diabetes and pancreatic cancer

IN PERSPECTIVE

Diabetes and Pancreatic Cancer

Donghui Li*

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas

Type 2 diabetes mellitus is likely the third modifiable risk factor for pancreatic cancer after cigarette smoking andobesity. Epidemiological investigations have found that long-term type 2 diabetes mellitus is associated with a 1.5-foldto 2.0-fold increase in the risk of pancreatic cancer. A causal relationship between diabetes and pancreatic cancer is

also supported by findings from prediagnostic evaluations of glucose and insulin levels in prospective studies. Insulinresistance and associated hyperglycemia, hyperinsulinemia, and inflammation have been suggested to be theunderlying mechanisms contributing to development of diabetes-associated pancreatic cancer. Signaling pathways

that regulate the metabolic process also play important roles in cell proliferation and tumor growth. Use of theantidiabetic drug metformin has been associated with reduced risk of pancreatic cancer in diabetics and recognized asan antitumor agent with the potential to prevent and treat this cancer. On the other hand, new-onset diabetes mayindicate subclinical pancreatic cancer, and patients with new-onset diabetes may constitute a population in whom

pancreatic cancer can be detected early. Biomarkers that help define high-risk individuals for clinical screening forpancreatic cancer are urgently needed. Why pancreatic cancer causes diabetes and how diabetes affects the clinicaloutcome of pancreatic cancer have yet to be fully determined. Improved understanding of the pathological

mechanisms shared by diabetes and pancreatic cancer would be the key to the development of novel preventive andtherapeutic strategies for this cancer. � 2011 Wiley Periodicals, Inc.

Key words: diabetes; pancreatic cancer; epidemiology

INTRODUCTION

As a consequence of the obesity epidemic, theincidence of diabetes is increasing globally, with anestimated 285 million people, or 6.6% of thepopulation from 20 to 79yr of age, affected. Type 2diabetes mellitus accounts for more than 95% of thecases. Type 2 diabetes mellitus has been associatedwith an increased risk of several humancancers, suchas liver, pancreatic, endometrial, colorectal, breast,and bladder cancer. After cigarette smoking andobesity, type 2 diabetes mellitus is likely the thirdmodifiable risk factor for pancreatic cancer. How-ever, the relationship between diabetes and pancre-atic cancer is complex and intertwined. On onehand, diabetes can be an early manifestation ofpancreatic cancer. On the other, diabetes has beenimplicated as a predisposing factor for pancreaticcancer [1–3]. An improved understanding of theassociation between diabetes and pancreatic cancerand the mechanism underlying this associationwould aid the development of novel strategies forthe prevention and treatment of this cancer.

Epidemiological Evidence of Diabetes as a Risk Factor forPancreatic Cancer

Diabetes or impaired glucose tolerance is presentin 50–80% of patients with pancreatic cancer [4–6].More than 85% of the diabetes cases in patients with

pancreatic cancer are diagnosed fewer than 2yrbefore the cancer diagnosis or during the cancercourse. Patients with new-onset diabetes, in otherwords, those in whom diabetes was diagnosed nomore than 2yr before cancer was diagnosed, areusually considered as having ‘‘secondary diabetes’’caused by the cancer under the assumption thatpancreatic cancer is a rapidly fatal disease: a personwith pancreatic cancer-caused diabetes would notlive for many years without his or her cancer beingdiagnosed. However, most cancers have long laten-cies, and many diabetes and prediabetic cases areundiagnosed before the cancer is diagnosed. Nocurrent clinical or laboratory methods accuratelydetermine the time when disease is initiated ordistinguish the type II diabetes from the pancreaticcancer-caused diabetes. Therefore, misclassification

MOLECULAR CARCINOGENESIS 51:64–74 (2012)

� 2011 WILEY PERIODICALS, INC.

Abbreviations: RR, relative risk; CI, confidence interval; OR, oddsratio; BMI, body mass index; IGF, insulin-like growth factor; mTOR,mammalian target of rapamycin; HNF, hepatocyte nuclear factor;ACF, aberrant crypt foci; AMPK, 50-AMP-activated protein kinase;LKB1, liver kinase B1; IAPP, islet amyloid peptide.

