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World Journal of Gastroenterology logoLink to World Journal of Gastroenterology
. 2013 Aug 14;19(30):4861–4866. doi: 10.3748/wjg.v19.i30.4861

Is diabetes mellitus a risk factor for pancreatic cancer?

Raffaele Pezzilli 1, Nico Pagano 1
PMCID: PMC3740415  PMID: 23946590

Abstract

The relationship between diabetes mellitus and the risk of pancreatic cancer has been a matter of study for a long period of time. The importance of this topic is due to two main causes: the possible use of recent onset diabetes as a marker of the disease and, in particular, as a specific marker of pancreatic cancer, and the selection of a population at risk for pancreatic cancer. Thus, we decided to make an in-depth study of this topic; thus, we carried out an extensive literature search in order to re-assess the current knowledge on this topic. Even if diabetes is found a decade before the appearance of pancreatic cancer as reported in meta-analytic studies, we cannot select those patients already having non detectable pancreatic cancer, at least with the imaging and biological techniques available today. We believe that more studies are necessary in order to definitively identify diabetes mellitus as a risk factor for pancreatic cancer taking into consideration that approximately 10 years are needed to diagnose symptomatic pancreatic cancer. At present, the answer to the as to whether diabetes and pancreatic cancer comes first similar to the adage of the chicken and the egg is that diabetes is the egg.

Keywords: Diabetes mellitus, Obesity, Pancreatic neoplasms, Risk factors, Clinical studies


Core tip: Even if diabetes is found a decade before the appearance of pancreatic cancer we cannot select those patients already having non detectable pancreatic cancer, at least with the imaging and biological techniques available today. We believe that more studies are necessary in order to definitively identify diabetes mellitus as a risk factor for pancreatic cancer taking into consideration that approximately 10 years are needed to diagnose symptomatic pancreatic cancer. At present, the answer to the as to whether diabetes and pancreatic cancer comes first similar to the adage of the chicken and the egg is that diabetes is the egg.

INTRODUCTION

The relationship between diabetes mellitus and the risk of pancreatic cancer has been a matter of study for a long period of time. The importance of this topic is due to two main causes: the possible use of recent onset diabetes as a marker of the disease and, in particular, as a specific marker of pancreatic cancer, and the selection of a population at risk for pancreatic cancer[1].

SEARCH STRATEGY

Taking into consideration diabetes mellitus irrespective of type, there is a lack of agreement regarding the data; thus, we decided to make an in-depth study of this topic. On July 24, 2012, we carried out a PubMed/Medline search using the following strategy: (“Diabetes Mellitus” [Mesh] or “Diabetes Mellitus, Type 2” [Mesh] or “Diabetes Mellitus, Type 1” [Mesh]) and “Pancreatic Neoplasms” [Mesh] and (“humans” [MeSH Terms] and English [lang]); other papers were manually extracted from the references of the papers selected. From 1966, a total of 787 papers were found and, of these, we selected 74 papers[2-75] and nine meta-analyses[76-84].

ANALYSIS OF LITERATURE AND CLINICAL CONSIDERATIONS

One of the first studies on the relationship between pancreatic cancer and diabetes is that of Maruchi et al[2] who found that there was an association between pancreatic carcinoma and diabetes from 1935 through 1974 only in cases of confirmed pancreatic carcinoma in residents of Olmsted County, Minnesota. In their series, 17% of the patients were diabetic (19/113) and nine cases (8%) of diabetes had appeared at least 2 years before the diagnosis of pancreatic cancer. Twenty years later, our group carried out a case-control study matching a large number of patients with and without pancreatic cancer[24]. The main findings were as follows: in the majority of cases, the diabetes was diagnosed at the same time as the cancer or within a few years prior to its identification, suggesting that it was the cancer which caused the diabetes. In fact, diabetes mellitus of long duration (> 7 years) had essentially no association with pancreatic cancer whereas, in a small group of patients who had had diabetes of a 5-7 years duration when the cancer was diagnosed, the association was statistically significant. Finally, all the patients in whom the diagnosis of diabetes had been made prior to that of the tumor had non-insulin-dependent diabetes, and no association was found with the insulin-dependent form.

