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Diabetes mellitus: a risk factor for pancreatic cancer?

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Abstract

The relationship between pancreatic cancer (PC) and diabetes is controversial. While some investigators assume that type II diabetes is a predisposition to PC, recent data argue that diabetes and altered glucose metabolism are a consequence of PC, and yet, the clinical presentation of the altered glucose metabolism in these patients varies considerably. Around 70% of patients with PC have impaired glucose tolerance (IGT) or frank diabetes. Of these, nearly 60% show an improvement of IGT or diabetes after surgery, whereas the rest show only mild or no improvement. It appears that biologically there are three types of PC: (1) PC not associated with IGT or diabetes; (2) PC associated with IGT or diabetes in which the abnormality improves postoperatively; (3) PC associated with IGT or diabetes in which the abnormality does not improve postoperatively. Based on our own studies, we suggest that the reason for impaired glucose metabolism in most patients is the alteration of islet cells either by the carcinogen directly, or by diabetogenic substances released by cancer cells. The extent of the islet alteration (i.e. focal or diffuse) may determine whether the removal of tumor alone can improve the metabolic alteration. The elucidation of the mechanism is of immense importance for providing an early tumor marker and for developing preventative or therapeutic modalities.

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References

  1. Ahmedin J, Thomas A, Murray T, Thun M (2002) Cancer Statistics. CA 52:23–42

    PubMed  Google Scholar 

  2. Cooperman AM (2001) Pancreatic cancer: the bigger picture. Surg Clin North Am 81:557–574

    CAS  PubMed  Google Scholar 

  3. Murphy R, Smith FH (1963) Abnormal carbohydrate metabolism in pancreatic carcinoma. Med Clin North Am 47:397–405

    CAS  PubMed  Google Scholar 

  4. Silverman DT, Swanson CA, Gridley G, et al (1998) Dietary and nutritional factors and pancreatic cancer: a case-control study based on direct interviews. J Natl Cancer Inst 90:1710–1719

    CAS  PubMed  Google Scholar 

  5. Cuzick J, Babiker AG (1989) Pancreatic cancer, alcohol, diabetes mellitus and gall-bladder disease. Int J Cancer 43:415–421

    CAS  PubMed  Google Scholar 

  6. Chow WH, Gridley G, Nyren O (1995) Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden. J Natl Cancer Inst 87:930–931

    CAS  PubMed  Google Scholar 

  7. Ragozzino M, Melton LJ, 3rd, Chu CP, Palumbo PJ (1982) Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus. J Chronic Dis 35:13–9

    CAS  PubMed  Google Scholar 

  8. Gullo L, Pezzilli R, Morselli-Labate AM (1994) Diabetes and the risk of pancreatic cancer. Italian Pancreatic Cancer Study Group. N Engl J Med 331:81–4

    CAS  PubMed  Google Scholar 

  9. Gullo L (1999) Diabetes and the risk of pancreatic cancer. Ann Oncol 10 Suppl 4:79–81

    Google Scholar 

  10. Silverman DT (2001) Risk factors for pancreatic cancer: a case-control study based on direct interviews. Teratog Carcinog Mutagen 21:7–25

    Article  CAS  PubMed  Google Scholar 

  11. Everhart J, Wright D (1995) Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. Jama 273:1605–1609

    Article  CAS  PubMed  Google Scholar 

  12. Smith GD, Egger M, Shipley MJ, Marmot MG (1992) Post-challenge glucose concentration, impaired glucose tolerance, diabetes, and cancer mortality in men. Am J Epidemiol 136:1110–1114

    CAS  PubMed  Google Scholar 

  13. Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A (2000) Abnormal glucose metabolism and pancreatic cancer mortality. Jama 283:2552–2558

    Article  CAS  PubMed  Google Scholar 

  14. Bonelli L, Aste H, Bovo P, Cavallini G, Felder M, Gusmaroli R, Morandini E, Ravelli P, Briglia R, Lombardo L, De Micheli A, Pugliese V (2003) Exocrine pancreatic cancer, cigarette smoking, and diabetes mellitus: a case-control study in Northern Italy. Pancreas 27:143–149

