Diabetes and Cancer

  • Riccardo VigneriEmail author
  • Laura Sciacca
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Cancer incidence and mortality are higher in diabetic patients. Although epidemiological data on the diabetes-cancer association mainly concern type 2 diabetes, recent data confirm that cancer is increase also in type 1.

The increased incidence of cancer in diabetic patients is documented for many organs (i.e., liver, pancreas, stomach, kidney, endometrium, breast) but not for all (prostate, lung).

Diabetes promotes cancer by multiple mechanisms that are both general (i.e., hyperinsulinemia and hyperglycemia) and site specific (i.e., increased hepatosteatosis and hepatitis in diabetes favor liver cancer).

Also the increased cancer mortality in diabetic patients is due to several mechanisms that, on one side, can make the cancer more aggressive and, on the other side, make the patient a fragile subject because of the frequent chronic complications of diabetes. Moreover, because of these complications, many diabetic patients receive less than optimal cancer therapy.

A matter of concern for cancer promotion is all conditions causing hyperinsulinemia, both endogenous (insulin-resistant diseases with compensatory hyperinsulinemia, like obesity and prediabetes) and exogenous. Treatments with high doses of insulin (with special attention to long-acting analogs) and with secretagogues like sulfonylureas may promote the growth of silent, subclinical tumors. In contrast, metformin, the most used first-line hypoglycemic agents , can decrease cancer risk because of its indirect effect (insulin sensitizer, reducing insulin resistance and hyperinsulinemia) and also with a direct effect, reducing cancer cell proliferation with multiple actions.

One additional problem in patients with diabetes and cancer is the hyperglycemic effect of many cancer drugs. Glucocorticoids, antiandrogens, and recent biological drugs targeting the insulin and IGF-1 signaling pathways may cause hyperglycemia, sometimes severe. This complication can concern patients unaware of diabetes or prediabetes and may adversely affect both patient well-being and cancer progression.

In conclusion, cancer and diabetes are two very prevalent diseases and each one can negatively influence the other one. Cancer-related death accounts for approximately one third of deaths in diabetic patients. It is important, therefore, to promote all preventive measures (often similar for the two diseases) and personalize the treatment according to the features of the diseases and the characteristics of the patient.


Diabetes and cancer Hyperglycemia and cancer Insulin and cancer Hypoglycemic agent and cancer Cancer drugs and hyperglycemia Insulin receptor and cancer 


  1. Aiello A, Pandini G, Frasca F, Conte E, Murabito A, Sacco A, et al. Peroxisomal proliferator-activated receptor-gamma agonists induce partial reversion of epithelial-mesenchymal transition in anaplastic thyroid cancer cells. Endocrinology. 2006;147(9):4463–75.PubMedCrossRefGoogle Scholar
  2. Ariaans G, de Jong S, Gietema JA, Lefrandt JD, de Vries EG, Jalving M. Cancer-drug induced insulin resistance: innocent bystander or unusual suspect. Cancer Treat Rev. 2015;41(4):376–84.PubMedCrossRefGoogle Scholar
  3. Bansal D, Bhansali A, Kapil G, Undela K, Tiwari P. Type 2 diabetes and risk of prostate cancer: a meta-analysis of observational studies. Prostate Cancer Prostatic Dis. 2013;16(2):151–8. S1PubMedCrossRefGoogle Scholar
  4. Bao C, Yang X, Xu W, Luo H, Xu Z, Su C, et al. Diabetes mellitus and incidence and mortality of kidney cancer: a meta-analysis. J Diabetes Complications. 2013;27(4):357–64.PubMedCrossRefGoogle Scholar
  5. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA. 2008;300(23):2754–64.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Barone I, Catalano S, Gelsomino L, Marsico S, Giordano C, Panza S, et al. Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. Cancer Res. 2012;72(6):1416–27.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Barrett-Connor E. Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Ann Intern Med. 1992;117(10):807–11.PubMedCrossRefGoogle Scholar
  8. Basso D, Valerio A, Seraglia R, Mazza S, Piva MG, Greco E, et al. Putative pancreatic cancer-associated diabetogenic factor: 2030 MW peptide. Pancreas. 2002;24(1):8–14.PubMedCrossRefGoogle Scholar