Taking into account all findings in the literature, all the studies and the meta-analyses found an association between diabetes mellitus and pancreatic cancer at the time of diagnosis. However, little is known about glucose tolerance and insulin secretion in patients with this tumor. Gapstur et al[85] prospectively studied the postload plasma glucose concentration in 84 patients with pancreatic cancer in order to determine the presence of an independent association between postload plasma glucose concentration and the risk of pancreatic cancer mortality among people without self-reported diabetes. Compared to a postload plasma glucose level of 119 mg/dL or less and, after adjusting for age, race, cigarette smoking and body mass index, the relative risks (95%CI) of pancreatic cancer mortality were 1.65 (1.05-2.60) for postload plasma glucose levels between 120 mg/dL and 159 mg/dL, 1.60 (0.95-2.70) for levels between 160 mg/dL and 199 mg/dL and 2.15 (1.22-3.80) for levels of 200 mg/dL or more. Such an association appeared to be stronger in men than in women. Estimates were only slightly lower after excluding 11 men and 2 women who died from pancreatic cancer during the first 5 years of follow-up. Elevated body mass index and serum uric acid concentration were also independently associated with an elevated risk of pancreatic cancer mortality in men only. This study provides evidence for a positive, dose-response relationship between postload glycemia and pancreatic cancer mortality. The possible mechanisms underlying the increased pancreatic cancer risk among patients with diabetes mellitus is the involvement of insulin resistance and hyperinsulinemia. In addition, whereas postoperative diabetes was seen in all long-standing diabetic patients, and in some patients with intolerance fasting glucose and normal fasting glucose, the diabetes was resolved in more than 50% of patients with new-onset diabetes despite removal of half of the beta-cell mass[52]. Thus, it seems that diabetes is caused by pancreatic cancer. The answer to whether the diabetes is a specific marker of the disease comes from the study of Aggarwal et al[86]; these authors retrospectively reviewed the medical records of 500 consecutive patients with cancer (lung, breast, prostate, colorectal cancers and pancreatic cancer) and 100 non-cancer controls, and found that whereas the prevalence of diabetes mellitus in pancreatic cancer is high, diabetes mellitus prevalence in other common cancers is no different from that in non-cancer controls. Thus, diabetes mellitus is not useful as an early or specific marker of pancreatic cancer.

Controversies also exist between the association of long-standing diabetes mellitus and pancreatic cancer; some, epidemiological studies have excluded the possibility that long-standing diabetes mellitus is a risk factor for pancreatic cancer[2,6,24,32,36,41,44,45,51,52,54,59,60,64,70] whereas others (Table 1) have found a relationship[3-5,7-31,33,35,37-40,42,43,46-49,53,55-58,61,63,65-69,71-75]. It should be pointed out that, in papers showing an association between long standing diabetes and pancreatic cancer there are some biases due to self-reported diabetes which could result in misclassification, heterogeneity among individuals with diabetes in terms of physiologic status, sequelae and treatment which could also confuse this relationship. In addition, Yachida et al[87], sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers, found that clonal populations which give rise to distant metastases are represented within the primary carcinoma (but these clones are genetically evolved from the original parental, non-metastatic clone) and they performed a quantitative analysis of the timing of the genetic evolution of pancreatic cancer found at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of 2 years thereafter[87]. Thus, even if diabetes is found a decade before the appearance of pancreatic cancer as reported in meta-analytic studies, we cannot select those patients already having non detectable pancreatic cancer, at least with the imaging and biological techniques available today (Figure 1).

Table 1.