*Correspondence to: Department of Gastrointestinal MedicalOncology, Unit 426, The University of Texas MD Anderson CancerCenter, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 13 December 2010; Revised 9 February 2011; Accepted18 February 2011

DOI 10.1002/mc.20771

Published online in Wiley Online Library(wileyonlinelibrary.com).

bias seems to be unavoidable in studies of theassociation between diabetes and pancreatic cancer.To date, more than 20 case–control studies [7–25]

and cohort and nested case–control studies [26–45]with information on the association between dia-betes and pancreatic cancer have been reported.Most of these studies were included in two meta-analyses investigating the riskof pancreatic cancer inrelation to diabetes [46,47]. The first meta-analysis,conducted in 1995, included 20 of these 40 pub-lished case–control and cohort studies and reportedan overall estimated relative risk (RR) of pancreaticcancer of 2.1 with a 95% confidence interval (CI) of1.6–2.8. These values were relatively unchangedwhen the analyses were restricted to patients whohad diabetes for at least 5 yr (RR, 2.0 [95% CI, 1.2–3.2]) [46]. The second meta-analysis, which wasconducted in 2005, included 17 case–control and19 cohort and nested case–control studies publishedfrom1996 to 2005 anddemonstrated an overall oddsratio (OR) for pancreatic cancer of 1.8 and 95% CI of1.7–1.9 [47]. Individuals diagnosed with diabeteswithin 4 yr before their pancreatic cancer diagnosishad a 50% greater risk of pancreatic cancer than didthose diagnosed with diabetes more than 5yr beforetheir cancer diagnosis (OR, 2.1 [95% CI, 1.9–2.3] vs.OR, 1.5 [95% CI, 1.3–1.8]; P¼0.005). In a recentpooled analysis of 2192 patients with pancreaticcancer and 5113 cancer-free controls in three largecase–control studies conducted in the United States(results of two of the three studies were publishedafter 2005), diabetes was associated with a 1.8-foldincrease in risk of pancreatic cancer (95% CI, 1.5–2.1). Risk estimates decreased as the number of yearswithdiabetes increased. Individualswithdiabetes for2 or fewer, 3–5, 6–10, 11–15, ormore than 15 yr hadORs (95% CIs) of 2.9 (2.1–3.9), 1.9 (1.3–2.6), 1.6(1.2–2.3), 1.3 (0.9–2.0), and 1.4 (1.0–2.0), respec-tively (P<0.0001 for trend) [48]. These resultssupport a modest association between type 2 dia-betes mellitus and pancreatic cancer.In general, risk estimates for diabetes-associated

pancreatic cancer were higher in individuals withshort durations of diabetes than in those with longdurations. This inverse associationbetweendurationof diabetes and risk of pancreatic cancer may beexplainedby twohypotheses. First, the increased riskof pancreatic cancer in individuals with shortdiabetes durations (�2yr) resulted primarily fromreverse causality. Second, the decreasing risk ofpancreatic cancer with increasing duration of dia-betes may have been partially related to lifestylechanges after diabetes diagnosis or use of certainantidiabetic medications. At present, little availableevidence supports or refutes these hypotheses.Because cardiovascular complications were muchmore common in diabetic patients than in non-diabetic patients in these studies, the risk of pancre-atic cancer in patients with long-term diabetes may

be underestimated because of the death of diabeticpatients not having pancreatic cancer diagnoses.Whereas cigarette smoking and obesity are estab-

lished risk factors for both type 2 diabetes mellitusand pancreatic cancer, whether diabetes is anindependent risk factor for pancreatic cancerremains questionable. Limited by the sample sizesin individual studies, this question was not exam-ined in most published reports. In the analysis ofpooleddata from the three large case–control studiesdescribed above, the researchers did not observesignificant interaction between diabetes and sex,race, education, smoking, alcohol, or body massindex (BMI) (P¼ 0.28, 0.52, 0.22, 0.95, 0.36, and0.35, respectively, for interaction terms) [48]. Inves-tigators observed comparable risk estimates amongnonsmokers (OR, 2.2 [95% CI, 1.7–2.7]), formersmokers (OR, 2.1 [95% CI, 1.7–2.6]), and currentsmokers (OR, 2.0 [95% CI, 1.4–2.8]) and betweenindividualswithBMIsofnomore than25kg/m2 (OR,1.9 [95% CI, 1.5–2.4]) and greater than 25kg/m2