  9. Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev. 2009;30(6):586–623.PubMedCrossRefGoogle Scholar
  10. Ben Q, Xu M, Ning X, Liu J, Hong S, Huang W, et al. Diabetes mellitus and risk of pancreatic cancer: a meta-analysis of cohort studies. Eur J Cancer. 2011;47(13):1928–37.PubMedCrossRefGoogle Scholar
  11. Betancourt-Albrecht M, Cunningham GR. Hypogonadism and diabetes. Int J Impot Res. 2003;15(Suppl 4):S14–20.PubMedCrossRefGoogle Scholar
  12. Bonovas S, Filioussi K, Tsantes A. Diabetes mellitus and risk of prostate cancer: a meta-analysis. Diabetologia. 2004;47(6):1071–8.PubMedCrossRefGoogle Scholar
  13. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29(2):254–8.PubMedCrossRefGoogle Scholar
  14. Brunello A, Kapoor R, Extermann M. Hyperglycemia during chemotherapy for hematologic and solid tumors is correlated with increased toxicity. Am J Clin Oncol. 2011;34(3):292–6.PubMedCrossRefGoogle Scholar
  15. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38.CrossRefGoogle Scholar
  16. Carstensen B, Read SH, Friis S, Sund R, Keskimaki I, Svensson AM, et al. Cancer incidence in persons with type 1 diabetes: a five-country study of 9,000 cancers in type 1 diabetic individuals. Diabetologia. 2016;59(5):980–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Castillo JJ, Mull N, Reagan JL, Nemr S, Mitri J. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood. 2012;119(21):4845–50.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 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(2):504–11.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, et al. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology. 2008;134(1):95–101.PubMedCrossRefGoogle Scholar
  20. Chen HF, Li CY, Chen P, See TT, Lee HY. Seroprevalence of hepatitis B and C in type 2 diabetic patients. J Chin Med Assoc. 2006;69(4):146–52.PubMedCrossRefGoogle Scholar
  21. Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med. 2000;343(18):1305–11.PubMedCrossRefGoogle Scholar
  22. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract. 2009;15(5):469–74.PubMedCrossRefGoogle Scholar
  23. Colhoun HM. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52(9):1755–65.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52(9):1766–77.PubMedCrossRefGoogle Scholar
  26. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 2005;54(4):533–9.PubMedPubMedCentralCrossRefGoogle Scholar
  27. De Block CE, De Leeuw IH, Van Gaal LF. High prevalence of manifestations of gastric autoimmunity in parietal cell antibody-positive type 1 (insulin-dependent) diabetic patients. The Belgian Diabetes Registry. J Clin Endocrinol Metab. 1999;84(11):4062–7.PubMedGoogle Scholar
  28. De Bruijn KM, Arends LR, Hansen BE, Leeflang S, Ruiter R, van Eijck CH. Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. Br J Surg. 2013;100(11):1421–9.PubMedCrossRefGoogle Scholar
  29. Dejgaard A, Lynggaard H, Rastam J, Krogsgaard Thomsen M. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia. 2009;52(12):2507–12.PubMedCrossRefGoogle Scholar
  30. Dibble CC, Cantley LC. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 2015;25(9):545–55.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012;48(3):R31–43.PubMedCrossRefPubMedCentralGoogle Scholar
  32. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol. 2006;4(3):369–80.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Elwing JE, Gao F, Davidson NO, Early DS. Type 2 diabetes mellitus: the impact on colorectal adenoma risk in women. Am J Gastroenterol. 2006;101(8):1866–71.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA. 1995;273(20):1605–9.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Ferrari SM, Materazzi G, Baldini E, Ulisse S, Miccoli P, Antonelli A, et al. Antineoplastic effects of PPARgamma agonists, with a special focus on thyroid cancer. Curr Med Chem. 2016;23:636.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Folsom AR, Anderson KE, Sweeney C, Jacobs DR Jr. Diabetes as a risk factor for death following endometrial cancer. Gynecol Oncol. 2004;94(3):740–5.PubMedCrossRefGoogle Scholar
  38. Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999;19(5):3278–88.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S, Belfiore A, et al. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem. 2008;114(1):23–37.PubMedCrossRefGoogle Scholar