Diabetes as a risk factor for pancreatic cancer according to diabetes duration

Meta-analysis Studies evaluated (n) Diabetes duration (yr) Risk 95%CI
Everhart et al[76] 20 All studies evaluated  > 1 RR = 2.1 1.6-2.8
11 All case-control studies  > 1 RR = 1.8 1.1-2.7
9 All cohort studies  > 1 RR = 2.6 1.6-4.1
11 All studies  > 5 RR = 2.0 1.2-3.2
6 All case-control studies  > 5 RR = 1.8 0.86-3.8
6 All cohort studies  > 5 RR = 2.4 0.85-7.0
Li et al[64] 3 ≤ 2 OR = 2.9 2.1-3.9
3 3-5 OR = 1.9 1.3-2.6
3 6-10 OR = 1.6 1.2-2.3
11-15 OR = 1.3 0.9.2.0
> 15 OR = 1.4 1.0-2.0
Huxley et al[80] 9 1-4 RR = 2.05 1.87-2.25
9 5-9 RR = 1.54 1.31-1.81
7 ≥ 10 RR = 1.51 1.16-1.96
Ben et al[84] 3 < 1 RR = 5.38 3.49-8.30
5 1-4 RR = 1.95 1.65-2.31
4 5-9 RR = 1.49 1.05-2.12
4 ≥ 10 RR = 1.47 0.94-2.31

Figure 1.

Figure 1

Relative risks and quantitative analysis. Panel A: Relative risks (RR) for the association between diabetes and pancreatic cancer according to the duration of the diabetes (originated from[63]). The risk disappears after 10 years; Panel B: Quantitative analysis of the timing of the genetic evolution of pancreatic cancer indicates that at least a decade is necessary between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell, that at least five more years are required for the acquisition of metastatic ability and patients usually die on an average of 2 years thereafter (originated from[87]).

CONCLUSION

We believe that more studies are necessary in order to definitively identify diabetes mellitus as a risk factor for pancreatic cancer taking into consideration that approximately 10 years are needed to diagnose symptomatic pancreatic cancer. At present, the answer to the question posed by Magruder et al[83] as to whether diabetes and pancreatic cancer comes first similar to the adage of the chicken and the egg is that diabetes is the egg.

Footnotes

P- Reviewers Chiaro MD, Pastromas S, Tarantino G S- Editor Gou SX L- Editor A E- Editor Ma S

