Paraneoplastic Syndromes in Pancreatic Cancer

  • Jens Werner
  • Stephan Herzig
Reference work entry


Paraneoplastic syndromes are defined as signs and symptoms which present distant to the site of primary cancer or metastases. However, they are closely associated with the malignant disease and comprise metabolic, dystrophic, and/or degenerative symptoms, which are consequences of humoral or hormonal factors. The clinical symptoms vary widely and include systemic and organ-specific manifestations. In some cases, these can become the major clinical problems determining survival. Systemic manifestations include frequent symptoms of pancreatic cancer patients such as fever and cachexia. Organ-specific symptoms may represent as cutaneous, neurological, hematological, or endocrine symptoms. A special focus of this chapter is on diabetes mellitus associated with pancreatic tumors. The best-understood syndromes result from tumor production of biologically active substances or, to a lesser extent, from autoimmune phenomena. Biological active agents may promote the growth of the tumor directly. In turn, growth-promoting agents of this type may become the focus of new approaches to anticancer treatment. After successful treatment of the underlying malignant disease, paraneoplastic symptoms may resolve completely. Thus, early recognition of paraneoplastic syndromes is very important in the management of patients with pancreatic cancer. In the following chapter, the most common paraneoplastic syndromes are described in detail.


Paraneoplastic syndrome Systemic manifestation Organ-specific manifestation Diagnostic value Treatment options Monitoring of disease progression Diabetes mellitus Fever Cachexia Cutaneous manifestation Neurological manifestation Hematologic symptoms Pancreatic enzymes and metabolism 


  1. 1.
    Maringhini A, CIambra A, Raimondo M, et al. Clinical presentation in the diagnosis of pancreaticcancer. Pancreas. 1993;8:146–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Uomo G, Gallucci F, Rabitti PG. Anorexia-cachexia syndrome in pancreatic cancer: recent development in research and management. JOP. 2006;7:157–62.PubMedGoogle Scholar
  3. 3.
    Bruera E, Sweeney C. Cachexia and asthenia in cancer patients. Lancet Oncol. 2000;1:138–47.PubMedCrossRefGoogle Scholar
  4. 4.
    Donthireddy KR, Ailawadhi S, Nasser E, et al. Malignant gastroparesis: pathogenesis and management of an underrecognized disorder. J Support Oncol. 2007;5:355–63.PubMedGoogle Scholar
  5. 5.
    Walker PK. The anorexia-cachexia syndrome. Primary Care Cancer. 2001;21:13–7.Google Scholar
  6. 6.
    Ellison NM, Chevlen E, Still CD, Dubugunta S. Supportive care for patients with pancreatic cancer. Hematol Oncol Clin North Am. 2002;16:105–21.PubMedCrossRefGoogle Scholar
  7. 7.
    El-Kamar FG, Grossbard ML, Kozuch PS. Metastatic pancreatic cancer: emerging strategies in chemotherapy and palliative care. Oncologist. 2003;8:18–34.PubMedCrossRefGoogle Scholar
  8. 8.
    Berenstein EG, Ortiz Z. Megestreol acetate for the treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2005;2:CD004310.Google Scholar
  9. 9.
    Gordon JN, Trebble TM, Ellis RD, et al. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut. 2005;54:540–5.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Chastain MA. The glucagonoma syndrome: a review of its features and discussion of new perspectives. Am J Med Sci. 2001;321:306–20.PubMedCrossRefGoogle Scholar
  11. 11.
    Durden FM, Variyam E, Chren MM. Fat necrosis with features of erythema nodosum in a patient with metastatic pancreatic carcinoma. J Dermatol. 1996;35:39–41.Google Scholar
  12. 12.
    Munoz Diaz F, Garcia Carrasco C, Monge Romero MI, et al. Acanthosis nigricans as the initial paraneoplastic manifestation of pancreatic cancer. Gastroenterol Hepatol. 2007;30:15–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Shakin EJ, Holland J. Depression and pancreatic cancer. J Pain Symptom Manage. 1988;3:194–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Sutton E, Winer JB. The immunopathogenesis of paraneoplastic neurological syndromes. Clin Sci. 2002;102:520–5.CrossRefGoogle Scholar
  15. 15.
    Tahrani AA, Sharma S, Rangan S, Macleod AF. A patient with worsening mobility: a diagnostic challenge. Eur IJ Intern Med. 2008;19:292–4.CrossRefGoogle Scholar
  16. 16.
    Qureshi KM, Raman AK, Tan D, Fakih MG. Leukemoid reaction in pancreaticcancer: a case report and review of the literature. JOP. 2006;7:631–4.PubMedGoogle Scholar
  17. 17.
