Download PDF
Exp Clin Endocrinol Diabetes 2016; 124(05): 263-275
DOI: 10.1055/s-0042-100910
Review
© Georg Thieme Verlag KG Stuttgart · New York

Diabetes and Cancer: a Review of Current Knowledge

J. Wojciechowska
1   Department and Clinic of Otolaryngology, Head and Neck Surgery, Wrocław Medical University Hospital, Borowska 213, Wrocław
,
W. Krajewski
2   Department and Clinic of Urology, Wrocław Medical University Hospital, Borowska 213, Wrocław
,
M. Bolanowski
3   Clinic of Endocrinology, Diabetology and Isotope Treatment, Wybrzeże Pasteura 4, Wrocław
,
T. Kręcicki
1   Department and Clinic of Otolaryngology, Head and Neck Surgery, Wrocław Medical University Hospital, Borowska 213, Wrocław
,
T. Zatoński
1   Department and Clinic of Otolaryngology, Head and Neck Surgery, Wrocław Medical University Hospital, Borowska 213, Wrocław
› Author Affiliations
Further Information

Publication History

received 27 September 2015
first decision 21 September 2015

accepted 13 January 2016

Publication Date:
24 May 2016 (online)

Also available at
    Permissions and Reprints

Abstract

Diabetes mellitus (DM), one of the most common life-threatening illnesses worldwide, is a group of metabolic diseases, characterized by sustained hyperglycemia. The global prevalence of diabetes mellitus among adults reached 387 millions in 2014 and is still rising. It is suggested there is a strong association between diabetes mellitus (especially type 2 diabetes mellitus) and carcinogenesis. The possible biological links between diabetes mellitus and cancer comprise hyperinsulinemia, hyperglycemia and fat-induced chronic inflammation. Although, the strongest association refers to pancreas and liver, there are many other organs involved in carcinogenesis in diabetic patients including breast, endometrium, bladder and kidney.

Recent studies suggest that there is also association between cancer incidence and anti-diabetic medications. It was observed that some medications decrease the risk of carcinogenesis and some increase that risk. The majority of studies concern metformin, a drug of choice in type 2 diabetes mellitus, and its anti-neoplastic and tumor-suppressing activity. The positive effect of metformin was found in numerous researches investigating breast, pancreas, liver, colon, ovaries and prostate tumors.

Because a variety of studies have suggested that diabetes mellitus and cancer are frequently coexisting diseases, recently published studies try to explain the influence of diabetes mellitus and anti-diabetic medications on carcinogenesis in different organs.

We present the review of the latest studies investigating the association between both diabetes mellitus and anti-diabetic medications and cancer incidence and prognosis.

Particularly we highlight the problem of concomitant head and neck cancers in diabetics, rarely analysed and often omitted in studies.