  40. Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia. 2007;50(7):1365–74.PubMedCrossRefGoogle Scholar
  41. Furstenberger G, Senn HJ. Insulin-like growth factors and cancer. Lancet Oncol. 2002;3(5):298–302.PubMedCrossRefGoogle Scholar
  42. Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA. 2000;283(19):2552–8.PubMedCrossRefGoogle Scholar
  43. Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol. 2006;207(1):12–22.PubMedCrossRefGoogle Scholar
  44. Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–28.PubMedCrossRefGoogle Scholar
  45. Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L, et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol. 2007;25(12):1476–81.PubMedCrossRefGoogle Scholar
  46. Grasso LF, Auriemma RS, Pivonello R, Colao A. Adverse events associated with somatostatin analogs in acromegaly. Expert Opin Drug Saf. 2015;14(8):1213–26.PubMedCrossRefGoogle Scholar
  47. Green A, Jensen OM. Frequency of cancer among insulin-treated diabetic patients in Denmark. Diabetologia. 1985;28(3):128–30.PubMedPubMedCentralGoogle Scholar
  48. Guraya SY. Association of type 2 diabetes mellitus and the risk of colorectal cancer: a meta-analysis and systematic review. World J Gastroenterol. 2015;21(19):6026–31.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Harding JL, Shaw JE, Peeters A, Cartensen B, Magliano DJ. Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care. 2015;38(2):264–70.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Harding JL, Shaw JE, Peeters A, Davidson S, Magliano DJ. Age-specific trends from 2000–2011 in all-cause and cause-specific mortality in type 1 and type 2 diabetes: a cohort study of more than one million people. Diabetes Care. 2016;39(6):1018–26.PubMedCrossRefGoogle Scholar
  51. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care. 1998;21(4):518–24.PubMedCrossRefGoogle Scholar
  52. Hassan MM, Curley SA, Li D, Kaseb A, Davila M, Abdalla EK, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer. 2010;116(8):1938–46.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Hemkens LG, Grouven U, Bender R, Gunster C, Gutschmidt S, Selke GW, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52(9):1732–44.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Je Y, Jeon JY, Giovannucci EL, Meyerhardt JA. Association between physical activity and mortality in colorectal cancer: a meta-analysis of prospective cohort studies. Int J Cancer. 2013;133(8):1905–13.PubMedCrossRefGoogle Scholar
  55. Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia. 2009;52(9):1745–54.PubMedCrossRefGoogle Scholar
  56. Kaaks R. Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes Control. 1996;7(6):605–25.PubMedCrossRefGoogle Scholar
  57. Kalli KR, Falowo OI, Bale LK, Zschunke MA, Roche PC, Conover CA. Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. Endocrinology. 2002;143(9):3259–67.PubMedCrossRefGoogle Scholar
  58. Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2056–62.PubMedCrossRefGoogle Scholar
  59. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448–56.PubMedCrossRefGoogle Scholar
  60. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745–51.PubMedCrossRefGoogle Scholar
  61. Kido Y, Nakae J, Accili D. Clinical review 125: the insulin receptor and its cellular targets. J Clin Endocrinol Metab. 2001;86(3):972–9.PubMedGoogle Scholar
  62. Koro C, Barrett S, Qizilbash N. Cancer risks in thiazolidinedione users compared to other anti-diabetic agents. Pharmacoepidemiol Drug Saf. 2007;16(5):485–92.PubMedCrossRefGoogle Scholar
  63. Kuo T, McQueen A, Chen TC, Wang JC. Regulation of glucose homeostasis by glucocorticoids. Adv Exp Med Biol. 2015;872:99–126.PubMedCrossRefGoogle Scholar
  64. Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;49(6):999–1005.CrossRefGoogle Scholar
  65. Labuzek K, Kozlowski M, Szkudlapski D, Sikorska P, Kozlowska M, Okopien B. Incretin-based therapies in the treatment of type 2 diabetes – more than meets the eye? Eur J Intern Med. 2013;24(3):207–12.PubMedCrossRefGoogle Scholar
  66. Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(22):1679–87.PubMedCrossRefGoogle Scholar
  67. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121(4):856–62.PubMedCrossRefGoogle Scholar