(OR, 2.1 [95% CI, 1.6–2.6]). These observationssupport an independent association between diabe-tes and pancreatic cancer regardless of smokingstatus or BMI. Additional large studies are requiredto confirm these findings and further examine theimpact of diabetes on the associations betweenpancreatic cancer and other known or suspected riskfactors, such as a family history of cancer and dietaryfactors.The relationship between long-standing diabetes

and risk of pancreatic cancer is also supported byresults from biomarker studies. One prospectivestudy directly examined the relationship betweenprediagnostic serum insulin levels and pancreaticcancer risk, demonstrating a twofold increase in riskafter excluding cases diagnosed in the first 5 yr offollow-up (RR, 2.01 [95% CI, 1.03–3.93] for thehighest versus lowest quartile insulin level) [49].Also, a meta-analysis of studies of cancers of thecolon and rectum, pancreas, breast, and endome-trium showed an excessively high risk of colorectaland pancreatic cancer associated with high levels ofcirculating C-peptide/insulin and markers of hyper-glycemia [50]. In three prospective cohort studieswith follow-up durations of more than 20 yr,researchers observed an increased risk of pancreaticcancer among subjects with high postload plasmaglucose levels [43,51,52]. In the last of these studies,the risk of pancreatic cancer was 2.2-fold higher inindividuals with a postload plasma glucose levelgreater than 200mg/dL at baseline than in thosewith a level of no more than 119mg/dL [52]. Theseresults indicate that glucose tolerance may precedethe onset of pancreatic cancer rather than just be aconsequence of this cancer.Based on these data, long-term type 2 diabetes

mellitus likely is an independent risk factor forpancreatic cancer. Additional larger studies are

DIABETES AND PANCREATIC CANCER 65

Molecular Carcinogenesis

required to further examine the potential confound-ing effect of smoking and obesity on the associationbetween diabetes and pancreatic cancer.

Mechanisms Between Diabetes and Pancreatic Cancer

The mechanism of the association between dia-betes andpancreatic cancer is elusive but is known toinclude metabolic, hormonal, and immunologicalalterations that influence tumor growth (Figure 1).Insulin resistance and compensatory hyperinsuline-mia as well as elevated levels of circulating insulin-like growth factors (IGFs) are perhaps the mosthypothesized mechanisms underlying the associa-tion between type 2 diabetesmellitus and pancreaticcancer. Data from animal studies suggest that isletcell turnover, which is associated with insulinresistance, is critical for pancreatic carcinogenesis.For example, in hamsters, stimulation of islet cellproliferation enhanced pancreatic ductal carcino-genesis [53], and destruction of islet cells by treat-ment with streptozotocin or alloxan inhibitedpancreatic cancer induction [54,55]. Furthermore,treatment with the biguanide metformin inhibitedthe induction of pancreatic tumors by N-nitrosobis-(2-oxopropyl)amine, a pancreatic carcinogens, andhigh-fat diets in hamsters by normalizing the rate ofislet cell turnover [56].Pancreaticb-cell hyperactivitywith an increasedb-

cell mass in the pancreas contributes to insulinoversecretion in response to insulin resistance. The

exocrine pancreatic tissue may be chronicallyexposed to local insulin concentrations that aremuch higher than the circulating insulin levels seenin hyperinsulinemic patients. Experimental evi-dence suggests that insulin is a growth-promotinghormone with mitogenic effects. Insulin promotescell proliferation and increases glucose use [57], bothof which are important to tumor development andprogression. Furthermore, insulin upregulates thebioavailability of IGFs by reducing hepatic produc-tion of IGF-binding proteins [58,59]. The mitogenicand antiapoptotic activities of IGF-1 aremore potentthan those of insulin and may act as growth stimuliin cells expressing insulin and the IGF-1 receptor(IGF1R). IGF-1 and IGF1R are highly expressed inpancreatic cancer cells [60], and IGF-1-mediatedsignaling transduction increases proliferation, inva-sion, and expression of angiogenesis mediators anddecreases apoptosis in pancreatic cancer cells [61–63]. IGF1R-mediated initiation of signal transduc-tion activates important intracellular signal path-ways, including the Ras/Raf/mitogen-activatedprotein kinase and phosphoinositide-3 kinase/Akt/mammalian target of rapamycin (mTOR) pathways[64]. Even though epidemiological investigationshave not found a significant association betweenpancreatic cancer risk and prediagnostic plasmalevels of IGF-1 and IGF-2 [65,66], investigators haveshown that reduced levels of IGF-binding protein 1are predictive of increased risk of pancreatic cancer