    Article  PubMed  Google Scholar 

  15. Fisher WE, Boros LG, Schirmer WJ (1996) Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res 63:310–313

    Article  CAS  PubMed  Google Scholar 

  16. Ishikawa O, Ohhigashi H, Wada A, Tateishi R, Ishiguro S, Okano Y, Sasaki Y, Imaoka S, Koyama H, Iwanaga T (1989) Morphologic characteristics of pancreatic carcinoma with diabetes mellitus. Cancer 64:1107–1112

    CAS  PubMed  Google Scholar 

  17. Birt DF, Julius AD, White LT, Pour PM (1989) Enhancement of pancreatic carcinogenesis in hamsters fed a high-fat diet ad libitum and at a controlled calorie intake. Cancer Res 49:5848-5851

    CAS  PubMed  Google Scholar 

  18. Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM (2001) Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120:1263–1270

    CAS  PubMed  Google Scholar 

  19. Fisher WE (2001) Diabetes: risk factor for the development of pancreatic cancer or manifestation of the disease? World J Surg 25:503–508

    Article  CAS  PubMed  Google Scholar 

  20. Harris MI, Klein R, Welborn TA, Knuiman MW (1992) Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 15:815–819

    CAS  PubMed  Google Scholar 

  21. Brat DJ, Lillemoe KD, Yeo CJ, Warfield PB, Hruban RH (1998) Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 22:163–169

    Article  CAS  PubMed  Google Scholar 

  22. Wakasugi H, Funakoshi A, Iguchi H (2001) Clinical observations of pancreatic diabetes caused by pancreatic carcinoma, and survival period. Int J Clin Oncol 6:50–54

    CAS  PubMed  Google Scholar 

  23. Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnqvist HJ, Larsson J (1993) Pancreatic cancer is associated with impaired glucose metabolism. Eur J Surg 159:101–107

    CAS  PubMed  Google Scholar 

  24. Schwarts SS, Zeidler A, Moossa AR, Kuku SF, Rubenstein AH (1978) A prospective study of glucose tolerance, insulin, C-peptide, and glucagon responses in patients with pancreatic carcinoma. Am J Dig Dis 23:1107–1114

    CAS  PubMed  Google Scholar 

  25. Karmody AJ, Kyle J (1969) The association between carcinoma of the pancreas and diabetes mellitus. Br J Surg 56:362–364

    CAS  PubMed  Google Scholar 

  26. Cetin M, Colak R, Bayram F, Altinbas M, Unal A, Kelestimur F (2002) High prevalence of diabetes in patients with pancreatic cancer in central Anatolia, Turkey. Diabetes Res Clin Pract 58:97–100

    Article  PubMed  Google Scholar 

  27. Ahren B, Andren-Sandberg A (1993) Glucose tolerance and insulin secretion in experimental pancreatic cancer in the Syrian hamster. Res Exp Med (Berl) 193:21–26

    Google Scholar 

  28. Andren-Sandberg A (1994) Alteration of pancreatic hormones in human and experimental pancreatic cancer. Int J Pancreatol 16

  29. Permert J, Herrington M, Kazakoff K, Pour PM, Adrian TE (2001) Early changes in islet hormone secretion in the hamster pancreatic cancer model. Teratog Carcinog Mutagen 21:59–67

    CAS  PubMed  Google Scholar 

  30. Ariyama J (1994) Abnormal glucose tolerance in patients with early pancreatic carcinoma. Int J Pancreatol 91

  31. Falconi M, Bassi, C., Zamboni., G, Talamini, G., Pederzoli, P (2000) Clinicopathological features and treatment of intraductal papillary mucinous tumor of the pancreas. Br J Surg 88:187–197

    Google Scholar 

  32. Schmied BM, Ulrich AB, Matsuzaki H, Li C, Friess H, Bochler MW, Andron-Sandberg A, Adrian TE, Pour PM (2000) Alteration of the Langerhans islets in pancreatic cancer patients. Int J Pancreatol 28:187–197

