Journal of Cancer Therapy, 2013, 4, 1459-1465
Published Online December 2013 (http://www.scirp.org/journal/jct)
http://dx.doi.org/10.4236/jct.2013.410175
Open Access JCT
1459
The Role of Hyperinsulenemia as a Risk Factor for
Pancreatic Cancer*
Giuseppe Preziosi1#, Jude A. Oben2, Giuseppe Fusai1
1Hepato-Pancreatico-Biliary Surgery and Liver Transplant Unit, Royal Free Hospital, London, United Kingdom; 2Centre for Liver
and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom.
Received October 20th, 2013; revised November 15th, 2013; accepted November 23rd, 2013
Copyright © 2013 Giuseppe Preziosi 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. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intellectual
property Giuseppe Preziosi et al. All Copyright © 2013 are guarded by law and by SCIRP as a guardian.
ABSTRACT
Background: Pancreatic cancer is associated with a very severe prognosis and identification of risk factors is essential.
Diabetes and obesity are both established risk factors, and they both cause hyperinsulenemia. With this review we
wished to appraise the evidence of a role of high insulin levels in causing pancreatic cancer. Methods: We searched
PubMed, Embase, Cochrane Library and Medline, and all evidence on potential pathophysiology of hyperinsulenemia
and pancreatic cancer was included. Meta- and pooled-analysis on epidemiological evidence are reported, as well as
individual studies were as appropriate for specific topics (role of therapies, central adiposity and role of physical exer-
cise). Conclusion: Hyperinsulenemia, and possibly hyperestrogenism secondary to a metabolic syndrome, are impor-
tant elements in the pathogenesis of pancreatic cancer. Modification of certain life-style factors (exercise and weight
loss) appears to modify the risk of pancreatic malignancy.
Keywords: Pancreatic Cancer; Obesity; Diabetes; Risk Factors; Hyperinsulenemia
1. Introduction
Worldwide, pancreatic cancer is the 13th most common
cancer but the 8th most common cause of death with little
improvement in survival over the last few decades [1].
Surgical resection remains the only potentially curative
treatment, but it is feasible in approximately 15% - 20%
of patients, as the majority present with metastatic dis-
eases [2]. Five-year survival in the operated patients is
around 10% - 15%, and the overall median survival for
those with metastatic disease at presentation averages at
6 months [3,4]. To date screening remains unfeasible and
it is therefore crucial to identify and correct the risk fac-
tors associated with the development of pancreatic can-
cer.
Cigarette smoking is a well-established risk factor [5],
but only a quarter of cases of pancreatic cancer are being
attributed to it [6]. It is also recognized that diabetes mel-
litus can be both a cause and a con sequen ce of pancreatic
malignancy [7] (Figure 1) [8-10]. More recently it has
been suggested that there is sufficient evidence of an
increased risk of pancreatic cancer in obese patients [11],
with increased body adiposity being an independent risk
factor for the malignancy (Figure 2).
These are all potentially reversible risk factors, and
therefore great emphasis should be placed on imple-
menting preventi on .
Figure 1. Relative risk and 95% confidence interval (Cl) of
pancreatic cancer for diabetic patients with disease dura-
tion between 5 to 10 years [8-10].
*The authors have no conflict of interest to disclose.
#Corresponding author.

The Role of Hyperinsulenemia as a Risk Factor for Pancreatic Cancer 1460
Figure 2. Odds Ratio and 95% confidence interval for class
1 obese patients (BMI > 30 and <35) versus individual of
normal weight (BMI < 25) [12-14].
Obesity and diabetes have in common increased levels
of circulating insulin. In fact the combination of insulin-
resistance, reduced glucose tolerance and hyperinsuline-
mia is typical of adult diabetes, but it is also present in-
dependently in obese individuals in what is known as
“metabolic syndrome” [12].
In this review we wished to summarize the evidence
linking hyperinsulenemia and pancreatic cancer, which
we think is highly relevant given the epidemic of diabe-
tes and obesity across the world.
2. Methods
2.1. Obesity and Hypeinsulenemia
The common ground between obesity and diabetesap-
pears to be a higher insulin level. Looking at obesity in
fact it seems quite clear that increased adiposity increases
insulinemia through what is known as “metabolic syn-
drome” [13-15].