Figure 1. Potential mechanisms underlying the associations ofdiabetes and cancer. AdipoR1/R2, adiponectin receptor 1/2; AMPK,50-AMP-activated protein kinase; IGF-1, insulin-like growth factor-1;IGF-1R, insulin-like growth factor-1 receptor; IKK, IkB kinase; IR,insulin receptor; IRS-1, insulin receptor substrate-1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin;NF-kB, nuclear factor-kB; ObR, leptin receptor; PAI-1, plasminogen

activator inhibitor-1; PI3-K, phosphatidylinositol 3-kinase; ROS,reactive oxygen species; TNF-a, tumor necrosis factor-a; TNF-R1,tumor necrosis factor-receptor 1; uPA, urokinase-type plasminogenactivator; uPAR, urokinase-type plasminogen activator receptor;VEGF, vascular endothelial growth factor; VEGFR, vascular endothe-lial growth factor receptor.

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[67]. A case–control study indicated a possibleassociation between polymorphic variants of theIGF-1 gene and risk of pancreatic cancer independ-ently of or jointly with diabetes [68].Abnormal glucose metabolism is a biochemical

hallmark of tumor cells, and most tumors havehighly effective upregulated, insulin-independentglucose uptake mechanisms. However, evidenceimplicating a direct role for glucose in promotionof tumor growth is lacking. In animals with diabetesinduced by b-cell destruction by alloxan, a studyshowed that tumor growth was reduced [69], sug-gesting that hyperglycemia does not increases neo-plastic growth, at least in the setting of insulindeficiency. Researchers have suspected that a highdietary glycemic index/load may increase the risk ofpancreatic cancer because of the adverse effects ofhigh postprandial glucose levels and resulting insu-lindemands [70].Many studieshave investigated theassociationsof carbohydrate and refined sugar intakeand glycemic index/load with pancreatic cancer,with inconsistent results [71]. In general, thesestudies found either no association or weak associ-ations that are not statistically significant. Thus,whether glucose is responsible for the associationbetween hyperglycemia and increased risk of pan-creatic cancer or is a surrogate for a causative factorsuch as insulin resistance remains unclear.In addition to the direct growth-promoting effect

of insulin and IGFs, type 2 diabetes mellitus and/orrelated obesity may increase the risk of pancreaticcancer by increasing oxidative stress and inflamma-tory responses. It has been suggested that oxidativestress is an initiating event in the pathogenesis ofinsulin resistance [72,73]. Also, several epidemiolog-ical surveys have reported a correlation betweenoxidative stress and insulin resistance [74,75]. Acausative link between oxidative stress and insulinresistance is further suggested by experimentalstudies showing that antioxidant supplementationwith vitamin E or a-lipoic acid could prevent orreduce insulin resistance [76,77]. In addition, variousexperimental models of induction of insulin resist-ance indicated that oxidative stress plays a criticalrole in the onset of this condition, particularly inanimals on high-sucrose or high-fructose diets[78,79]. In these models, hyperglycemia, especiallyduring the postprandial period, was a direct cause ofoxidative stress via various mechanisms that mayhave been related to overproduction of superoxideby the mitochondrial electron-transport chain [80].Resulting impairment of the cellular redox stateboth decreased the tyrosine phosphorylation andincreased the serine phosphorylation of insulinreceptor substrate 1, two events that lead to inacti-vation of the insulin-signaling pathway [80].A growing amount of evidence suggests that

inflammation plays an important role in pancreaticcancer development [81]. Macronutrient intake and

obesity may activate inflammatory signaling path-ways [82,83]. Glucose and fat intake may induceinflammation by increasing oxidative stress and theactivating transcriptional factors such as nuclearfactor-kB, activating protein-1, and early growthresponse-1 [84–86]. In addition, adipose tissues actas endocrine organs to regulate the release of fattyacids, hormones, and proinflammatory cytokinessuch as tumor necrosis factor-a, interleukin-6, andresistin [87]. Some adipocytokines are keymoleculesinvolved in innate immunity, inflammation, apop-tosis, metabolism, and development. Elevated levelsof the proinflammatory cytokines promote angio-genesis, tumor progression, and metastasis. Further-more, altered levels or functions of severalmoleculespreviously implicated in obesity and/or diabetes,such as leptin [88], IGF-1 [89], and peroxisomeproliferator-activated receptor-g [90], may contrib-ute to pancreatic cancer development by impairingimmune function.A number of genome-wide association studies