References

  • 1.Pezzilli R, Fabbri D, Imbrogno A. Pancreatic ductal adenocarcinoma screening: new perspectives. World J Gastroenterol. 2012;18:4973–4977. doi: 10.3748/wjg.v18.i36.4973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Maruchi N, Brian D, Ludwig J, Elveback LR, Kurland LT. Cancer of the pancreas in Olmsted County, Minnesota, 1935-1974. Mayo Clin Proc. 1979;54:245–249. [PubMed] [Google Scholar]
  • 3.Blot WJ, Fraumeni JF, Stone BJ. Geographic correlates of pancreas cancer in the United States. Cancer. 1978;42:373–380. doi: 10.1002/1097-0142(197807)42:1<373::aid-cncr2820420156>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  • 4.Wynder EL. An epidemiological evaluation of the causes of cancer of the pancreas. Cancer Res. 1975;35:2228–2233. [PubMed] [Google Scholar]
  • 5.Mizuno S, Watanabe S, Nakamura K, Omata M, Oguchi H, Ohashi K, Ohyanagi H, Fujiki T, Motojima K. A multi-institute case-control study on the risk factors of developing pancreatic cancer. Jpn J Clin Oncol. 1992;22:286–291. [PubMed] [Google Scholar]
  • 6.Bueno de Mesquita HB, Maisonneuve P, Moerman CJ, Walker AM. Aspects of medical history and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands. Int J Cancer. 1992;52:17–23. doi: 10.1002/ijc.2910520105. [DOI] [PubMed] [Google Scholar]
  • 7.Cuzick J, Babiker AG. Pancreatic cancer, alcohol, diabetes mellitus and gall-bladder disease. Int J Cancer. 1989;43:415–421. doi: 10.1002/ijc.2910430312. [DOI] [PubMed] [Google Scholar]
  • 8.Norell S, Ahlbom A, Erwald R, Jacobson G, Lindberg-Navier I, Olin R, Wiechel KL. Diabetes, gall stone disease, and pancreatic cancer. Br J Cancer. 1986;54:377–378. doi: 10.1038/bjc.1986.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.O’Mara BA, Byers T, Schoenfeld E. Diabetes mellitus and cancer risk: a multisite case-control study. J Chronic Dis. 1985;38:435–441. doi: 10.1016/0021-9681(85)90139-0. [DOI] [PubMed] [Google Scholar]
  • 10.Wynder EL, Mabuchi K, Maruchi N, Fortner JG. Epidemiology of cancer of the pancreas. J Natl Cancer Inst. 1973;50:645–667. doi: 10.1093/jnci/50.3.645. [DOI] [PubMed] [Google Scholar]
  • 11.Wynder EL, Mabuchi K, Maruchi N, Fortner JG. A case control study of cancer of the pancreas. Cancer. 1973;31:641–648. doi: 10.1002/1097-0142(197303)31:3<641::aid-cncr2820310323>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  • 12.Levin DL, Connelly RR. Cancer of the pancreas. Available epidemiologic information and its implications. Cancer. 1973;31:1231–1236. doi: 10.1002/1097-0142(197305)31:5<1231::aid-cncr2820310529>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  • 13.Lowe WC, Palmer ED. Carcinoma of the pancreas. An analysis of 100 patients. Am J Gastroenterol. 1967;47:412–420. [PubMed] [Google Scholar]
  • 14.Karmody A, Kyle J. Diabetes mellitus and carcinoma of the pancreas. Bull Soc Int Chir. 1968;27:119–124. [PubMed] [Google Scholar]
  • 15.Karmody AJ, Kyle J. The association between carcinoma of the pancreas and diabetes mellitus. Br J Surg. 1969;56:362–364. doi: 10.1002/bjs.1800560512. [DOI] [PubMed] [Google Scholar]
  • 16.Morris DV, Nabarro JD. Pancreatic cancer and diabetes mellitus. Diabet Med. 1984;1:119–121. doi: 10.1111/j.1464-5491.1984.tb01941.x. [DOI] [PubMed] [Google Scholar]
  • 17.Andrén-Sandberg A, Ihse I. Factors influencing survival after total pancreatectomy in patients with pancreatic cancer. Ann Surg. 1983;198:605–610. doi: 10.1097/00000658-198311000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Manousos O, Trichopoulos D, Koutselinis A, Papadimitriou C, Polychronopoulou A, Zavitsanos X. Epidemiologic characteristics and trace elements in pancreatic cancer in Greece. Cancer Detect Prev. 1981;4:439–442. [PubMed] [Google Scholar]
  • 19.Chow WH, Gridley G, Nyrén O, Linet MS, Ekbom A, Fraumeni JF, Adami HO. Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden. J Natl Cancer Inst. 1995;87:930–931. doi: 10.1093/jnci/87.12.930. [DOI] [PubMed] [Google Scholar]
