2 levels
were indicative instead (Gao et al. 2012). Considering that
most studies evaluating the link between ILP molecules
and cancer risk have been performed on small cohorts,
large prospective studies are required to better characterize
the potential roles of ILP molecules for cancer risk
evaluation and reduce the bias created by interindividual
variability. Interestingly, findings from a population-
based study, where components of the IGF axis did not
appear to be risk factors for pancreatic cancer, have
indicated that it cannot be excluded that a relatively
large amount of IGF1 together with very low levels of
IGFBP3 might still be associated with an increase in cancer
risk (Rohrmann et al. 2012), given that statistical sub-
analysis may not reflect the physiopathological reality.
Data from a study adopting such approach have indicated
that high-grade prostate cancers would be more autono-
mous and, thus, less sensitive to the action of IGF1 than
low-grade cancers (Nimptsch et al. 2011), explaining
discrepancies in the findings between different studies
and the lack of statistical significance reported by many
investigators. Further studies should consider bet ter
experimental design to reduce biases in statistical sub-
analysis and should be designed to analyze the data
mainly on the basis of their clinical value and less so on
their mathematical/statistical significance.
Similar findings have been reported in other types
of cancers. IGF1 and IGF1/IGFBP3 molar ratio might
increase mammographic density and thus the risk of
developing breast cancer (Campagnoli et al. 1992, Byrne
et al. 2000). In familial breast cancer, an association
between IGF1 levels and cancer development has been
reported (Rosen et al. 1991, Bruning et al. 1995, Pasanisi
et al. 2011), and IGF1 may predict higher risk of recurrence
in breast cancer survivors (Al-Delaimy et al. 2011).
Associations of IGF1 and IGF1/IGFBP3 ratio with mortality
in women with breast cancer have also been reported
(Duggan et al . 2012, Izzo et al. 2012). However, all these
data need to be confirmed in larger breast cancer survivor
cohorts, considering that other reports have indicated that
serum concentrations of IGF1 and IGFBP3 do not correlate
with breast cancer development/risk (Trinconi et al. 2011).
Other controversies have been reported. Although
most investigators have reported a positive association
between IGF1 level (or IGF1/IGFBP3 ratio) and cancer risk,
others have reported signific ant inverse associations,
including in prostate cancer (Alokail et al. 2011) and
melanoma (Panasiti et al. 2011, Park et al. 2011b), for
example. In addition, whereas large increases in IGFBP1
were reported to significantly raise the risk of overall
cancer mortality in patients (Kaplan et al. 2012), global
Igfbp1 deletion does not affect prostate cancer develop-
ment in a c-Myc transgenic mouse model (Gray et al.
2011). These observations emphasize the need for large
cohort studies.
Energy balance, insulin resistance, and cancer risk
Although many independent reports have suggested the
existence of a link between energy imbalance and cancer
in insulin resistance-associated metabolic disorders, data
demonstrating such a direct mechanistic link are lacking.
Interestingly, it has been reported that long-term low-
protein, low-calorie diet and endurance exercise, which
lowers insulin levels, modulate metabolic factors associ-
ated with cancer risk (Fontana et al. 2006). More recent
studies have revealed that diets leading to weight gain and
hyperinsulinemia increase the expre ssion of IR-A on
cancer cells (Algire et al. 2011), indicating that insulin
level changes can mediate the effects of energy balance in
cancer. A recent meta-analysis assessed the correlation
between intentional weight loss and cancer risk reduction
(Byers & Sedjo 2011). The inves tigators analyzed all
available l iterature reporting chan ges in cancer risk
Endocrine-Related Cancer
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http://erc.endocrinology-journals.org q 2013 Society for Endocrinology
DOI: 10.1530/ERC-12-0324 Printed in Great Britain
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following intentional weight loss, as well as rep orts
addressing changes in major cancer risk factors, including
IGFs and IGFBPs, estrogens, and sex hormone binding
globulin (SHBG), as well as inflammatory markers such as
C-reactive protein (CRP), tumor necrosis factor-a (TNF-a),
and interleukin 6 (IL6). Interestingly, the findings from
this study suggest that cancer incidence was reduced after
intentional weight loss in about all observational cohort
studies and randomized controlled trials of both dietary
interventions and bariatric surgery. In addition, a corre-
lation was observed between intentional weight loss and
decrease in estrogen level as well as SHBG level increase
with up to threefold reduction in free estradiol from a
10% weight loss. The weight loss was accompanied by a
decrease in pro-inflammatory factor expression, notably,
with a comparable 3:1 ratio in CRP levels drop. The
reductions in circulating TNF-a and IL6 were consistent as
well, although at smaller magnitude. Surprisingly, IGF1
and IGFBP changes observed after weight loss were
inconsistent. Collectively, these observations suggest
that estrogen and circulating pro-inflammatory factors
are the major players in cancer risk decrease caused by
body weight loss, unlike IGF1. It has been hypothesized
that abnormally high levels of growth factors, adipokines,
reactive oxygen species, adhesion factors, and pro-inflam-
matory cytokines observed under conditions of insulin
resistance create a favorable niche for neoplastic tissue
survival and cancer stem cell development, with tumors
behaving like ‘wounds that never heal’ to ensure their
maintenance (Sakurai & Kudo 2011, Pollak 2012, Seke Etet
et al. 2012). Considering that in most cases both cancer
incidence and levels of circulating cancer biomarkers drop
relatively rapidly following intentional weight loss (Byers
& Sedjo 2011), the latter should be further investigated as a
meaningful approach for cancer risk reduction.