have identified unexpected genetic variants thatmodify the risk of diabetes, and some of the type 2diabetes mellitus susceptibility loci often tend to beimplicated in differentiation and development [91].Interestingly, one of the pancreatic cancer suscept-ibility genes identified in genome-wide associationstudies is NR5A2 (or LRH1) [92], which is a directtarget of the pancreatic duodenal homeobox (PDX-1) gene during pancreatic differentiation and devel-opment [93]. NR5A2 controls the expression of anumber of developmental genes, such as the tran-scription factors hepatocyte nuclear factor (HNF)-3b,HNF-4a, and HNF-1b. Conversely, expression ofNR5A2 is regulated by HNF-3b and HNF-1. PDX-1 isrequired not only for pancreatic development butalso for normal b-cell function and insulin secretion[94]. Mutations of the human HNF-1b gene arelinked with maturity-onset diabetes of the young,type 3 [95]. Findings from mouse models withcompound heterozygous mutations of PDX-1þ/�/HNF-3bþ/� and PDX-1þ/�/HNF-1bþ/� further under-score the importance of PDX-1,HNF-1b, andHNF-3bin controlling glucose tolerance, glucose-stimulatedinsulin secretion, and islet architecture [96].Improved understanding of the biological signifi-cance of the NR5A2 gene in the development ofpancreatic cancer and identification of other genesthatmodify the riskof diabetes-associatedpancreaticcancerwouldprovide further insight into thegeneticmechanisms that link diabetes and pancreaticcancer.

Antidiabetic Therapy and Risk of Pancreatic Cancer

Over the past several years, a number of studies ofdiabetics have shown that treatment with metfor-min, the most commonly used antidiabetic drug, isassociatedwith lower risk of cancer than is treatment



with insulin or insulin secretagogues [97–101]. Ameta-analysis of three studies using cancer incidenceas the endpoint found a 32% lower overall summaryRR for cancer (0.68 [95% CI, 0.52–0.88]) in subjectstaking metformin than in those taking other anti-diabetic drugs [102]. Regarding pancreatic cancer inparticular, a retrospective cohort study of 62809patientswithdiabetes [100] and a case–control studyof 973 patientswith pancreatic adenocarcinoma and863 cancer-free controls [103] independently but atnearly the same time demonstrated a very signifi-cantly lower risk of pancreatic cancer in metforminusers than in insulin or sulfonylurea users. In theretrospective cohort study, the researchers identified89 pancreatic cancer cases. The hazard ratios inmetformin users were 0.20 (95% CI, 0.11–0.36) and0.22 (95% CI, 0.12–0.38) compared to sulfonylureausers or insulin users, respectively. In the case–control study, the OR for pancreatic cancer was 0.38(95% CI, 0.21–0.67) in metformin users versusmetformin nonusers after adjustment for potentialconfounders such as smoking status, BMI, familyhistory of cancer, and duration of diabetes. The riskestimates remained statistically significant when theanalysis was restricted to patients with diabetesduration of more than 2yr or those who never usedinsulin. Although the choice of antidiabetic therapymay be related to the severity of the diabetes, whichmay confound the association between antidiabetictherapy and risk of pancreatic cancer, the validity ofthese observations is supported by a large amountof experimental evidence of the antitumor activityof metformin [56,105–108].In a hamstermodel ofN-nitrosobis-(2-oxopropyl)-

amine and high-fat diet-induced pancreatic cancer,administration of metformin in drinking watercompletely prevented tumor development, whereastumors developed in 50%of the control animals thatdid not take metformin [56]. Metformin can inhibitproliferation and stimulate apoptosis in tumor celllines [104] and inhibit the growth of humanpancreatic cancer cells xenografted into nude mice[105]. Investigators have also observed the antitu-mor activity of metformin in various animal modelsof other common cancers, such as those of the colon[106], breast [107], and lung [108]. More interest-ingly, a clinical trial conducted in nondiabeticpatients with colorectal aberrant crypt foci (ACF)showed that 1mo of metformin use significantlydecreased the mean (� standard deviation) numberof ACF per patient from 8.78�6.45 before treatmentto 5.11�4.99 (P¼0.007), whereas themeannumberof ACF did not change significantly in the controlgroup (7.23�6.65 vs. 7.56�6.75; P¼0.609) [109].In patients taking metformin, researchers detectedreduced cell proliferation in normal rectal epithe-lium. These observations suggest thatmetformin is apromising chemopreventive drug for use againstcancer and that use of it may not be limited to