The adipose tissue has effectively endocrine functions,
regulating free fatty acids metabolism and releasing cy-
tokines and hormones, which have effects on distant tar-
gets [16]. There is also evidence to suggest that obesity
can cause cancer in multiple sites and that a central role
appears to lie with hyperinsulinaemia [11,17].
In the presence of excess adiposity, an imbalance is
generated as a result of an increase in circulating fatty
acids, resistin and Tumor Necrosis Factor-α (TNF-α) by
adipose tissue, and reduced release of adiponectin
[18,19]. This increases the sensitivity of peripheral cells
to insulin (reduced insulin tolerance) and hyperinsulene-
mia. Higher levels of adiponectin have been associated
with a reduced risk of pancreatic cancer in smokers [20].
2.2. The Role of Insulin in Pancreatic Cancer
Insulin is per se an anabolic hormone, promoting cell
growth directly by binding on target cells [21]. The exo-
crine pancreatic tissue is particularly exposed to it
through a portal system from the insulin producing islet
cells [22]. This exposure is enhanced by the effect of
insulin in increasing localized p ancreatic blood flow [23].
A tumorigenic effect on pancreatic tissue has been
proved both in vitro [22,24,25] and in animal models
[26-31].
Insulin can also act indirectly through an increased
production of Insulin-like Growth Factor 1 (IGF1). In
fact, both insulin and IGF1 can promote cell growth and
inhibit apoptosis [32,33]. Activation of IGF1 receptors
has been shown to increase pancreatic cells proliferation
[34].
A study examined the expression of 2 neoplastic mark-
ers, cytokeratin and Ki67, in pancreatic ductal epithelia
from 45 human autopsy and 9 surgical pathology speci-
mens. Obese non-diabetic individuals ductal cells ap-
peared to replicate 10 times more than in lean non-dia-
betic, whereas, in lean diabetics, the replication rate was
4 times higher than lean non-diabetic [35]. So it appears
that markers of pancreatic ductal replication were in-
creased synergistically in obese diabetic subjects.
Ding et al. found that physiologic concentrations of
insulin increased pancreatic cancer cell proliferation and
glucose utilization by activating mitogen-activated pro-
tein kinase, phophotidyl inositol-3 kinase, and glucose
transporter1 expression [36].
Three prospective studies have directly investigated
abnormal glucose metabolism and the risk of pancreatic
cancer. Cumulatively, they reported an increased risk
with increasing levels of glucose intolerance, regardless
of clinical diabetic status [37-39].
2.3. Diabetes, Its Treatment and Pancreatic
Cancer
If an increased level of endogenous insulin is associated
with a higher risk of pancreatic malignancy, then insulin
treatment could also potentially affect this risk.
This was addressed for the first time in 2003 with a
case-control study, which assessed if diabetics treated
with insulin therapy were more likely to develop pancre-
atic cancer than those not treated with insulin [40]. It was
found that although diabetes was associated with a
2.86-fold increase in the risk for pancreatic cancer, the
risk increased to 6.49-fold for those treated with insulin
compared to 2.12-fold for those treated with oral hypo-
glycemic agents. Furthermore, although the duration of
insulin treatment had no effect on the high relative risk
(RR), longer duration of oral hypoglycemic therapy was
associated with a lower RR for the development of pan-
creatic cancer. This trend was also observed in a mul-
ti-centric case-control study, involving 823 patients with
pancreatic cancer and 1679 controls [41]. Diabetics with
a diagnosis of between 2 - 9 years had an odds ratio (OR)
of 1.58, but those who had been treated with insulin had
an OR of 3.54, whereas those who had been treated only
with oral medi cati on had a n OR of 1. 7 8 (Figure 3 ).
Open Access JCT

The Role of Hyperinsulenemia as a Risk Factor for Pancreatic Cancer
Open Access JCT
1461
An overview of the mechanisms responsible for hy-
perinsulenemia is summarized in Figure 4. ways are criticalregulators of cell replication and have
been found to be inhibitedby metformin in pancreatic
cancer [26].
The key factors therefore appears to be insulin-acti-
vated enhancement of cell proliferation, and the central
role is probably played by insulin/insulin-like growth
factor-1 (IGF-1) receptor in the regulation of neoplastic
degeneration [42,43].