Key words

antidiabetic medications - cancer - diabetes
 

  • References

  • 1 Giovannucci E, Harlan DM, Archer MC et al. Diabetes and cancer: a consensus report. Diabetes Care 2010; 33: 1674-1685
    CrossrefPubMedGoogle Scholar
  • 2 Jee SH, Ohrr H, Sull JW et al. Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005; 293: 194-202
    CrossrefPubMedGoogle Scholar
  • 3 Tseng KS, Lin C, Lin YS et al. Risk of head and neck cancer in patients with diabetes mellitus: a retrospective cohort study in Taiwan. JAMA Otolaryngol Head Neck Surg 2014; 140: 746-753
    CrossrefPubMedGoogle Scholar
  • 4 Noto H, Tsujimoto T, Sasazuki T et al. Significantly increased risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Endocr Pract 2011; 17: 616-628
    CrossrefPubMedGoogle Scholar
  • 5 Zendehdel K, Nyren O, Ostenson CG et al. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 2003; 95: 1797-1800
    CrossrefPubMedGoogle Scholar
  • 6 Decensi A, Puntoni M, Goodwin P et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 2010; 3: 1451-1461
    CrossrefPubMedGoogle Scholar
  • 7 Vigneri P, Frasca F, Sciacca L et al. Diabetes and cancer. Endocr Relat Cancer 2009; 16: 1103-1123
    CrossrefPubMedGoogle Scholar
  • 8 Shu X, Ji J, Li X et al. Cancer risk among patients hospitalized for Type 1 diabetes mellitus: a population-based cohort study in Sweden. Diabet Med 2010; 27: 791-797
    CrossrefPubMedGoogle Scholar
  • 9 Gallagher EJ, LeRoith D. Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. Ann N Y Acad Sci 2011; 1243: 54-68
    CrossrefPubMedGoogle Scholar
  • 10 Kourelis TV, Siegel RD. Metformin and cancer: new applications for an old drug. Med Oncol 2012; 29: 1314-1327
    CrossrefPubMedGoogle Scholar
  • 11 Belfiore A. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 2007; 13: 671-686
    CrossrefPubMedGoogle Scholar
  • 12 Kiselyov VV, Versteyhe S, Gauguin L et al. Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation. Mol Syst Biol 2009; 5: 243
    PubMedGoogle Scholar
  • 13 Cui Y, Andersen DK. Diabetes and pancreatic cancer. Endocr Relat Cancer 2012; 19: F9-F26
    CrossrefPubMedGoogle Scholar
  • 14 Del Barco S, Vazquez-Martin A, Cufi S et al. Metformin: multi-faceted protection against cancer. Oncotarget 2011; 2: 896-917
    CrossrefPubMedGoogle Scholar
  • 15 Noto H, Goto A, Tsujimoto T et al. Latest insights into the risk of cancer in diabetes. J Diabetes Investig 2013; 4: 225-232
    CrossrefPubMedGoogle Scholar
  • 16 Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY) 2010; 2: 760-774
    PubMedGoogle Scholar
  • 17 Memmott RM, Dennis PA. LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin. J Clin Oncol 2009; 27: e226 author reply e227
    CrossrefPubMedGoogle Scholar
  • 18 Baxter RC, Brown AS, Turtle JR. Association between serum insulin, serum somatomedin and liver receptors for human growth hormone in streptozotocin diabetes. Horm Metab Res 1980; 12: 377-381
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Friberg E, Mantzoros CS, Wolk A. Diabetes and risk of endometrial cancer: a population-based prospective cohort study. Cancer Epidemiol Biomarkers Prev 2007; 16: 276-280
    CrossrefPubMedGoogle Scholar
  • 20 van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 2009; 18: 2569-2578
    CrossrefPubMedGoogle Scholar
  • 21 Somasundar P, Yu AK, Vona-Davis L et al. Differential effects of leptin on cancer in vitro. J Surg Res 2003; 113: 50-55
    CrossrefPubMedGoogle Scholar
  • 22 Adekola K, Rosen ST, Shanmugam M. Glucose transporters in cancer metabolism. Curr Opin Oncol 2012; 24: 650-654
    CrossrefPubMedGoogle Scholar
  • 23 Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029-1033
    CrossrefPubMedGoogle Scholar
  • 24 Ryu TY, Park J, Scherer PE. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J 2014; 38: 330-336
    CrossrefPubMedGoogle Scholar