patients with diabetes. The challenges that remainare identification of predictive biomarkers for select-ing the patients most likely to benefit from suchintervention and gaining a clear understanding ofthe primary mechanism of metformin’s antitumoraction [110].Metformin lowers glucose levels mainly by reduc-

ing hepatic glucose output [111]. Consequently,metformin decreases rather than increases fastingplasma insulin concentrations and indirectly inhib-its the growth-promoting effects of insulin and IGFs.Metformin has been shown to have a cardioprotec-tive effect, causing changes in fat metabolism andproduction of adipose tissue hormones, particularlyleptin [112]. Inpatientswith type2diabetesmellitus,metformin-based treatment has been associatedwith biochemical evidence of improvement ofendothelial function, including decreased plasmalevels of von Willebrand factor, soluble vascular celladhesion molecule-1, soluble E-selectin, tissue-typeplasminogen activator and inhibitor, and vascularendothelial growth factor [113–116]. Most of thesemolecules play important roles in thrombosis,fibrosis, and angiogenesis, which may contribute topancreatic tumor development and progression.However, the main molecular mechanism of met-formin’s effect onmetabolismandgrowth inhibitionare mediated through the liver kinase B1 (LKB1)/50-AMP-activated protein kinase (AMPK) signalingpathway. In a quiescent cell, most of the energy (inthe form of ATP) is generated in the mitochondriathrough oxidative phosphorylation, including oxi-dation of fatty acids and amino acids, known ascatabolic metabolism. Metformin increases glucoseuptake and glycolysis and reduces ATP productionin mitochondria, which leads to activation of theLKB1/AMPK signaling pathway.LKB1 is a tumor suppressor gene, and patients

with Peutz–Jeghers syndrome, which is caused bygermline mutations of LKB1, have a significantlyincreased risk of pancreatic cancer [117]. AMPK is ahighly conserved sensor of cellular energy status andis activated under conditions with low intracellularATP levels. AMPK responds to energy stress bysuppressing cell growth and biosynthetic processes,in part through its inhibition of the rapamycin-sensitive mTOR complex 1 pathway via tuberoussclerosis 2 protein [118]. mTOR upregulates manyenergy-consuming cellular processes and has acentral role in regulating cell growth by controllingmRNA translation and ribosome biogenesis. AMPKacts as a metabolic checkpoint, coordinating cellgrowth andenergy status to ensure the initiation andmaintenance of cell polarity and completion ofnormal cell division [119]. Also, the LKB1/AMPKpathway regulates p27(kip1) phosphorylation,which permits cells to survive growth factor with-drawal and metabolic stress via autophagy [120].Studies showed that by altering cellular metabolism,

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metformin enhanced immune-cell (T-cell) memoryover the long termaswell as theefficacyof anticancervaccination [121,122]Thus, the antitumor activity ofmetformin results from not only metabolic andhormonal regulation but also cell division andimmune functions. Whether metformin or otherAMPKagonists canpreventor treat pancreatic cancerdeserves further investigation in the laboratory andprospective clinical trials.Insulin secretagogues such as sulfonylurea, which

cause b cells to release insulin, reportedly increasethe risk of cancer in patients with type 2 diabetesmellitus [98,100,123]. However, most of the studiesincluded very few cases of cancer; therefore, nospecific cancer sites were implicated. Two studiesthat showed a protective effect of metformin onpancreatic cancer also demonstrated an increasedrisk of this cancer associatedwith use of sulfonylurea[100,103]. Because type 2 diabetes mellitus is aprogressive disease, few patients with it receivemonotherapy over the entire disease course, somostpatients receive combined therapy with differentmedications. Therefore, determining whether theobserved risk associations reflect increased risk insulfonylurea users or decreased risk in comparativegroups, such as metformin users, is difficult.Because of the tumor-promoting effect of an