    Article  CAS  PubMed  Google Scholar 

  33. Pour PM, Schmied BM, Ulrich AB, Friess H, Andren-Sandberg A, Buchler MW (2001) Abnormal differentiation of islet cells in pancreatic cancer. Pancreatology 1:110–116

    Article  CAS  PubMed  Google Scholar 

  34. Schmied BM, Ulrich A, Matsuzaki H, Ding X, Ricordi C, Weide L, Moyer MP, Batra SK, Adrian TE, Pour PM (2001) Transdifferentiation of human islet cells in a long-term culture. Pancreas 23:157–171

    Article  CAS  PubMed  Google Scholar 

  35. Schmied BM, Liu G, Matsuzaki H, Ulrich A, Hernberg S, Moyer MP, Weide L, Murphy L, Batra SK, Pour PM (2000) Differentiation of islet cells in long-term culture. Pancreas 20:337–347

    Article  CAS  PubMed  Google Scholar 

  36. Bouwens L (1998) Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas. Microsc Res Tech 43:332–336

    Article  CAS  PubMed  Google Scholar 

  37. Bouwens L, Kloppel G (1996) Islet cell neogenesis in the pancreas. Virchows Arch 427:553–560

    CAS  PubMed  Google Scholar 

  38. Kerr-Conte J, Pattou F, Xia Y, Lefebvre AM, Lefebvre J, Proye C (1995) Model for human islet neogenesis in vitro from adult pancreatic preparations. Transplant Proc 27:3268

    CAS  PubMed  Google Scholar 

  39. Yuan S, Paraskevas S, Duguid WP, Rosenberg L (1995) Phenotypic transformation of isolated human islets in collagen matrix culture. Transplant Proc 27:3364

    CAS  PubMed  Google Scholar 

  40. Yuan S, Rosenberg L, Paraskevas S, Agapitos D, Duguid WP (1996) Transdifferentiation of human islets to pancreatic ductal cells in collagen matrix culture. Differentiation 61:67–75

    CAS  PubMed  Google Scholar 

  41. Hunziker E, Stein M (2000) Nestin-expressing cells in the pancreatic islets of Langerhans. Biochem Biophys Res Commun 271:116–119

    Article  CAS  PubMed  Google Scholar 

  42. Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF (2001) Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50:521–533

    CAS  PubMed  Google Scholar 

  43. Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnquist HJ, Larsson J (1993) Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer. Br J Surg 80:1047–1050

    CAS  PubMed  Google Scholar 

  44. Permert J, Adrian TE, Jacobsson P, Jorfelt L, Fruin AB, Larsson J (1993) Is profound peripheral insulin resistance in patients with pancreatic cancer caused by a tumor-associated factor? Am J Surg 165:61–66; discussion 66–67

    CAS  PubMed  Google Scholar 

  45. Permert J, Larsson J, Westermark GT, Herrington MK, Christmanson L, Pour PM, Westermark P, Adrian TE (1994) Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. N Engl J Med 330:313–318

    CAS  PubMed  Google Scholar 

  46. Li J, Adrian TE (1999) A factor from pancreatic and colonic cancer cells stimulates glucose uptake and lactate production in myoblasts. Biochem Biophys Res Commun 260:626–633

    Article  CAS  PubMed  Google Scholar 

  47. Basso D, Valerio A, Seraglia R, Mazza S, Piva MG, Greco E, Fogar P, Gallo N, Pedrazzoli S, Tiengo A, Plebani M (2002) Putative pancreatic cancer-associated diabetogenic factor: 2030 MW peptide. Pancreas 24:8–14

    Article  PubMed  Google Scholar 

  48. Tezel E, Kawase Y, Takeda S, Oshima K, Nakao A (2001) Expression of neural cell adhesion molecule in pancreatic cancer. Pancreas 22:122–125

    Article  CAS  PubMed  Google Scholar 

  49. Kamisawa T, Fukayama M, Tabata I, Isawa T, Tsuruta K, Okamoto A, Koike (1996) Neuroendocrine differentiation in pancreatic duct carcinoma special emphasis on duct-endocrine cell carcinoma of the pancreas. Pathol Res Pract 192:901–908

