Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies.

BACKGROUND Diabetes mellitus (DM) is widely considered to be associated with risk of pancreatic cancer (PaC), however, whether DM is a cause or a consequence of PaC is still controversial. We examined this association by conducting a detailed meta-analysis of cohort studies. METHODS Studies were identified by searching Medline and Embase through November 30, 2010. Summary relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS A total of thirty-five cohort studies were included in this meta-analysis. DM was associated with an increased risk of PaC (the summary RRs=1.94; 95% CI, 1.66-2.27), with significant evidence of heterogeneity among these studies (p<0.001, I²=93.6%). Subgroup analyses revealed that the increased risk of PaC was independent of geographic locations, sex, study design, alcohol consumption, body mass index (BMI) and smoking status. In addition, the relative risk of PaC was correlated negatively with the duration of DM, with the highest risk of PaC found among patients diagnosed within less than 1 year. There was no significant publication bias (p=0.136 for Egger's regression asymmetry test). CONCLUSIONS Findings from this meta-analysis strongly support that diabetes is associated with an increased risk of PaC in both males and females and that DM is both an early manifestation and an etiologic factor of pancreatic cancer.

[1]  M. Marmot,et al.  Post-challenge glucose concentration, impaired glucose tolerance, diabetes, and cancer mortality in men. , 1992, American journal of epidemiology.

[2]  H. El‐Serag,et al.  Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population‐based study of U.S. veterans , 2009, Hepatology.

[3]  H. Adami,et al.  Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. , 2003, Journal of the National Cancer Institute.

[4]  G. Lanfranchi,et al.  Altered glucose metabolism and proteolysis in pancreatic cancer cell conditioned myoblasts: searching for a gene expression pattern with a microarray analysis of 5000 skeletal muscle genes , 2004, Gut.

[5]  H. Friess,et al.  Impaired Insulin Action on Phosphatidylinositol 3-Kinase Activity and Glucose Transport in Skeletal Muscle of Pancreatic Cancer Patients , 2003, Pancreas.

[6]  A. Morris,et al.  A cohort study of the risk of cancer associated with type 2 diabetes , 2009, British Journal of Cancer.

[7]  M. Thun,et al.  Are Racial Disparities in Pancreatic Cancer Explained by Smoking and Overweight/Obesity? , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[8]  W. L. Beeson,et al.  Dietary habits and past medical history as related to fatal pancreas cancer risk among adventists , 1988, Cancer.

[9]  L. Melton,et al.  Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus. , 1982, Journal of chronic diseases.

[10]  A. Dyer,et al.  Abnormal glucose metabolism and pancreatic cancer mortality. , 2000, JAMA.

[11]  J. Everhart,et al.  Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. , 1995, JAMA.

[12]  S. Larsson,et al.  Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts , 2005, British Journal of Cancer.

[13]  M. Woodward,et al.  The Effect of Modifiable Risk Factors on Pancreatic Cancer Mortality in Populations of the Asia-Pacific Region , 2006, Cancer Epidemiology Biomarkers & Prevention.

[14]  E. Barrett-Connor,et al.  Diabetes and pancreatic carcinoma. , 1993, Diabete & metabolisme.

[15]  Mariza de Andrade,et al.  Probability of pancreatic cancer following diabetes: a population-based study. , 2005, Gastroenterology.

[16]  Mariza de Andrade,et al.  Temporal Association of Changes in Fasting Blood Glucose and Body Mass Index With Diagnosis of Pancreatic Cancer , 2009, The American Journal of Gastroenterology.

[17]  L. Jorfeldt,et al.  Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer , 1993, The British journal of surgery.

[18]  A. Tiengo,et al.  Putative Pancreatic Cancer-Associated Diabetogenic Factor: 2030 MW Peptide , 2002, Pancreas.

[19]  Donghui Li,et al.  New Strategies in Pancreatic Cancer: Emerging Epidemiologic and Therapeutic Concepts , 2010, Clinical Cancer Research.

[20]  M. de Andrade,et al.  Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. , 2008, Gastroenterology.

[21]  Qiwen Ben,et al.  The relationship between new-onset diabetes mellitus and pancreatic cancer risk: a case-control study. , 2011, European journal of cancer.

[22]  Kenneth J. Chang,et al.  Diabetes mellitus as a risk factor for gastrointestinal cancer among American veterans. , 2009, World journal of gastroenterology.

[23]  H. El‐Serag,et al.  The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[24]  E. Riboli,et al.  The second expert report, Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective , 2007 .

[25]  Douglas Hanahan,et al.  Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy , 2010, Proceedings of the National Academy of Sciences.

[26]  M. Inoue,et al.  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 , 2007, Cancer Causes & Control.

[27]  M. Plebani,et al.  Diabetes mellitus in pancreatic cancer follow-up. , 1994, Anticancer research.

[28]  K. Hemminki,et al.  Risk of Cancer Following Hospitalization for Type 2 Diabetes , 2010, The oncologist.

[29]  A. Whittemore,et al.  Early precursors of pancreatic cancer in college men. , 1983, Journal of chronic diseases.