    Nunnensiek C, Rüther U, Rothe B. Paraneoplastic endocrinopathy. In: Rüther, Nunnensiek, Bokemeyer, editors. Paraneoplastic syndromes. Basel: Karger; 1998.Google Scholar
  18. 18.
    Kahn CR. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes. 1994;43:1066–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Skyler JS, Oddo C. Diabetes trends in the USA. Diabetes Metab Res Rev. 2002;18(Suppl 3):S21–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340:925–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance--a population-based twin study. Diabetologia. 1999;42:139–45.PubMedCrossRefGoogle Scholar
  22. 22.
    Rich SS. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes. 1990;39:1315–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Roden M. Diabetes mellitus--definition, classification and diagnosis. Acta Med Austriaca. 2004;31:156–7.PubMedGoogle Scholar
  24. 24.
    Mahler RJ, Adler ML. Clinical review 102: Type 2 diabetes mellitus: update on diagnosis, pathophysiology, and treatment. J Clin Endocrinol Metab. 1999;84:1165–71.PubMedCrossRefGoogle Scholar
  25. 25.
    Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806.PubMedCrossRefGoogle Scholar
  26. 26.
    Saltiel AR. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell. 2001;104:517–29.PubMedCrossRefGoogle Scholar
  27. 27.
    Saltiel AR, Pessin JE. Insulin signaling pathways in time and space. Trends Cell Biol. 2002;12:65–71.PubMedCrossRefGoogle Scholar
  28. 28.
    Araki E, Lipes MA, Patti ME, Bruning JC, Haag B 3rd, Johnson RS, Kahn CR. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994;372:186–90.PubMedCrossRefGoogle Scholar
  29. 29.
    Kharitonenkov A, Chen Z, Sures I, Wang H, Schilling J, Ullrich A. A family of proteins that inhibit signalling through tyrosine kinase receptors. Nature. 1997;386:181–6.PubMedCrossRefGoogle Scholar
  30. 30.
    White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem. 1998;182:3–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 2001;15:2099–111.PubMedCrossRefGoogle Scholar
  32. 32.
    Ribon V, Saltiel AR. Insulin stimulates tyrosine phosphorylation of the proto-oncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem J. 1997;324(Pt 3):839–45.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.PubMedCrossRefGoogle Scholar
  34. 34.
    Thirone AC, Huang C, Klip A. Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab. 2006;17:72–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr. 2007;27:79–101.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Wahren J, Ekberg K. Splanchnic regulation of glucose production. Annu Rev Nutr. 2007;27:329–45.PubMedCrossRefGoogle Scholar
  37. 37.
    Patti ME, Kahn CR. Lessons from transgenic and knockout animals about noninsulin-dependent diabetes mellitus. Trends Endocrinol Metab. 1996;7(9):311.PubMedCrossRefGoogle Scholar
  38. 38.
    Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond). 1999;96:513–23.CrossRefGoogle Scholar
  39. 39.
    Rosmond R, Bjorntorp P. The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J Intern Med. 2000;247:188–97.PubMedCrossRefGoogle Scholar
  40. 40.
    Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (second of two parts). N Engl J Med. 1981;304:1575–80.PubMedCrossRefGoogle Scholar
  41. 41.
    Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (first two parts). N Engl J Med. 1981;304:1518–24.PubMedCrossRefGoogle Scholar
  42. 42.
    Consoli A. Role of liver in pathophysiology of NIDDM. Diabetes Care. 1992;15:430–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Lemaigre FP, Rousseau GG. Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver. Biochem J. 1994;303(Pt 1):1–14.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Nordlie RC, Foster JD, Lange AJ. Regulation of glucose production by the liver. Annu Rev Nutr. 1999;19:379–406.PubMedCrossRefGoogle Scholar
  45. 45.
    Hanson RW, Reshef L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu Rev Biochem. 1997;66:581–611.PubMedCrossRefGoogle Scholar
  46. 46.
    Lam TK, Carpentier A, Lewis GF, van de Werve G, Fantus IG, Giacca A. Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab. 2003;284:E863–73.PubMedCrossRefGoogle Scholar
  47. 47.
    Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Randle PJ, Newsholme EA, Garland PB. Regulation of glucose uptake by muscle. 8. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. Biochem J. 1964;93:652–65.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Randle PJ, Garland PB, Newsholme EA, Hales CN. The glucose fatty acid cycle in obesity and maturity onset diabetes mellitus. Ann N Y Acad Sci. 1965;131:324–33.PubMedCrossRefGoogle Scholar
  50. 50.
    Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106:171–6.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Gibbons GF, Islam K, Pease RJ. Mobilisation of triacylglycerol stores. Biochim Biophys Acta. 2000;1483:37–57.PubMedCrossRefGoogle Scholar
  52. 52.
    Duplus E, Glorian M, Forest C. Fatty acid regulation of gene transcription. J Biol Chem. 2000;275:30749–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem. 2000;275:8456–60.PubMedCrossRefGoogle Scholar
  54. 54.
    Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell. 1996;87:377–89.PubMedCrossRefGoogle Scholar
  55. 55.
    Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C. Life without white fat: a transgenic mouse. Genes Dev. 1998;12:3168–81.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6:87–97.PubMedCrossRefGoogle Scholar
  57. 57.
    Du K, Herzig S, Kulkarni RN, Montminy M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science. 2003;300:1574–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Baudry A, Jackerott M, Lamothe B, Kozyrev SV, Leroux L, Durel B, Saint-Just S, Joshi RL. Partial rescue of insulin receptor-deficient mice by transgenic complementation with an activated insulin receptor in the liver. Gene. 2002;299:219–25.PubMedCrossRefGoogle Scholar
  59. 59.
    Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell. 2001;104:503–16.PubMedCrossRefGoogle Scholar
  60. 60.
    Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Garg R, Tripathy D, Dandona P. Insulin resistance as a proinflammatory state: mechanisms, mediators, and therapeutic interventions. Curr Drug Targets. 2003;4:487–92.PubMedCrossRefGoogle Scholar
  62. 62.
    Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev. 2002;2:664–74.Google Scholar
  63. 63.
    Miyazaki Y, Pipek R, Mandarino LJ, DeFronzo RA. Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients. Int J Obes Relat Metab Disord. 2003;27:88–94.PubMedCrossRefGoogle Scholar
  64. 64.
    Mingrone G, Rosa G, Di Rocco P, Manco M, Capristo E, Castagneto M, Vettor R, Gasbarrini G, Greco AV. Skeletal muscle triglycerides lowering is associated with net improvement of insulin sensitivity, TNF-alpha reduction and GLUT4 expression enhancement. Int J Obes Relat Metab Disord. 2002;26:1165–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Alexandraki K, Piperi C, Kalofoutis C, Singh J, Alaveras A, Kalofoutis A. Inflammatory process in type 2 diabetes: the role of cytokines. Ann N Y Acad Sci. 2006;1084:89–117.PubMedCrossRefGoogle Scholar
  66. 66.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389:610–4.PubMedCrossRefGoogle Scholar
  67. 67.
    Uysal KT, Wiesbrock SM, Hotamisligil GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology. 1998;139:4832–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Song Y, Miyaki K, Araki J, Zhang L, Omae K, Muramatsu M. The interaction between the interleukin 6 receptor gene genotype and dietary energy intake on abdominal obesity in Japanese men. Metabolism. 2007;56:925–30.PubMedCrossRefGoogle Scholar
  69. 69.
    de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582:97–105.PubMedCrossRefGoogle Scholar
  70. 70.
    Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132:2169–80.PubMedCrossRefGoogle Scholar
  71. 71.
    Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002;277:1531–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005;87:99–109.PubMedCrossRefGoogle Scholar
  73. 73.
    Burgering BM. A brief introduction to FOXOlogy. Oncogene. 2008;27:2258–62.PubMedCrossRefGoogle Scholar
  74. 74.
    Obsil T, Obsilova V. Structure/function relationships underlying regulation of FOXO transcription factors. Oncogene. 2008;27:2263–75.PubMedCrossRefGoogle Scholar
  75. 75.
    Gross DN, van den Heuvel AP, Birnbaum MJ. The role of FoxO in the regulation of metabolism. Oncogene. 2008;27:2320–36.PubMedCrossRefGoogle Scholar
  76. 76.
    Nakae J, Kitamura T, Silver DL, Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest. 2001;108:1359–67.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Barthel A, Schmoll D, Kruger KD, Bahrenberg G, Walther R, Roth RA, Joost HG. Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. Biochem Biophys Res Commun. 2001;285:897–902.PubMedCrossRefGoogle Scholar
  78. 78.
    Buteau J, Accili D. Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. Diabetes Obes Metab. 2007;9(Suppl 2):140–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Nakae J, Kitamura T, Kitamura Y, Biggs WH 3rd, Arden KC, Accili D. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell. 2003;4:119–29.PubMedCrossRefGoogle Scholar
  80. 80.
    Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996;137:354–66.PubMedCrossRefGoogle Scholar
  81. 81.
    Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402:880–3.PubMedCrossRefGoogle Scholar
  82. 82.
    Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998;20:284–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999;20:649–88.PubMedGoogle Scholar
  84. 84.
    Hara K, Kubota N, Tobe K, Terauchi Y, Miki H, Komeda K, Tamemoto H, Yamauchi T, Hagura R, Ito C, Akanuma Y, Kadowaki T. The role of PPARgamma as a thrifty gene both in mice and humans. Br J Nutr. 2000;84(Suppl 2):S235–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Hevener AL, He W, Barak Y, Le J, Bandyopadhyay G, Olson P, Wilkes J, Evans RM, Olefsky J. Muscle-specific Pparg deletion causes insulin resistance. Nat Med. 2003;9:1491–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer B Jr, Reitman ML, Gonzalez FJ. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest. 2003;111:737–47.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Miles PD, Barak Y, He W, Evans RM, Olefsky JM. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest. 2000;105:287–92.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest. 2003;112:608–18.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Rosen ED, Kulkarni RN, Sarraf P, Ozcan U, Okada T, Hsu CH, Eisenman D, Magnuson MA, Gonzalez FJ, Kahn CR, Spiegelman BM. Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis. Mol Cell Biol. 2003;23:7222–9.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–14.PubMedCrossRefGoogle Scholar
  92. 92.
    Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996;45:1661–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Doria A, Patti ME, Kahn CR. The emerging genetic architecture of type 2 diabetes. Cell Metab. 2008;8:186–200.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Flegal KM, Ezzati TM, Harris MI, Haynes SG, Juarez RZ, Knowler WC, Perez-Stable EJ, Stern MP. Prevalence of diabetes in Mexican Americans, Cubans, and Puerto Ricans from the Hispanic health and nutrition examination survey, 1982-1984. Diabetes Care. 1991;14:628–38.PubMedCrossRefGoogle Scholar
  95. 95.
    Weijnen CF, Rich SS, Meigs JB, Krolewski AS, Warram JH. Risk of diabetes in siblings of index cases with type 2 diabetes: implications for genetic studies. Diabet Med. 2002;19:41–50.PubMedCrossRefGoogle Scholar
  96. 96.
    Cauchi S, Choquet H, Gutierrez-Aguilar R, Capel F, Grau K, Proenca C, Dina C, Duval A, Balkau B, Marre M, Potoczna N, Langin D, et al. Effects of TCF7L2 polymorphisms on obesity in European populations. Obesity (Silver Spring). 2008;16:476–82.CrossRefGoogle Scholar
  97. 97.
    Watanabe RM, Allayee H, Xiang AH, Trigo E, Hartiala J, Lawrence JM, Buchanan TA. Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans. Diabetes. 2007;56(5):1481.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Prestwich TC, Macdougald OA. Wnt/beta-catenin signaling in adipogenesis and metabolism. Curr Opin Cell Biol. 2007;19:612–7.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445:881–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Moore AF, Jablonski KA, McAteer JB, Saxena R, Pollin TI, Franks PW, Hanson RL, Shuldiner AR, Knowler WC, Altshuler D, Florez JC. Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program. Diabetes. 2008;57:2503–10.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI, Frayling TM, Walker M. Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function. Diabetes. 2007;56:3101–4.PubMedCrossRefGoogle Scholar
  102. 102.
    Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, Styrkarsdottir U, Gretarsdottir S, Emilsson V, Ghosh S, Baker A, Snorradottir S, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39:770–5.PubMedCrossRefGoogle Scholar
  103. 103.
    Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316:1341–5.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Bostrom KB, et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40:638–45.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi D, Cheskin LJ, Andres R, Roth J, Shuldiner AR. Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes. 1998;47:1806–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Oliver-Krasinski JM, Stoffers DA. On the origin of the beta cell. Genes Dev. 2008;22:1998–2021.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors. Hum Pathol. 1982;13:263–71.PubMedCrossRefGoogle Scholar
  109. 109.
    House MG, Schulick RD. Endocrine tumors of the pancreas. Curr Opin Oncol. 2006;18:23–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Moldow RE, Connelly RR. Epidemiology of pancreatic cancer in Connecticut. Gastroenterology. 1968;55:677–86.PubMedGoogle Scholar
  111. 111.
    O'Grady HL, Conlon KC. Pancreatic neuroendocrine tumours. Eur J Surg Oncol. 2008;34:324–32.PubMedCrossRefGoogle Scholar
  112. 112.
    Larsson LI. Endocrine pancreatic tumors. Hum Pathol. 1978;9:401–16.PubMedCrossRefGoogle Scholar
  113. 113.