  • 25 Fukada T, Yamasaki S, Nishida K et al. Zinc homeostasis and signaling in health and diseases: Zinc signaling. J Biol Inorg Chem 2011; 16: 1123-1134
    CrossrefPubMedGoogle Scholar
  • 26 Li D. Diabetes and pancreatic cancer. Mol Carcinog 2012; 51: 64-74
    CrossrefPubMedGoogle Scholar
  • 27 Siebel AL, Fernandez AZ, El-Osta A. Glycemic memory associated epigenetic changes. Biochem Pharmacol 2010; 80: 1853-1859
    CrossrefPubMedGoogle Scholar
  • 28 Johnson JA, Bowker SL. Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia 2011; 54: 25-31
    CrossrefPubMedGoogle Scholar
  • 29 Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat Rev Cancer 2015; 15: 484-498
    CrossrefPubMedGoogle Scholar
  • 30 Grossmann ME, Nkhata KJ, Mizuno NK et al. Effects of adiponectin on breast cancer cell growth and signaling. Br J Cancer 2008; 98: 370-379
    CrossrefPubMedGoogle Scholar
  • 31 O'Rourke RW. Obesity and cancer: at the crossroads of cellular metabolism and proliferation. Surg Obes Relat Dis 2014; 10: 1208-1219
    CrossrefPubMedGoogle Scholar
  • 32 Balasubramanyam M. Diabetic oncopathy – one more yet another deadly diabetic complication!. Indian J Med Res 2014; 140: 15-18
    PubMedGoogle Scholar
  • 33 Ben Q, Xu M, Ning X et al. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur J Cancer 2011; 47: 1928-1937
    CrossrefPubMedGoogle Scholar
  • 34 Elena JW, Steplowski E, Yu K et al. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control 2013; 24: 13-25
    CrossrefPubMedGoogle Scholar
  • 35 Hsu C, Saif MW. Diabetes and pancreatic cancer. Highlights from the “2011 ASCO Annual Meeting”. Chicago, IL, USA; June 3–7, 2011. JOP. 2011 12. 330-333
    PubMedGoogle Scholar
  • 36 Prizment AE, Gross M, Rasmussen-Torvik L et al. Genes related to diabetes may be associated with pancreatic cancer in a population-based case-control study in Minnesota. Pancreas 2012; 41: 50-53
    CrossrefPubMedGoogle Scholar
  • 37 Pierce BL, Austin MA, Ahsan H. Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes Control 2011; 22: 877-883
    CrossrefPubMedGoogle Scholar
  • 38 Butler AE, Galasso R, Matveyenko A et al. Pancreatic duct replication is increased with obesity and type 2 diabetes in humans. Diabetologia 2010; 53: 21-26
    CrossrefPubMedGoogle Scholar
  • 39 Davila JA, Morgan RO, Shaib Y et al. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005; 54: 533-539
    CrossrefPubMedGoogle Scholar
  • 40 Lawson DH, Gray JM, McKillop C et al. Diabetes mellitus and primary hepatocellular carcinoma. Q J Med 1986; 61: 945-955
    PubMedGoogle Scholar
  • 41 Dyson J, Jaques B, Chattopadyhay D et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014; 60: 110-117
    CrossrefPubMedGoogle Scholar
  • 42 Wang C, Wang X, Gong G 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: 1639-1648
    CrossrefPubMedGoogle Scholar
  • 43 Noureddin M, Rinella ME. Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015; 19: 361-379
    CrossrefPubMedGoogle Scholar
  • 44 Wiencke JK. Impact of race/ethnicity on molecular pathways in human cancer. Nat Rev Cancer 2004; 4: 79-84
    CrossrefPubMedGoogle Scholar
  • 45 Wang P, Kang D, Cao W et al. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 2012; 28: 109-122
    CrossrefPubMedGoogle Scholar
  • 46 Ueyama M, Nishida N, Korenaga M et al. The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus. J Gastroenterol. 2015
    PubMedGoogle Scholar
  • 47 Gao C, Yao SK. Diabetes mellitus: a “true” independent risk factor for hepatocellular carcinoma?. Hepatobiliary Pancreat Dis Int 2009; 8: 465-473
    PubMedGoogle Scholar
  • 48 Liao S, Li J, Wei W et al. Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature. Asian Pac J Cancer Prev 2011; 12: 1061-1065
    PubMedGoogle Scholar
  • 49 Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007; 121: 856-862