  68. Lee JY, Jeon I, Lee JM, Yoon JM, Park SM. Diabetes mellitus as an independent risk factor for lung cancer: a meta-analysis of observational studies. Eur J Cancer. 2013;49(10):2411–23.PubMedCrossRefGoogle Scholar
  69. LeRoith D, Roberts CT Jr. The insulin-like growth factor system and cancer. Cancer Lett. 2003;195(2):127–37.PubMedCrossRefGoogle Scholar
  70. LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007;3(3):302–10.PubMedCrossRefGoogle Scholar
  71. Liao C, Zhang D, Mungo C, Tompkins DA, Zeidan AM. Is diabetes mellitus associated with increased incidence and disease-specific mortality in endometrial cancer? A systematic review and meta-analysis of cohort studies. Gynecol Oncol. 2014;135(1):163–71.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Limburg PJ, Vierkant RA, Fredericksen ZS, Leibson CL, Rizza RA, Gupta AK, et al. Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol. 2006;101(8):1872–9.PubMedCrossRefGoogle Scholar
  73. Lindblad P, Adami HO. Kidney cancer. In: Adami HO, Hunter D, Trichopoulos D, editors. Textbook of cancer epidemiology. New York: Oxford University Press; 2002. p. 467–85.Google Scholar
  74. Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE. The impact of diabetes on survival following breast cancer. Breast Cancer Res Treat. 2008;109(2):389–95.PubMedCrossRefGoogle Scholar
  75. Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006;116(7):1776–83.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Luo W, Cao Y, Liao C, Gao F. Diabetes mellitus and the incidence and mortality of colorectal cancer: a meta-analysis of 24 cohort studies. Colorectal Dis. 2012;14(11):1307–12.PubMedCrossRefGoogle Scholar
  77. Ma J, Li H, Giovannucci E, Mucci L, Qiu W, Nguyen PL, et al. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 2008;9(11):1039–47.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202(3):654–62.CrossRefPubMedGoogle Scholar
  79. Mannucci E, Monami M, Balzi D, Cresci B, Pala L, Melani C, et al. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2010;33(9):1997–2003.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Markussen J, Havelund S, Kurtzhals P, Andersen AS, Halstrom J, Hasselager E, et al. Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs. Diabetologia. 1996;39(3):281–8.PubMedCrossRefGoogle Scholar
  81. Mayer D, Shukla A, Enzmann H. Proliferative effects of insulin analogues on mammary epithelial cells. Arch Physiol Biochem. 2008;114(1):38–44.PubMedCrossRefGoogle Scholar
  82. Meyerhardt JA, Catalano PJ, Haller DG, Mayer RJ, Macdonald JS, Benson AB 3rd, et al. Impact of diabetes mellitus on outcomes in patients with colon cancer. J Clin Oncol. 2003;21(3):433–40.PubMedCrossRefGoogle Scholar
  83. Mitri J, Castillo J, Pittas AG. Diabetes and risk of non-Hodgkin’s lymphoma: a meta-analysis of observational studies. Diabetes Care. 2008;31(12):2391–7.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Monami M, Balzi D, Lamanna C, Barchielli A, Masotti G, Buiatti E, et al. Are sulphonylureas all the same? A cohort study on cardiovascular and cancer-related mortality. Diabetes Metab Res Rev. 2007;23(6):479–84.PubMedCrossRefGoogle Scholar
  85. Muti P, Quattrin T, Grant BJ, Krogh V, Micheli A, Schunemann HJ, et al. Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev. 2002;11(11):1361–8.PubMedGoogle Scholar
  86. Nasrallah SN, Reynolds LR. Insulin degludec, the new generation basal insulin or just another basal insulin? Clin Med Insights Endocrinol Diabetes. 2012;5:31–7.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 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(5):1223–31.PubMedGoogle Scholar
  88. Oldenburg B, Diepersloot RJ, Hoekstra JB. High seroprevalence of Helicobacter pylori in diabetes mellitus patients. Dig Dis Sci. 1996;41(3):458–61.PubMedCrossRefGoogle Scholar
  89. 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(4):981–7.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10(1):88–95.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Papa V, Pezzino V, Costantino A, Belfiore A, Giuffrida D, Frittitta L, et al. Elevated insulin receptor content in human breast cancer. J Clin Invest. 1990;86(5):1503–10.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Pierce JP, Stefanick ML, Flatt SW, Natarajan L, Sternfeld B, Madlensky L, et al. Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol. 2007;25(17):2345–51.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Pocock SJ, Smeeth L. Insulin glargine and malignancy: an unwarranted alarm. Lancet. 2009;374(9689):511–3.PubMedCrossRefGoogle Scholar