    CAS  PubMed  Google Scholar 

  50. Pour PM, Permert J, Mogaki M, Fujii H, Kazakoff K (1993) Endocrine aspects of exocrine cancer of the pancreas. Their patterns and suggested biologic significance. Am J Clin Pathol 100:223–230

    CAS  PubMed  Google Scholar 

  51. Stridsberg M, Berne C, Sandler S, Wilander E, Oberg K (1993) Inhibition of insulin secretion, but normal peripheral insulin sensitivity, in a patient with a malignant endocrine pancreatic tumour producing high amounts of an islet amyloid polypeptide-like molecule. Diabetologia 36:843–849

    CAS  PubMed  Google Scholar 

  52. Jamal H, Jones PM, Byrne J, Suda K, Ghatei MA, Kanse SM, Bloom SR (1991) Peptide contents of neuropeptide Y, vasoactive intestinal polypeptide, and beta-calcitonin gene-related peptide and their messenger ribonucleic acids after dexamethasone treatment in the isolated rat islets of Langerhans. Endocrinology 129:3372–3380

    CAS  PubMed  Google Scholar 

  53. Ebiou JC, Bulant M, Nicolas P, Aratan-Spire S (1992) Pattern of thyrotropin-releasing hormone secretion from the adult and neonatal rat pancreas: comparison with insulin secretion. Endocrinology 130:1371–1379

    Article  CAS  PubMed  Google Scholar 

  54. Borelli MI, Morano MI, Estivariz FE, Gagliardino JJ (1994) Glucose-induced secretion of ACTH-like products by rat pancreatic islets. Arch Int Physiol Biochim Biophys 102:17–20

    CAS  PubMed  Google Scholar 

  55. Ordonez NG, Balsaver AM, Mackay B (1988) Mucinous islet cell (amphicrine) carcinoma of the pancreas associated with watery diarrhea and hypokalemia syndrome. Hum Pathol 19:1458–1461

    CAS  PubMed  Google Scholar 

  56. Laine VJ, Ekfors TO, Gullichsen R, Nevalainen TJ (1992) Immunohistochemical characterization of an amphicrine mucinous islet-cell carcinoma of the pancreas. Case report. Apmis 100:335–340

    CAS  PubMed  Google Scholar 

  57. Fogar P, Pasquali C, Basso D, Sperti C, Panozzo MP, Tessari G, D’Angeli F, Del Favero G, Plebani M (1994) Diabetes mellitus in pancreatic cancer follow-up. Anticancer Res 14:2827–2830

    CAS  PubMed  Google Scholar 

  58. Permert J, Larsson J, Fruin AB, Tatemoto K, Herrington MK, von Schenck H, Adrian TE (1997) Islet hormone secretion in pancreatic cancer patients with diabetes. Pancreas 15:60–68

    CAS  PubMed  Google Scholar 

  59. Liu J, Knezetic JA, Strommer L, Permert J, Larsson J, Adrian TE (2000) The intracellular mechanism of insulin resistance in pancreatic cancer patients. J Clin Endocrinol Metab 85:1232–1238

    Article  CAS  PubMed  Google Scholar 

  60. Isaksson B, Strommer L, Friess H, Buchler MW, Herrington MK, Wang F, Zierath JR, Wallberg-Henriksson H, Larsson J, Permert J (2003) Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose transport in skeletal muscle of pancreatic cancer patients. Pancreas 26:173–177

    Article  Google Scholar 

  61. Liu J, Kazakoff K, Pour PM, Adrian TE (1998) The intracellular mechanism of insulin resistance in the hamster pancreatic ductal adenocarcinoma model. Pancreas 17:359–366

    CAS  PubMed  Google Scholar 

  62. DeFronzo RA, Bonadonna RC, Ferrannini E (1992) Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15:318–368

    CAS  PubMed  Google Scholar 

  63. Hotamisligil GS (2000) Molecular mechanisms of insulin resistance and the role of the adipocyte. Int J Obes Relat Metab Disord 24 Suppl 4:S23–S27