Although there are controversial data, recent findings,
mostly from population-based studies, have pointed out
a link between glucose metabolism, insulin levels, and
cancer risk. For instance, an epidemiologi cal study
evaluating pancreatic cancer risk factors has revealed
that type 2 diabetes is the third major risk factor for this
disease (Li 2012). A recent meta-analysis of observational
studies has revealed that insulin resistance is a significant
risk factor for endometrial cancer, particularly when
associated with high levels of circulating adipokines like
adiponectin, leptin, and plasminogen activator inhibitor-
1, as well as androgens and inflammatory mediators (Mu
et al. 2012). It is widely accepted that diabetic patients
have relatively increased cancer risk as well as worse cancer
prognosis, i n comparison with individuals without
diabetes. How ever, a recent study involving 25 476
patients with type 2 diabetes has not found any
association between HbA1c and risks for all cancers or
specific types of cancer (Miao Jonasson et al. 2012).
Instead, experimental data indicate the overexpression
of ILP observed in these patients as a cancer risk factor
(Ferguson et al.2012,Gallagheret al. 2012). The
hyperinsulinemia resulting from the body’s attempt to
compensate insulin resistance in type 2 diabetes may
benefit fully insulin-sensitive cancer tissue by substan-
tially i ncreasing their growth through IR-A/IGF1R
increased signaling. However, whether type 2 diabetes
leads to increased IR-A/IGF1R signaling in neoplastic
cells in comparison with normal insulin target tissues is
still controversial and requires further studies. Whereas
some reports indicate that tumors respond favorably to
ILP overexpression (Nagamani & Stuart 1998, Ferguson
et al. 2012, Gallagher et al. 2012), other reports indicate
that hyperinsulinemia is associated with only a modest
increase in tumor growth rate (Kalme et al. 2003, Algire
et al. 2011, Pollak 2012). Further studies investigating
ILP signaling role in cancer tissues may provide better
understanding of cancer biology and reveal novel thera-
peutic targets.
ILP molecules and carcinogenesis
Various striking observations and findin gs indicating
a link between ILP molecules and cancer are summarized
in Table 1.
Insulin
Studies evaluating insulin secretion, as reflected by
C-peptide levels, have pointed out a correlation between
high plasma concentration of insulin and poor clinical
outcome and death in prostate cancer (Ma et al. 2008).
A recent study has shown that aldo-keto reductase 1B10
(AKR1B10), which plays a critical role in tumor develop-
ment and progression through promoting lipogenesis and
eliminating cytotoxic carbonyls, is induced by mitogen
epidermal growth factor (EGF) and insulin through the
activator protein-1 (AP-1) signaling pathway in human
hepatocellular carcinoma cells (Liu et al. 2012). Most
recent reports have also suggested that insulin has
mitogenic and anti-apoptotic effects in endometrial
cancer, and the activation of IR-A, IR substrate 1, and
Akt is associated with aggressive features (Wang et al.
2012). Proinsulin, the prohormone precursor to insulin
characterized by low metabolic activity, binds with high
Endocrine-Related Cancer
Review
S Djiogue et al. Insulin resistance and cancer
20:1 R5
http://erc.endocrinology-journals.org q 2013 Society for Endocrinology
DOI: 10.1530/ERC-12-0324 Printed in Great Britain
Published by Bioscientifica Ltd.
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