  94. Quinn TJ, Yuan Z, Adem A, Geha R, Vrikshajanani C, Koba W, et al. Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. Surgery. 2012;152(6):1068–77.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Ramos-Nino ME, MacLean CD, Littenberg B. Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System. BMC Med. 2007;5:17.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Raz I, Bhatt DL, Hirshberg B, Mosenzon O, Scirica BM, Umez-Eronini A, et al. Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin. Diabetes Care. 2014;37(9):2435–41.PubMedCrossRefGoogle Scholar
  97. Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363(9418):1346–53.PubMedCrossRefGoogle Scholar
  98. Rizos CV, Elisaf MS. Metformin and cancer. Eur J Pharmacol. 2013;705(1–3):96–108.PubMedCrossRefGoogle Scholar
  99. Rizzi M, Trevisan R. Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors. Nutr Metab Cardiovasc Dis. 2016;26(11):963–70.PubMedCrossRefGoogle Scholar
  100. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol. 2009;181:1998.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Sciacca L, Costantino A, Pandini G, Mineo R, Frasca F, Scalia P, et al. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene. 1999;18(15):2471–9.PubMedCrossRefGoogle Scholar
  102. Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli R, Squatrito S, et al. Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia. 2010;53(8):1743–53.PubMedCrossRefGoogle Scholar
  103. Sciacca L, Vigneri R, Tumminia A, Frasca F, Squatrito S, Frittitta L, et al. Clinical and molecular mechanisms favoring cancer initiation and progression in diabetic patients. Nutr Metab Cardiovasc Dis. 2013;23(9):808–15.PubMedCrossRefGoogle Scholar
  104. Sciacca L, Cassarino MF, Genua M, Vigneri P, Giovanna Pennisi M, Malandrino P, et al. Biological effects of insulin and its analogs on cancer cells with different insulin family receptor expression. J Cell Physiol. 2014;229(11):1817–21.PubMedCrossRefGoogle Scholar
  105. Shin HY, Jung KJ, Linton JA, Jee SH. Association between fasting serum glucose levels and incidence of colorectal cancer in Korean men: the Korean Cancer Prevention Study-II. Metabolism. 2014;63(10):1250–6.PubMedCrossRefGoogle Scholar
  106. Shukla A, Grisouard J, Ehemann V, Hermani A, Enzmann H, Mayer D. Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines. Endocr Relat Cancer. 2009;16(2):429–41.PubMedCrossRefGoogle Scholar
  107. Sommerfeld MR, Muller G, Tschank G, Seipke G, Habermann P, Kurrle R, et al. In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PLoS One. 2010;5(3):e9540.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Stadler J, Yeung KS, Furrer R, Marcon N, Himal HS, Bruce WR. Proliferative activity of rectal mucosa and soluble fecal bile acids in patients with normal colons and in patients with colonic polyps or cancer. Cancer Lett. 1988;38(3):315–20.PubMedCrossRefGoogle Scholar
  109. 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(3):507–9.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Suissa S, Azoulay L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care. 2012;35(12):2665–73.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Szlosarek P, Charles KA, Balkwill FR. Tumour necrosis factor-alpha as a tumour promoter. Eur J Cancer. 2006;42(6):745–50.PubMedCrossRefGoogle Scholar
  112. Tang H, Dai Q, Shi W, Zhai S, Song Y, Han J. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60:1862.PubMedCrossRefGoogle Scholar
  113. Vangoitsenhoven R, Mathieu C, Van der Schueren B. GLP1 and cancer: friend or foe? Endocr Relat Cancer. 2012;19(5):F77–88.PubMedCrossRefGoogle Scholar
  114. Vella V, Sciacca L, Pandini G, Mineo R, Squatrito S, Vigneri R, et al. The IGF system in thyroid cancer: new concepts. Mol Pathol. 2001;54(3):121–4.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R, Pezzino V, et al. A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab. 2002;87(1):245–54.PubMedCrossRefGoogle Scholar
  116. Verges B, Cariou B. mTOR inhibitors and diabetes. Diabetes Res Clin Pract. 2015;110(2):101–8.PubMedCrossRefGoogle Scholar