  • 20.La Vecchia C, Negri E, Franceschi S, D’Avanzo B, Boyle P. A case-control study of diabetes mellitus and cancer risk. Br J Cancer. 1994;70:950–953. doi: 10.1038/bjc.1994.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Shibata A, Mack TM, Paganini-Hill A, Ross RK, Henderson BE. A prospective study of pancreatic cancer in the elderly. Int J Cancer. 1994;58:46–49. doi: 10.1002/ijc.2910580109. [DOI] [PubMed] [Google Scholar]
  • 22.Fernandez E, La Vecchia C, D’Avanzo B, Negri E, Franceschi S. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 1994;3:209–212. [PubMed] [Google Scholar]
  • 23.Balkau B, Barrett-Connor E, Eschwege E, Richard JL, Claude JR, Ducimetiere P. Diabetes and pancreatic carcinoma. Diabete Metab. 1993;19:458–462. [PubMed] [Google Scholar]
  • 24.Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. N Engl J Med. 1994;331:81–84. doi: 10.1056/NEJM199407143310203. [DOI] [PubMed] [Google Scholar]
  • 25.Kalapothaki V, Tzonou A, Hsieh CC, Toupadaki N, Karakatsani A, Trichopoulos D. Tobacco, ethanol, coffee, pancreatitis, diabetes mellitus, and cholelithiasis as risk factors for pancreatic carcinoma. Cancer Causes Control. 1993;4:375–382. doi: 10.1007/BF00051341. [DOI] [PubMed] [Google Scholar]
  • 26.Friedman GD, van den Eeden SK. Risk factors for pancreatic cancer: an exploratory study. Int J Epidemiol. 1993;22:30–37. doi: 10.1093/ije/22.1.30. [DOI] [PubMed] [Google Scholar]
  • 27.Balkau B, Eschwege E. Risk factors and their identification. Third Part: Examples. Diabete Metab. 1995;21:299–308. [PubMed] [Google Scholar]
  • 28.Lee CT, Chang FY, Lee SD. Risk factors for pancreatic cancer in orientals. J Gastroenterol Hepatol. 1996;11:491–495. doi: 10.1111/j.1440-1746.1996.tb00296.x. [DOI] [PubMed] [Google Scholar]
  • 29.Calle EE, Murphy TK, Rodriguez C, Thun MJ, Heath CW. Diabetes mellitus and pancreatic cancer mortality in a prospective cohort of United States adults. Cancer Causes Control. 1998;9:403–410. doi: 10.1023/a:1008819701485. [DOI] [PubMed] [Google Scholar]
  • 30.Silverman DT, Schiffman M, Everhart J, Goldstein A, Lillemoe KD, Swanson GM, Schwartz AG, Brown LM, Greenberg RS, Schoenberg JB, et al. Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer. 1999;80:1830–1837. doi: 10.1038/sj.bjc.6690607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Hjalgrim H, Frisch M, Ekbom A, Kyvik KO, Melbye M, Green A. Cancer and diabetes--a follow-up study of two population-based cohorts of diabetic patients. J Intern Med. 1997;241:471–475. doi: 10.1111/j.1365-2796.1997.tb00004.x. [DOI] [PubMed] [Google Scholar]
  • 32.Frye JN, Inder WJ, Dobbs BR, Frizelle FA. Pancreatic cancer and diabetes: is there a relationship A case-controlled study. Aust N Z J Surg. 2000;70:722–724. doi: 10.1046/j.1440-1622.2000.01940.x. [DOI] [PubMed] [Google Scholar]
  • 33.Silverman DT. Risk factors for pancreatic cancer: a case-control study based on direct interviews. Teratog Carcinog Mutagen. 2001;21:7–25. doi: 10.1002/1520-6866(2001)21:1<7::aid-tcm3>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  • 34.Kessler II. Cancer mortality among diabetics. J Natl Cancer Inst. 1970;44:673–686. [PubMed] [Google Scholar]
  • 35.Ye W, Lagergren J, Nyrén O, Ekbom A. Risk of pancreatic cancer after cholecystectomy: a cohort study in Sweden. Gut. 2001;49:678–681. doi: 10.1136/gut.49.5.678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Talamini G, Falconi M, Bassi C, Casetti L, Fantin A, Salvia R, Pederzoli P. Previous cholecystectomy, gastrectomy, and diabetes mellitus are not crucial risk factors for pancreatic cancer in patients with chronic pancreatitis. Pancreas. 2001;23:364–367. doi: 10.1097/00006676-200111000-00005. [DOI] [PubMed] [Google Scholar]
  • 37.Lin Y, Tamakoshi A, Kawamura T, Inaba Y, Kikuchi S, Motohashi Y, Kurosawa M, Ohno Y. Risk of pancreatic cancer in relation to alcohol drinking, coffee consumption and medical history: findings from the Japan collaborative cohort study for evaluation of cancer risk. Int J Cancer. 2002;99:742–746. doi: 10.1002/ijc.10402. [DOI] [PubMed] [Google Scholar]