    Google Scholar 

  64. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946

    CAS  PubMed  Google Scholar 

  65. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005–2010

    CAS  PubMed  Google Scholar 

  66. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8:731–737

    CAS  PubMed  Google Scholar 

  67. >Permert J, Larsson J, Ihse I, Pour PM (1991) Diagnosis of pancreatic cancer. Alteration of glucose metabolism. Int J Pancreatol 9:113–117

    Google Scholar 

  68. Gullo L, Ancona D, Pezzilli R, Casadei R, Campione O (1993) Glucose tolerance and insulin secretion in pancreatic cancer. Ital J Gastroenterol 25:487–489

    CAS  PubMed  Google Scholar 

  69. Ishikawa O, Ohigashi H, Imaoka S (1994) Increased secretion of proinsulin in patients with pancreatic cancer. Int J Pancreatol 16

  70. Nakamori S, Ishikawa O, Ohigashi H, Sasakuma F, Shimizu T, Nakaizumi A, Furukawa H, Sasaki Y, Imaoka S (1999) Increased blood proinsulin and decreased C-peptide levels in patients with pancreatic cancer. Hepatogastroenterology 46:16–24

    CAS  PubMed  Google Scholar 

  71. Larsson J (1994) Relationship between pancreatic cancer and diabetes. Int J Pancreatol 16

  72. Del Favero G, Foagar P, Panozzo MP, et al (1994) Alterations of serum hormones in pancreatic cancer patients. Int J Pancreatol 16

  73. Amikura K, Kobari M, Matsuno S (1995) The time of occurrence of liver metastasis in carcinoma of the pancreas. Int J Pancreatol 17:139–146

    CAS  PubMed  Google Scholar 

  74. Savarino V, Mansi C, Bistolfi L, Zentilin P, Celle G (1983) Failure of new diagnostic aids in improving detection of pancreatic cancer at a resectable stage. Dig Dis Sci 28:1078–1082

    CAS  PubMed  Google Scholar 

  75. Cubilla AL, Fitzgerald PJ (1978) Pancreas cancer (non-endocrine): a review—part I. Clin Bull 8:91–99

    CAS  PubMed  Google Scholar 

  76. Pfeffer F, Nauck MA, Benz S, Hopt UT (1999) Secondary diabetes in pancreatic carcinoma and after pancreatectomy: pathophysiology, therapeutic peculiarities and prognosis. Z Gastroenterol Suppl 1:10–14

    Google Scholar 

  77. Ogawa Y, Tanaka M, Inoue K, Yamaguchi K, Chijiiwa K, Mizumoto K, Tsutsu N, Nakamura Y (2002) A prospective pancreatographic study of the prevalence of pancreatic carcinoma in patients with diabetes mellitus. Cancer 94:2344–2349

    Article  PubMed  Google Scholar 

  78. Schirmer WJ RR, Braasch JW, Guay AT, Heiss FW, Shea JA (1991) Diabetes and pancreatic cancer: Association and prognostic complications. Gastroenterology 100:A18

    Google Scholar 

  79. Talar-Wojnarowska R, Gasiorowska A, Strzelczyk J, Janiak A, Malecka-Panas E (2003) Prognostic factors in the operative and palliative treatment of pancreatic cancer. Neoplasma 50:383–387

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Cancer Institute Grant, 5ROICA60479 and SPORE Grant P50CA72712, the National Cancer Institute Laboratory Cancer Research Center Support Grant CA367127, and the American Cancer Special Institutional Grant.

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Correspondence to P. M. Pour.

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M. Yalniz is the recipient of a fellowship from the Turkish Gastroenterology Foundation

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Yalniz, M., Pour, P.M. Diabetes mellitus: a risk factor for pancreatic cancer?. Langenbecks Arch Surg 390, 66–72 (2005). https://doi.org/10.1007/s00423-004-0469-8

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