[30]  A. Roddam,et al.  Pancreatic cancer in type 1 and young-onset diabetes: systematic review and meta-analysis , 2007, British Journal of Cancer.

[31]  U. Nöthlings,et al.  Association of a diabetes risk score with risk of myocardial infarction, stroke, specific types of cancer, and mortality: a prospective study in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort , 2009, European Journal of Epidemiology.

[32]  M. Marmot,et al.  Diabetes status and post-load plasma glucose concentration in relation to site-specific cancer mortality: findings from the original Whitehall study , 2004, Cancer Causes & Control.

[33]  Manfred S. Green,et al.  Diabetes and risk of incident cancer: a large population-based cohort study in Israel , 2010, Cancer Causes & Control.

[34]  M. Thun,et al.  Diabetes mellitus and pancreaticcancer mortality in a prospectivecohort of United States adults , 1998, Cancer Causes & Control.

[35]  J. Samet,et al.  Fasting serum glucose level and cancer risk in Korean men and women. , 2005, JAMA.

[36]  E. Bonora,et al.  Mortality from site-specific malignancies in type 2 diabetic patients from Verona. , 2003, Diabetes care.

[37]  K. Hemminki,et al.  Cancer risk among patients hospitalized for Type 1 diabetes mellitus: a population‐based cohort study in Sweden , 2010, Diabetic medicine : a journal of the British Diabetic Association.

[38]  L. Phillips,et al.  Differential regulation of IGF-1 and IGF-binding protein-1 by dietary composition in humans. , 1993, The American journal of the medical sciences.

[39]  E. Vittinghoff,et al.  New-onset diabetes and pancreatic cancer. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[40]  Mitsuhiko Noda,et al.  Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. , 2006, Archives of internal medicine.

[41]  Ananda Basu,et al.  Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. , 2008, Gastroenterology.

[42]  D. Silverman,et al.  Cancer risk in patients with diabetes mellitus , 1991, Cancer Causes & Control.

[43]  A. Tamakoshi,et al.  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 , 2002, International journal of cancer.

[44]  R. Hiatt,et al.  Pancreatic cancer, blood glucose and beverage consumption , 1988, International journal of cancer.

[45]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[46]  D. Mukhopadhyay,et al.  Role of Insulin Receptor Substrates and Protein Kinase C-ζ in Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Pancreatic Cancer Cells* , 2004, Journal of Biological Chemistry.

[47]  M. Woodward,et al.  Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies , 2005, British Journal of Cancer.

[48]  A. Tamakoshi,et al.  Site-specific cancer risk due to diabetes mellitus history: evidence from the Japan Collaborative Cohort (JACC) Study. , 2006, Asian Pacific journal of cancer prevention : APJCP.

[49]  V. Beral,et al.  Factors associated with incident and fatal pancreatic cancer in a cohort of middle‐aged women , 2009, International journal of cancer.

[50]  P. Maisonneuve,et al.  Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds. , 2003, Gastroenterology.

[51]  B. Henderson,et al.  A prospective study of pancreatic cancer in the elderly , 1994, International journal of cancer.

[52]  D. Albanes,et al.  A prospective study of medical conditions, anthropometry, physical activity, and pancreatic cancer in male smokers (Finland) , 2002, Cancer Causes & Control.

[53]  O. Nyrén,et al.  Risk of pancreatic cancer after cholecystectomy: a cohort study in Sweden , 2001, Gut.

[54]  A. Veronesi,et al.  The pancreatic cancer cell line MIA PaCa2 produces one or more factors able to induce hyperglycemia in SCID mice. , 1995, Anticancer research.

[55]  I. I. Kessler.  Cancer mortality among diabetics. , 1970, Journal of the National Cancer Institute.

[56]  Y. Friedlander,et al.  Gestational diabetes as a risk factor for pancreatic cancer: a prospective cohort study , 2007, BMC medicine.

[57]  N. Waugh,et al.  Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study , 2005, British Journal of Cancer.

[58]  M Linet,et al.  Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. , 1997, Journal of the National Cancer Institute.

[59]  P. Maisonneuve,et al.  Risk factors for pancreatic cancer , 2005, Journal of cellular biochemistry.

[60]  Hidemi Ito,et al.  Epidemiology of pancreatic cancer in Japan: a nested case-control study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). , 2003, International journal of epidemiology.

[61]  H. Adami,et al.  Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden. , 1995, Journal of the National Cancer Institute.

[62]  S. Mousses,et al.  Intersex-like (IXL) is a cell survival regulator in pancreatic cancer with 19q13 amplification. , 2007, Cancer research.

[63]  S. K. Van Den Eeden,et al.  Risk factors for pancreatic cancer: an exploratory study. , 1993, International journal of epidemiology.

[64]  J. Liu,et al.  The intracellular mechanism of insulin resistance in pancreatic cancer patients. , 2000, The Journal of clinical endocrinology and metabolism.

[65]  M. Thun,et al.  Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. , 2004, American journal of epidemiology.

[66]  Steven S. Coughlin,et al.  Predictors of pancreatic cancer mortality among a large cohort of United States adults , 2000, Cancer Causes & Control.