  • 38.Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, Virtamo J, Albanes D. A prospective study of medical conditions, anthropometry, physical activity, and pancreatic cancer in male smokers (Finland) Cancer Causes Control. 2002;13:417–426. doi: 10.1023/a:1015729615148. [DOI] [PubMed] [Google Scholar]
  • 39.Silverman DT, Hoover RN, Brown LM, Swanson GM, Schiffman M, Greenberg RS, Hayes RB, Lillemoe KD, Schoenberg JB, Schwartz AG, et al. Why do Black Americans have a higher risk of pancreatic cancer than White Americans. Epidemiology. 2003;14:45–54. doi: 10.1097/00001648-200301000-00013. [DOI] [PubMed] [Google Scholar]
  • 40.Bonelli L, Aste H, Bovo P, Cavallini G, Felder M, Gusmaroli R, Morandini E, Ravelli P, Briglia R, Lombardo L, et al. Exocrine pancreatic cancer, cigarette smoking, and diabetes mellitus: a case-control study in northern Italy. Pancreas. 2003;27:143–149. doi: 10.1097/00006676-200308000-00007. [DOI] [PubMed] [Google Scholar]
  • 41.Egawa N, Tu Y, Sanaka M, Kamisawa T. Family history of diabetes and pancreatic cancer. Pancreas. 2005;30:15–19. [PubMed] [Google Scholar]
  • 42.Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology. 2005;129:504–511. doi: 10.1053/j.gastro.2005.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Larsson SC, Permert J, Håkansson N, Näslund I, Bergkvist L, Wolk A. Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts. Br J Cancer. 2005;93:1310–1315. doi: 10.1038/sj.bjc.6602868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Wang F, Gupta S, Holly EA. Diabetes mellitus and pancreatic cancer in a population-based case-control study in the San Francisco Bay Area, California. Cancer Epidemiol Biomarkers Prev. 2006;15:1458–1463. doi: 10.1158/1055-9965.EPI-06-0188. [DOI] [PubMed] [Google Scholar]
  • 45.Gupta S, Vittinghoff E, Bertenthal D, Corley D, Shen H, Walter LC, McQuaid K. New-onset diabetes and pancreatic cancer. Clin Gastroenterol Hepatol. 2006;4:1366–1372; quiz 1301. doi: 10.1016/j.cgh.2006.06.024. [DOI] [PubMed] [Google Scholar]
  • 46.Luo J, Iwasaki M, Inoue M, Sasazuki S, Otani T, Ye W, Tsugane S. Body mass index, physical activity and the risk of pancreatic cancer in relation to smoking status and history of diabetes: a large-scale population-based cohort study in Japan--the JPHC study. Cancer Causes Control. 2007;18:603–612. doi: 10.1007/s10552-007-9002-z. [DOI] [PubMed] [Google Scholar]
  • 47.Lo AC, Soliman AS, El-Ghawalby N, Abdel-Wahab M, Fathy O, Khaled HM, Omar S, Hamilton SR, Greenson JK, Abbruzzese JL. Lifestyle, occupational, and reproductive factors in relation to pancreatic cancer risk. Pancreas. 2007;35:120–129. doi: 10.1097/mpa.0b013e318053e7d3. [DOI] [PubMed] [Google Scholar]
  • 48.Perrin MC, Terry MB, Kleinhaus K, Deutsch L, Yanetz R, Tiram E, Calderon R, Friedlander Y, Paltiel O, Harlap S. Gestational diabetes as a risk factor for pancreatic cancer: a prospective cohort study. BMC Med. 2007;5:25. doi: 10.1186/1741-7015-5-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Hassan MM, Bondy ML, Wolff RA, Abbruzzese JL, Vauthey JN, Pisters PW, Evans DB, Khan R, Chou TH, Lenzi R, et al. Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol. 2007;102:2696–2707. doi: 10.1111/j.1572-0241.2007.01510.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Fryzek JP, Garabrant DH, Schenk M, Kinnard M, Greenson JK, Sarkar FH. The association between selected risk factors for pancreatic cancer and the expression of p53 and K-ras codon 12 mutations. Int J Gastrointest Cancer. 2006;37:139–145. doi: 10.1007/s12029-007-9005-8. [DOI] [PubMed] [Google Scholar]
  • 51.Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, Petersen GM. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology. 2008;134:95–101. doi: 10.1053/j.gastro.2007.10.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology. 2008;134:981–987. doi: 10.1053/j.gastro.2008.01.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Batty GD, Kivimaki M, Morrison D, Huxley R, Smith GD, Clarke R, Marmot MG, Shipley MJ. Risk factors for pancreatic cancer mortality: extended follow-up of the original Whitehall Study. Cancer Epidemiol Biomarkers Prev. 2009;18:673–675. doi: 10.1158/1055-9965.EPI-08-1032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Kuang TT, Jin da Y, Wang DS, Xu XF, Ni XL, Wu WC, Lou WH. Clinical epidemiological analysis of the relationship between pancreatic cancer and diabetes mellitus: data from a single institution in China. J Dig Dis. 2009;10:26–29. doi: 10.1111/j.1751-2980.2008.00359.x. [DOI] [PubMed] [Google Scholar]