    CrossrefPubMedGoogle Scholar
  • 50 Novosyadlyy R, Lann DE, Vijayakumar A et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 2010; 70: 741-751
    CrossrefPubMedGoogle Scholar
  • 51 Joh HK, Willett WC, Cho E. Type 2 diabetes and the risk of renal cell cancer in women. Diabetes Care 2011; 34: 1552-1556
    CrossrefPubMedGoogle Scholar
  • 52 Inoue M, Iwasaki M, Otani T et al. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med 2006; 166: 1871-1877
    CrossrefPubMedGoogle Scholar
  • 53 Svacina S. Tumours of kidneys, urinary bladder and prostate in obesity and diabetes. Vnitr Lek 2008; 54: 464-467
    PubMedGoogle Scholar
  • 54 Lucenteforte E, Bosetti C, Talamini R et al. Diabetes and endometrial cancer: effect modification by body weight, physical activity and hypertension. Br J Cancer 2007; 97: 995-998
    CrossrefPubMedGoogle Scholar
  • 55 Chen HF, Liu MD, Chen P et al. Risks of Breast and Endometrial Cancer in Women with Diabetes: A Population-Based Cohort Study. PLoS One 2013; 8: e67420
    CrossrefPubMedGoogle Scholar
  • 56 Lambe M, Wigertz A, Garmo H et al. Impaired glucose metabolism and diabetes and the risk of breast, endometrial, and ovarian cancer. Cancer Causes Control 2011; 22: 1163-1171
    CrossrefPubMedGoogle Scholar
  • 57 Sun L, Yu S. Diabetes mellitus is an independent risk factor for colorectal cancer. Dig Dis Sci 2012; 57: 1586-1597
    CrossrefPubMedGoogle Scholar
  • 58 Wu L, Yu C, Jiang H et al. Diabetes mellitus and the occurrence of colorectal cancer: an updated meta-analysis of cohort studies. Diabetes Technol Ther 2013; 15: 419-427
    CrossrefPubMedGoogle Scholar
  • 59 Woolcott CG, Maskarinec G, Haiman CA et al. Diabetes and urothelial cancer risk: the Multiethnic Cohort study. Cancer Epidemiol 2011; 35: 551-554
    CrossrefPubMedGoogle Scholar
  • 60 Zhu Z, Wang X, Shen Z et al. Risk of bladder cancer in patients with diabetes mellitus: an updated meta-analysis of 36 observational studies. BMC Cancer 2013; 13: 310
    CrossrefPubMedGoogle Scholar
  • 61 Xu X, Wu J, Mao Y et al. Diabetes mellitus and risk of bladder cancer: a meta-analysis of cohort studies. PLoS One 2013; 8: e58079
    CrossrefPubMedGoogle Scholar
  • 62 Nakamura K, Wada K, Tamai Y et al. Diabetes mellitus and risk of cancer in Takayama: a population-based prospective cohort study in Japan. Cancer Sci 2013; 104: 1362-1367
    CrossrefPubMedGoogle Scholar
  • 63 Bosetti C, Rosato V, Polesel J et al. Diabetes mellitus and cancer risk in a network of case-control studies. Nutr Cancer 2012; 64: 643-651
    CrossrefPubMedGoogle Scholar
  • 64 Kuriki K, Hirose K, Tajima K. Diabetes and cancer risk for all and specific sites among Japanese men and women. Eur J Cancer Prev 2007; 16: 83-89
    CrossrefPubMedGoogle Scholar
  • 65 Stott-Miller M, Chen C, Chuang SC et al. History of diabetes and risk of head and neck cancer: a pooled analysis from the international head and neck cancer epidemiology consortium. Cancer Epidemiol Biomarkers Prev 2012; 21: 294-304
    CrossrefPubMedGoogle Scholar
  • 66 Atchison EA, Gridley G, Carreon JD et al. Risk of cancer in a large cohort of U.S. veterans with diabetes. Int J Cancer 2011; 128: 635-643
    CrossrefPubMedGoogle Scholar
  • 67 Tseng CH. Oral cancer in Taiwan: is diabetes a risk factor?. Clin Oral Investig 2013; 17: 1357-1364
    CrossrefPubMedGoogle Scholar
  • 68 Stott-Miller M, Chen C, Schwartz SM. Type II diabetes and metabolic syndrome in relation to head and neck squamous cell carcinoma risk: a SEER-Medicare database study. Cancer Epidemiol 2013; 37: 428-433
    CrossrefPubMedGoogle Scholar
  • 69 Becker C, Jick SS, Meier CR et al. Metformin and the risk of head and neck cancer: a case-control analysis. Diabetes Obes Metab 2014; 16: 1148-1154
    CrossrefPubMedGoogle Scholar