elevated level of insulin and resulting IGF-1,whetherthe use of insulin in diabetic patients increases therisk of cancer has garnered a great deal of attention.Previous studies have reviewed and debated thisissue [124,125]. In general, evidence that insulin useincreases the risk of cancer is insufficient [126].Although insulin use has been associated with anincreased risk of pancreatic cancer, the risk wasusually restricted to patients who took insulin for ashort time (<3yr) [22,23,25,26,48]. In a pooledanalysis of data from three large case–control studies[48], long-term insulin use (>10 yr) was associatedwith a reduced risk of pancreatic cancer, whereas therisk in those who used insulin for 3–10 yr was 20%higher than that in diabeticswhodidnot use insulin.In another study, among patients with pancreaticcancer, more than 70% of insulin users beganreceiving it at least 2 yr before their cancer diagnoses[103]. These cases were either pancreatic cancercaused by diabetes or long-term diabetes aggravatedby the cancer. In either type of case, the associationbetween short-term insulin use and pancreaticcancer is most likely a result of reverse causality. Offour published case–control studies that examinedthe duration of insulin use and risk of pancreaticcancer, three studies demonstrated no associationor a reduced risk in those who used insulin formore than5yr [22,23,26]. No experimental evidencehas shown that improved glycemic control withinsulin use actually reduces the risk of pancreaticcancer. Most analyses of pancreatic cancer riskin diabetics have had limited numbers of insulin

users; larger sample sizes are required to fully assessany possible effect of insulin use on the risk ofpancreatic cancer.

Pancreatic Cancer-Associated Diabetes and Implication inEarly Detection of This Cancer

It has been reported that the prevalenceof diabetesand impaired glucose tolerance in pancreatic cancercases is as high as 80%. In the majority of cases,diabetes associated with pancreatic cancer is diag-nosed fewer than 2yr prior to the cancer diagnosis orduring the cancer course. Amongpatientswith early-stagepancreatic cancer, diabeteshasdevelopedmoreoften in patients with carcinoma of the head of thepancreas than in those with carcinoma of the bodyand/or tail of the organ [5]. However, why diabetesdevelops in patients with pancreatic cancer remainsunclear. One hypothesis is that cancer-causingagents such as tobacco carcinogens and cancer cellproducts cause islet cell destruction, resulting inb-cell dysfunction and diabetes. Reduced insulinrelease in response to glucose in animals withchemically induced pancreatic tumors [127] and inpatients with pancreatic cancer [128] have beenobserved. However, clinical studies have shown thatthe majority of patients with pancreatic cancer havenormal b-cell function [129], and diabetes in pan-creatic cancer cases is characterized by peripheralinsulin resistance. Another hypothesis is that dia-betes is caused by biliary obstruction and distalpancreatitis associated with a tumor [5]. An earlystudy showed a higher frequency of elevated bilir-ubin levels in patients with pancreatic cancer whohad abnormal glucose metabolism (66%) than inpatients with no evidence of disturbed glucosemetabolism (51%) [130]. The finding that insulinresistance and diabetes improved markedly 3wkafter tumor resection in patients with pancreaticcancer suggests a causal role for tumors in thedevelopment of diabetes in patients with pancreaticcancer [131]. Interestingly, pancreatic cancer cellsreportedly produced unidentified factors that wereable to induce hyperglycemia in severe combinedimmunodeficiency mice [132] and altered glucosemetabolism in cultured rat hepatocytes [133]. Someof the putative ‘‘diabetogenic factors’’ have beenidentified as the S-100A8 N-terminal peptide[134,135]. Anothermolecule thathas been suggestedto be a diabetogenic factor is the islet amyloidpeptide (IAPP). IAPP is a hormonal factor secretedfrom pancreatic b cells that reduces insulin sensitiv-ity in vivo and glycogen synthesis in vitro [136]. Anincreased level of IAPP was found in the plasma ofpatients with pancreatic cancer and diabetes and thelevel was significantly reduced after tumor resection,supporting a role for IAPP in the development ofinsulin resistance and diabetes in patients withpancreatic cancer [137]. However, elevated plasma



level of IAPP has also been found in chronicpancreatitis, other gastrointestinal malignanciesand biliary obstruction thus is not specific forpancreatic cancer [138,139]. A recent study hasshown that pancreas tissues from patients withdiabetes and tumor tissues form patients withpancreatic cancer had reduced number of IAPP-expressing cells andb cellswhile thenormal adjacenttissues from patients with pancreatic cancer hadincreased number of IAPP-expressing cells and b cellsbut reduced number of a cells [140]. These findingsdid not support the hypothesis that undiagnoseddiabetes or impaired glucose tolerance is the maincause of the pancreatic cancer-associated diabetes.The difference in the expression of IAPP betweentumor and normal adjacent tissues also suggests therole of cancer cells in the expression of IAPP.Findings from a retrospective cohort study of 2122