  • 55.Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137:482–488. doi: 10.1053/j.gastro.2009.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Ogunleye AA, Ogston SA, Morris AD, Evans JM. A cohort study of the risk of cancer associated with type 2 diabetes. Br J Cancer. 2009;101:1199–1201. doi: 10.1038/sj.bjc.6605240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Chu CK, Mazo AE, Goodman M, Egnatashvili V, Sarmiento JM, Staley CA, Galloway JR, Adsay NV, Jacobs S, Kooby DA. Preoperative diabetes mellitus and long-term survival after resection of pancreatic adenocarcinoma. Ann Surg Oncol. 2010;17:502–513. doi: 10.1245/s10434-009-0789-6. [DOI] [PubMed] [Google Scholar]
  • 58.Jamal MM, Yoon EJ, Vega KJ, Hashemzadeh M, Chang KJ. Diabetes mellitus as a risk factor for gastrointestinal cancer among American veterans. World J Gastroenterol. 2009;15:5274–5278. doi: 10.3748/wjg.15.5274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Maisonneuve P, Lowenfels AB, Bueno-de-Mesquita HB, Ghadirian P, Baghurst PA, Zatonski WA, Miller AB, Duell EJ, Boffetta P, Boyle P. Past medical history and pancreatic cancer risk: Results from a multicenter case-control study. Ann Epidemiol. 2010;20:92–98. doi: 10.1016/j.annepidem.2009.11.010. [DOI] [PubMed] [Google Scholar]
  • 60.Olson SH, Chou JF, Ludwig E, O’Reilly E, Allen PJ, Jarnagin WR, Bayuga S, Simon J, Gonen M, Reisacher WR, et al. Allergies, obesity, other risk factors and survival from pancreatic cancer. Int J Cancer. 2010;127:2412–2419. doi: 10.1002/ijc.25240. [DOI] [PubMed] [Google Scholar]
  • 61.Hemminki K, Li X, Sundquist J, Sundquist K. Risk of cancer following hospitalization for type 2 diabetes. Oncologist. 2010;15:548–555. doi: 10.1634/theoncologist.2009-0300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Price S, Cole D, Alcolado JC. Diabetes due to exocrine pancreatic disease--a review of patients attending a hospital-based diabetes clinic. QJM. 2010;103:759–763. doi: 10.1093/qjmed/hcq127. [DOI] [PubMed] [Google Scholar]
  • 63.Ben Q, Cai Q, Li Z, Yuan Y, Ning X, Deng S, Wang K. The relationship between new-onset diabetes mellitus and pancreatic cancer risk: a case-control study. Eur J Cancer. 2011;47:248–254. doi: 10.1016/j.ejca.2010.07.010. [DOI] [PubMed] [Google Scholar]
  • 64.Li D, Tang H, Hassan MM, Holly EA, Bracci PM, Silverman DT. Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-control studies. Cancer Causes Control. 2011;22:189–197. doi: 10.1007/s10552-010-9686-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20. doi: 10.1186/1471-2407-11-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Lipworth L, Zucchetto A, Bosetti C, Franceschi S, Talamini R, Serraino D, McLaughlin JK, La Vecchia C, Negri E. Diabetes mellitus, other medical conditions and pancreatic cancer: a case-control study. Diabetes Metab Res Rev. 2011;27:255–261. doi: 10.1002/dmrr.1162. [DOI] [PubMed] [Google Scholar]
  • 67.Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150–156. doi: 10.1053/j.gastro.2011.02.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Chen HF, Chen P, Li CY. Risk of malignant neoplasm of the pancreas in relation to diabetes: a population-based study in Taiwan. Diabetes Care. 2011;34:1177–1179. doi: 10.2337/dc10-2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Chuang SC, Stolzenberg-Solomon R, Ueland PM, Vollset SE, Midttun Ø, Olsen A, Tjønneland A, Overvad K, Boutron-Ruault MC, Morois S, et al. A U-shaped relationship between plasma folate and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Eur J Cancer. 2011;47:1808–1816. doi: 10.1016/j.ejca.2011.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Pierce BL, Austin MA, Ahsan H. Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes Control. 2011;22:877–883. doi: 10.1007/s10552-011-9760-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Matsubayashi H, Maeda A, Kanemoto H, Uesaka K, Yamazaki K, Hironaka S, Miyagi Y, Ikehara H, Ono H, Klein A, et al. Risk factors of familial pancreatic cancer in Japan: current smoking and recent onset of diabetes. Pancreas. 2011;40:974–978. doi: 10.1097/MPA.0b013e3182156e1b. [DOI] [PubMed] [Google Scholar]
