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. Email: #g.preziosi@ucl.ac.uk 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. 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