  • 70 Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006; 15: 2056-2062
    CrossrefPubMedGoogle Scholar
  • 71 Waters KM, Henderson BE, Stram DO et al. Association of diabetes with prostate cancer risk in the multiethnic cohort. Am J Epidemiol 2009; 169: 937-945
    CrossrefPubMedGoogle Scholar
  • 72 Bansal D, Bhansali A, Kapil G et al. Type 2 diabetes and risk of prostate cancer: a meta-analysis of observational studies. Prostate Cancer Prostatic Dis 2013; 16: 151-158 S151
    PubMedGoogle Scholar
  • 73 Li Q, Kuriyama S, Kakizaki M et al. History of diabetes mellitus and the risk of prostate cancer: the Ohsaki Cohort Study. Cancer Causes Control 2010; 21: 1025-1032
    CrossrefPubMedGoogle Scholar
  • 74 Onitilo AA, Engel JM, Glurich I et al. Diabetes and cancer II: role of diabetes medications and influence of shared risk factors. Cancer Causes Control 2012; 23: 991-1008
    CrossrefPubMedGoogle Scholar
  • 75 Simo R, Plana-Ripoll O, Puente D et al. Impact of glucose-lowering agents on the risk of cancer in type 2 diabetic patients. The Barcelona case-control study. PLoS One 2013; 8: e79968
    CrossrefPubMedGoogle Scholar
  • 76 Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52: 1766-1777
    CrossrefPubMedGoogle Scholar
  • 77 Brunetti L, Kalabalik J. Management of type-2 diabetes mellitus in adults: focus on individualizing non-insulin therapies. PT 2012; 37: 687-696
    PubMedGoogle Scholar
  • 78 Rattan R, Ali Fehmi R, Munkarah A. Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. J Oncol 2012; 2012: 928127
    PubMedGoogle Scholar
  • 79 Evans JM, Donnelly LA, Emslie-Smith AM et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304-1305
    CrossrefPubMedGoogle Scholar
  • 80 Rosta A. Diabetes and cancer risk: oncologic considerations. Orv Hetil 2011; 152: 1144-1155
    CrossrefPubMedGoogle Scholar
  • 81 Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2012; 2: 778-790
    CrossrefPubMedGoogle Scholar
  • 82 Pollak M. Potential applications for biguanides in oncology. J Clin Invest 2013; 123: 3693-3700
    CrossrefPubMedGoogle Scholar
  • 83 Miller RA, Chu Q, Xie J et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494: 256-260
    CrossrefPubMedGoogle Scholar
  • 84 Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A 2013; 110: 972-977
    CrossrefPubMedGoogle Scholar
  • 85 Pearce EL, Walsh MC, Cejas PJ et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460: 103-107
    CrossrefPubMedGoogle Scholar
  • 86 Mani SA, Guo W, Liao MJ et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704-715
    CrossrefPubMedGoogle Scholar
  • 87 Hirsch HA, Iliopoulos D, Tsichlis PN et al. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69: 7507-7511
    CrossrefPubMedGoogle Scholar
  • 88 Hollier BG, Evans K, Mani SA. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 2009; 14: 29-43
    CrossrefPubMedGoogle Scholar
  • 89 Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253-262
    CrossrefPubMedGoogle Scholar
  • 90 Tadakawa M, Takeda T, Li B et al. The anti-diabetic drug metformin inhibits vascular endothelial growth factor expression via the mammalian target of rapamycin complex 1/hypoxia-inducible factor-1alpha signaling pathway in ELT-3 cells. Mol Cell Endocrinol 2015; 399: 1-8
    CrossrefPubMedGoogle Scholar
  • 91 Kim HG, Hien TT, Han EH et al. Metformin inhibits P-glycoprotein expression via the NF-kappaB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol 2011; 162: 1096-1108
    CrossrefPubMedGoogle Scholar
  • 92 Anisimov VN, Berstein LM, Egormin PA et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 2005; 40: 685-693
    CrossrefPubMedGoogle Scholar
  • 93 Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S et al. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 2011; 126: 355-364
    CrossrefPubMedGoogle Scholar