diabetic patients suggested that pancreatic cancerdeveloped within 3 yr after the diagnosis of diabetesin1%of thepatientswhowereat least 50 yrold [141].In a later case–control study of pancreatic cancerincludingdetailed fastingbloodglucose level dataupto 60mo before cancer diagnosis in cases or recruit-ment to the study in controls, pancreatic cancer-induced hyperglycemia developed up to 24–36moprior to the cancer diagnosis [142]. These observa-tions suggest that diabetes is a biomarker of early-stage pancreatic cancer and that identifying patientswith cancer-associated diabetes at the onset of theirdiabetes would offer the opportunity for earlydetection of pancreatic cancer. However, screeningfor exocrine pancreatic cancer inpatientswithnewlydiagnosed diabetes may not be practical, as only 2%of them have tumors, and computed tomographicand endoscopic ultrasonographic scanning of thepancreas as screening procedures are neither cost-effective nor adequately sensitive or specific. Defin-ing biomarkers that may help identify new-onsetdiabetes in patients with the greatest risk of pancre-atic cancer for diagnostic clinical screening is anurgent need. Carbohydrate antigen 19-9 is the mostcommonly used biomarker for diagnosis of andmonitoring treatment response topancreatic cancer.However, as a screening marker in asymptomaticpatients, carbohydrate antigen 19-9 had a predictivevalue of less than 1%, because its level was highlyassociated with tumor size [143,144]. A gene expres-sion profiling study using peripheral lymphocytessuggested that expression of vanin 1 and matrixmetalloproteinase 9 together may be useful indiscriminatingpancreatic cancer-associateddiabetesfrom type 2 diabetes mellitus [145]. Further researchin this area is important and promising for earlydetection of pancreatic cancer.

Diabetes and Clinical Outcome of Pancreatic Cancer

Increasing evidence suggests that patients withcertain types of cancer, such as colon, endometrial,

and breast cancer and leukemia, who also havediabetes or impaired glucose tolerance are atincreased risk for cancer recurrence, cancer-relateddeath, and death due to any cause [146–150]. Thesestudies also indicated that hormonal or metabolicabnormalities, such as hyperinsulinemia and hyper-glycemia, affect tumor biology at multiple stages,including malignant transformation, growth, andmetastasis. For certain malignancies, metabolicabnormalities associated with diabetes and impairedglucose tolerance apparently have an adverse effecton the response of these malignancies to treatment[148,149,151]. Despite the high prevalence of dia-betes in patients with pancreatic cancer, the avail-able information on how diabetes affects thesepatients’ treatment and clinical outcomes is limited.A few studies have examined the associationsbetween diabetes and survival of pancreatic cancer,but their findings have been inconsistent. Somestudies found that diabetes did not have a significanteffect on the overall survival time [148,152,153] oron the mortality of pancreatic cancer [45], whereasothers found that diabetes was associated withsignificantly reduced survival durations [5,154–156]. These inconsistent findings may be partiallyexplained by the different patient populationsstudied, as the negative effect of diabetes on survivaloccurredmostly in patients with resected pancreatictumors, whereas patients with late-stage disease hadno effect of diabetes on survival. In addition, few ofthese studies considered the potential confoundingeffect of obesity, which has exhibited a significantimpact on survival inpatientswithpancreatic cancer[157,158]. Because most of the current therapeuticapproaches for cancer treatment that focus oninhibition of cell proliferation and death signalingpathways do not significantly impact the survival ofpancreatic cancer, new therapeutic regimens target-ing energy metabolism or inflammation via inhib-ition of the insulin/IGF axis signaling pathway andmodulation of lipid metabolism may hold greatpromise in the treatment of pancreatic cancer,especially that associated with diabetes and obesity[159].

CONCLUSION

The relationship between diabetes and pancreaticcancer is complex. The observed causal relationshipbetween long-term type 2 diabetes mellitus andpancreatic cancer and the protective effect of theantidiabetic drug metformin against pancreaticcancer offer opportunities for the prevention andintervention of this cancer. Increased understand ofthe mechanisms of the relationship between diabe-tes and pancreatic cancer would provide newresearch avenues for the development of novelpreventive and therapeutic strategies for this deadlydisease.

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ACKNOWLEDGMENTS

This research is supported in part by the NationalInstitutes of Health through MD Anderson’s CancerCenter Support Grant CA016672, NIH grant RO1CA098380 and National Institute of EnvironmentalSciences Center grant P30 ES07784.

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