  117. Vigneri R, Squatrito S, Sciacca L. Insulin and its analogs: actions via insulin and IGF receptors. Acta Diabetol. 2010;47(4):271–8.PubMedCrossRefGoogle Scholar
  118. Vigneri R, Vigneri P, Frittitta L. Basal insulin and cardiovascular and other outcomes. N Engl J Med. 2012;367(18):1761–2; author reply 3–4PubMedCrossRefGoogle Scholar
  119. Vigneri PG, Tirro E, Pennisi MS, Massimino M, Stella S, Romano C, et al. The insulin/IGF system in colorectal cancer development and resistance to therapy. Front Oncol. 2015;5:230.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Vissers PA, Cardwell CR, van de Poll-Franse LV, Young IS, Pouwer F, Murray LJ. The association between glucose-lowering drug use and mortality among breast cancer patients with type 2 diabetes. Breast Cancer Res Treat. 2015;150(2):427–37.PubMedCrossRefGoogle Scholar
  121. Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012;130(7):1639–48.PubMedCrossRefGoogle Scholar
  122. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.CrossRefPubMedGoogle Scholar
  123. Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev. 2009;25(1):41–9.PubMedCrossRefGoogle Scholar
  124. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.CrossRefPubMedPubMedCentralGoogle Scholar
  125. Will JC, Galuska DA, Vinicor F, Calle EE. Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol. 1998;147(9):816–25.PubMedCrossRefGoogle Scholar
  126. Williams JA, Goldfine ID. The insulin-pancreatic acinar axis. Diabetes. 1985;34(10):980–6.PubMedCrossRefGoogle Scholar
  127. Wu JW, Filion KB, Azoulay L, Doll MK, Suissa S. The effect of long-acting insulin analogs on the risk of cancer: a systematic review of observational studies. Diabetes Care. 2016;39:486.PubMedCrossRefGoogle Scholar
  128. Xu H, Jiang HW, Ding GX, Zhang H, Zhang LM, Mao SH, et al. Diabetes mellitus and prostate cancer risk of different grade or stage: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2013a;99(3):241–9.PubMedCrossRefGoogle Scholar
  129. Xu X, Wu J, Mao Y, Zhu Y, Hu Z, Lin Y, et al. Diabetes mellitus and risk of bladder cancer: a meta-analysis of cohort studies. PLoS One. 2013b;8(3):e58079.PubMedPubMedCentralCrossRefGoogle Scholar
  130. Yang X, Ko GT, So WY, Ma RC, Yu LW, Kong AP, et al. Associations of hyperglycemia and insulin usage with the risk of cancer in type 2 diabetes: the Hong Kong diabetes registry. Diabetes. 2010;59(5):1254–60.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Yang IP, Tsai HL, Huang CW, Lu CY, Miao ZF, Chang SF, et al. High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2. Oncotarget. 2016;7(14):18837–50.PubMedPubMedCentralGoogle Scholar
  132. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013;18(12):1248–55.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Yuan JM, Castelao JE, Gago-Dominguez M, Ross RK, Yu MC. Hypertension, obesity and their medications in relation to renal cell carcinoma. Br J Cancer. 1998;77(9):1508–13.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Zendehdel K, Nyren O, Ostenson CG, Adami HO, Ekbom A, Ye W. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst. 2003;95(23):1797–800.PubMedCrossRefGoogle Scholar
  135. Zeng L, Biernacka KM, Holly JM, Jarrett C, Morrison AA, Morgan A, et al. Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase. Endocr Relat Cancer. 2010;17(2):539–51.PubMedCrossRefGoogle Scholar
  136. Zhang ZH, Su PY, Hao JH, Sun YH. The role of preexisting diabetes mellitus on incidence and mortality of endometrial cancer: a meta-analysis of prospective cohort studies. Int J Gynecol Cancer. 2013;23(2):294–303.PubMedCrossRefGoogle Scholar
  137. Zhu Z, Wang X, Shen Z, Lu Y, Zhong S, Xu C. Risk of bladder cancer in patients with diabetes mellitus: an updated meta-analysis of 36 observational studies. BMC Cancer. 2013;13:310.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Zucchetto A, Dal Maso L, Tavani A, Montella M, Ramazzotti V, Talamini R, et al. History of treated hypertension and diabetes mellitus and risk of renal cell cancer. Ann Oncol. 2007;18(3):596–600.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Endocrinology, Department of Clinical and Experimental MedicineUniversity of Catania, Garibaldi-Nesima HospitalCataniaItaly

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