    Thompson NW, Eckhauser FE. Malignant islet-cell tumors of the pancreas. World J Surg. 1984;8:940–51.PubMedCrossRefGoogle Scholar
  114. 114.
    Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM. Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer. 2008;15:409–27.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Legaspi A, Brennan MF. Management of islet cell carcinoma. Surgery. 1988;104:1018–23.PubMedGoogle Scholar
  116. 116.
    Scarlett JA, Mako ME, Rubenstein AH, Blix PM, Goldman J, Horwitz DL, Tager H, Jaspan JB, Stjernholm MR, Olefsky JM. Factitious hypoglycemia. Diagnosis by measurement of serum C-peptide immunoreactivity and insulin-binding antibodies. N Engl J Med. 1977;297:1029–32.PubMedCrossRefGoogle Scholar
  117. 117.
    Marks V, Teale JD. Hypoglycemia: factitious and felonious. Endocrinol Metab Clin N Am. 1999;28:579–601.CrossRefGoogle Scholar
  118. 118.
    Marks V, Teale JD. Drug-induced hypoglycemia. Endocrinol Metab Clin N Am. 1999;28:555–77.CrossRefGoogle Scholar
  119. 119.
    Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N, Sutton R, Thakker R, Aylwin S, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54(Suppl 4):iv1–16.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Grant CS. Insulinoma. Surg Oncol Clin N Am. 1998;7:819–44.PubMedGoogle Scholar
  121. 121.
    Nightingale KJ, Davies MG, Kingsnorth AN. Glucagonoma syndrome: survival 24 years following diagnosis. Dig Surg. 1999;16:68–71.PubMedCrossRefGoogle Scholar
  122. 122.
    Stacpoole PW. The glucagonoma syndrome: clinical features, diagnosis, and treatment. Endocr Rev. 1981;2:347–61.PubMedCrossRefGoogle Scholar
  123. 123.
    Krause W. Skin diseases in consequence of endocrine alterations. Aging Male. 2006;9:81–95.PubMedCrossRefGoogle Scholar
  124. 124.
    Akerstrom G, Hellman P. Surgery on neuroendocrine tumours. Best Pract Res. 2007;21:87–109.CrossRefGoogle Scholar
  125. 125.
    de Herder WW. Biochemistry of neuroendocrine tumours. Best Pract Res. 2007;21:33–41.CrossRefGoogle Scholar
  126. 126.
    Nesi G, Marcucci T, Rubio CA, Brandi ML, Tonelli F. Somatostatinoma: clinico-pathological features of three cases and literature reviewed. J Gastroenterol Hepatol. 2008;23:521–6.PubMedCrossRefGoogle Scholar
  127. 127.
    Stephen AE, Hodin RA. Neuroendocrine tumors of the pancreas, excluding gastrinoma. Surg Oncol Clin N Am. 2006;15:497–510.PubMedCrossRefGoogle Scholar
  128. 128.
    Strowski MZ, Blake AD. Function and expression of somatostatin receptors of the endocrine pancreas. Mol Cell Endocrinol. 2008;286:169–79.PubMedCrossRefGoogle Scholar
  129. 129.
    Kleeff J, Beckhove P, Esposito I, Herzig S, Huber PE, Lohr JM, Friess H. Pancreatic cancer microenvironment. Int J Cancer. 2007;121:699–705.PubMedCrossRefGoogle Scholar
  130. 130.
    Ding XZ, Fehsenfeld DM, Murphy LO, Permert J, Adrian TE. Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. Pancreas. 2000;21:310–20.PubMedCrossRefGoogle Scholar
  131. 131.
    Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res. 1996;63:310–3.PubMedCrossRefGoogle Scholar
  132. 132.
    Fienhold MA, Kazakoff K, Pour PM. The effect of streptozotocin and a high-fat diet on BOP-induced tumors in the pancreas and in the submandibular gland of hamsters bearing transplants of homologous islets. Cancer Lett. 1997;117:155–60.PubMedCrossRefGoogle Scholar
  133. 133.
    Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 2001;120:1263–70.PubMedCrossRefGoogle Scholar
  134. 134.
    Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol. 2004;159(12):1160–7. Scholar
  135. 135.
    Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer. 2009;16(4):1103–23. Scholar
  136. 136.
    Ryu TY, Park J, Scherer PE. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J. 2014;38(5):330–6. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Surgery, University HospitalLudwig-Maximilians-UniversityMunichGermany
  2. 2.Institute for Diabetes and CancerHelmholtz Center MunichNeuherbergGermany
  3. 3.Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1Heidelberg University HospitalHeidelbergGermany

Personalised recommendations