2.4. Hyperinsulenemia and Estrogen Levels
Another indirect effect of hyperinsulemia is the increased
synthesis and bioavailab ility of both male and female sex
hormones [49]. Adipose tissue is the main source of oes-
trogens in both male and post-menopausal females. In
particular, synthesis of oestone and oestradiolare in-
creased and liver production of a sex-hormone binding
globulin is reduced. The latter results in an increased
bioavailability of both oestrogens and testosterone.
Further indirect evidence comes form the protective
effect of Metformin.
Metformin activates the liver kinaseB1 (LKB1)-
adenosine monophosphate protein-activated kinase
(AMPK) pathway, which inhibits the signaling mecha-
nisms that regulate cellular proliferation [44,45]. LKB1
is a known tumor suppressor, which activates AMPK, a
potent inhibitor of mammalian target of rapamycin com-
plex 1, and disrupts cross talk between insulin/IGF-1
receptors and G protein-coupled receptors, which regu-
lateprotein synthesis and replication [46-48]. These path-
In severely obese men the increase of testosterone
drives a negative feedback, inducing a reduced produc
tion of gonadotrophin and an increased conversion of
testosterone into oestogens. The net effect is an increase
Figure 3. Odds ratio and 95% confidence interval (Cl) for patients with diabetes mellitus (overall), for those who had been
treated with insulin only, and for diabetic patients treated with tablets only.
Figure 4. Pathophysiology of hyperinsulenemia in obesity and diabetes.

The Role of Hyperinsulenemia as a Risk Factor for Pancreatic Cancer 1462
in oestrogens in obese male individuals [49]. A role of
hyper-oestrogenism has been suggested in the patho-
genesis of cancer [50] and might justify the increase risk
of pancreatic malignancy according to parity, age of me-
narche and possibly oral contraception in obese women
compared to normal weight women [51].
2.5. Central Adiposity and Insulin Resistance
Central adiposity is more associated with insulin resis-
tance [52]. Most of the studies that have looked at central
adiposity (waist circumference, waist to hip ratio and
central torso weight gain) to evaluate risk of pancreatic
cancer, had positive findings [53-58]. In a North Ameri-
can cohort, a central weight gain was found to confer
significant risk in the development of pancreatic cancer,
in comparison to peripheral weight gain [53]. In the
AARP study waist circumference was positively associ-
ated with pancreatic cancer in women, independently
from body mass index (BMI). This, however, was not
observed in men. Furthermore, no association was found
in relation to waist to hip ratio [57].
2.6. Physical Activity and Pancreatic Cancer
Physical activity has been shown to improve glucose
tolerance and insulin resistance, independently from its
effects on weight [59,60]. A large study that addressed
this topic in relation to pancreatic cancer, involving 2
cohorts of patients, found that physical activity reduced
the risk of pancreatic cancer, particularly in overweight
patients [61]. However only high levels of physical ac-
tivity have been found to reduce risk [62,63].
In a meta-analysis, both waist circumference and waist
to hip ratio were moderately associated with pancreatic
cancer risk [64]. Two pooled analyses demonstrated a
positive association with waist to hip ratio only [65,66],
with a higher risk for women specifically in one study
[66].
Two studies involving patients who underwent bariat-
ric surgery are also consistent with the finding that effec-
tive treatment of obesity and concomitant diabetes mel-
litus reduces cancer risk [67,68 ].
3. Conclusion
Chronic hyperinsulinemia secondary to diabetes or obe-
sity increases the risk of the developing pancreatic cancer.
Therapeutic insulin , and treatment with drugs that stimu-
late insulin secretion, seem to increase the risk of carci-
noma by enhanced activation IGF activated signaling
pathways. Therapies that reduce insulin levels, such as
exercise, weight loss and drugs seem to reduce the risk of
pancreatic malignancy. Metformin has a protective effect,
by reducing insulin levels and improving glucose me-
tabolism, also due to its specific antineoplastic effects.
High calories intake and poor diabetic control should
therefore be tackled at institutional lev el, in an attempt to
reduce the incidence of pancreatic cancer particularly as
they can act synergistically.
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