  • 72.Li C, Balluz LS, Ford ES, Okoro CA, Tsai J, Zhao G. Association between diagnosed diabetes and self-reported cancer among U.S. adults: findings from the 2009 Behavioral Risk Factor Surveillance System. Diabetes Care. 2011;34:1365–1368. doi: 10.2337/dc11-0020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Chang CH, Toh S, Lin JW, Chen ST, Kuo CW, Chuang LM, Lai MS. Cancer risk associated with insulin glargine among adult type 2 diabetes patients--a nationwide cohort study. PLoS One. 2011;6:e21368. doi: 10.1371/journal.pone.0021368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Grote VA, Rohrmann S, Nieters A, Dossus L, Tjønneland A, Halkjær J, Overvad K, Fagherazzi G, Boutron-Ruault MC, Morois S, et al. Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: a study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Diabetologia. 2011;54:3037–3046. doi: 10.1007/s00125-011-2316-0. [DOI] [PubMed] [Google Scholar]
  • 75.Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol. 2012;107:620–626. doi: 10.1038/ajg.2011.483. [DOI] [PubMed] [Google Scholar]
  • 76.Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA. 1995;273:1605–1609. [PubMed] [Google Scholar]
  • 77.Noy A, Bilezikian JP. Clinical review 63: Diabetes and pancreatic cancer: clues to the early diagnosis of pancreatic malignancy. J Clin Endocrinol Metab. 1994;79:1223–1231. doi: 10.1210/jcem.79.5.7962312. [DOI] [PubMed] [Google Scholar]
  • 78.Fisher WE. Diabetes: risk factor for the development of pancreatic cancer or manifestation of the disease. World J Surg. 2001;25:503–508. doi: 10.1007/s002680020344. [DOI] [PubMed] [Google Scholar]
  • 79.Berrington de Gonzalez A, Sweetland S, Spencer E. A meta-analysis of obesity and the risk of pancreatic cancer. Br J Cancer. 2003;89:519–523. doi: 10.1038/sj.bjc.6601140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Huxley R, Ansary-Moghaddam A, Berrington de González A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076–2083. doi: 10.1038/sj.bjc.6602619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Ansary-Moghaddam A, Huxley R, Barzi F, Lawes C, Ohkubo T, Fang X, Jee SH, Woodward M. The effect of modifiable risk factors on pancreatic cancer mortality in populations of the Asia-Pacific region. Cancer Epidemiol Biomarkers Prev. 2006;15:2435–2440. doi: 10.1158/1055-9965.EPI-06-0368. [DOI] [PubMed] [Google Scholar]
  • 82.Stevens RJ, Roddam AW, Beral V. Pancreatic cancer in type 1 and young-onset diabetes: systematic review and meta-analysis. Br J Cancer. 2007;96:507–509. doi: 10.1038/sj.bjc.6603571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Magruder JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: chicken or egg. Pancreas. 2011;40:339–351. doi: 10.1097/MPA.0b013e318209e05d. [DOI] [PubMed] [Google Scholar]
  • 84.Ben Q, Xu M, Ning X, Liu J, Hong S, Huang W, Zhang H, Li Z. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur J Cancer. 2011;47:1928–1937. doi: 10.1016/j.ejca.2011.03.003. [DOI] [PubMed] [Google Scholar]
  • 85.Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA. 2000;283:2552–2558. doi: 10.1001/jama.283.19.2552. [DOI] [PubMed] [Google Scholar]
  • 86.Aggarwal G, Kamada P, Chari ST. Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas. 2013;42:198–201. doi: 10.1097/MPA.0b013e3182592c96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–1117. doi: 10.1038/nature09515. [DOI] [PMC free article] [PubMed] [Google Scholar]

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