  • 94 Jiralerspong S, Palla SL, Giordano SH et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009; 27: 3297-3302
    CrossrefPubMedGoogle Scholar
  • 95 Li D, Yeung SC, Hassan MM et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009; 137: 482-488
    CrossrefPubMedGoogle Scholar
  • 96 Bodmer M, Becker C, Meier C et al. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol 2012; 107: 620-626
    CrossrefPubMedGoogle Scholar
  • 97 Zhang ZJ, Zheng ZJ, Shi R et al. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012; 97: 2347-2353
    CrossrefPubMedGoogle Scholar
  • 98 Lee MS, Hsu CC, Wahlqvist ML et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011; 11: 20
    CrossrefPubMedGoogle Scholar
  • 99 Singh S, Singh H, Singh PP et al. Antidiabetic medications and the risk of colorectal cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2013; 22: 2258-2268
    CrossrefPubMedGoogle Scholar
  • 100 Bodmer M, Becker C, Meier C et al. Use of metformin is not associated with a decreased risk of colorectal cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev 2012; 21: 280-286
    CrossrefPubMedGoogle Scholar
  • 101 Murtola TJ, Tammela TL, Lahtela J et al. Antidiabetic medication and prostate cancer risk: a population-based case-control study. Am J Epidemiol 2008; 168: 925-931
    CrossrefPubMedGoogle Scholar
  • 102 Preston MA, Riis AH, Ehrenstein V et al. Metformin use and prostate cancer risk. Eur Urol 2014; 66: 1012-1020
    CrossrefPubMedGoogle Scholar
  • 103 Kato H, Sekine Y, Furuya Y et al. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. 2015
    PubMedGoogle Scholar
  • 104 Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control 2009; 20: 1617-1622
    CrossrefPubMedGoogle Scholar
  • 105 Tan BX, Yao WX, Ge J et al. Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer 2011; 117: 5103-5111
    CrossrefPubMedGoogle Scholar
  • 106 Lai SW, Liao KF, Chen PC et al. Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan. Clin Lung Cancer 2012; 13: 143-148
    CrossrefPubMedGoogle Scholar
  • 107 Gotlieb WH, Saumet J, Beauchamp MC et al. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol 2008; 110: 246-250
    CrossrefPubMedGoogle Scholar
  • 108 Febbraro T, Lengyel E, Romero IL. Old drug, new trick: Repurposing metformin for gynecologic cancers? Gynecol Oncol 2014; 135: 614-621
    PubMed
  • 109 Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W et al. The effects of metformin on ovarian cancer: a systematic review. Int J Gynecol Cancer 2013; 23: 1544-1551
    CrossrefPubMedGoogle Scholar
  • 110 Yang FQ, Wang JJ, Yan JS et al. Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells. Int J. Clin Exp Med 2014; 7: 3289-3296
    PubMedGoogle Scholar
  • 111 Liu J, Li M, Song B et al. Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft. Urol Oncol 2013; 31: 264-270
    CrossrefPubMedGoogle Scholar
  • 112 Rego DF, Pavan LM, Elias ST et al. Effects of metformin on head and neck cancer: A systematic review. Oral Oncol 2015; 51: 416-422
    CrossrefPubMedGoogle Scholar
  • 113 Sikka A, Kaur M, Agarwal C et al. Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation. Cell Cycle 2012; 11: 1374-1382
    CrossrefPubMedGoogle Scholar
  • 114 Sandulache VC, Hamblin JS, Skinner HD et al. Association between metformin use and improved survival in patients with laryngeal squamous cell carcinoma. Head Neck 2014; 36: 1039-1043
    CrossrefPubMedGoogle Scholar
  • 115 Yen YC, Lin C, Lin SW et al. Effect of metformin on the incidence of head and neck cancer in diabetics. Head Neck 2014;
    PubMedGoogle Scholar
  • 116 Yasukagawa T, Niwa Y, Simizu S et al. Suppression of cellular invasion by glybenclamide through inhibited secretion of platelet-derived growth factor in ovarian clear cell carcinoma ES-2 cells. FEBS Lett 2012; 586: 1504-1509
    CrossrefPubMedGoogle Scholar
  • 117 Chang CH, Lin JW, Wu LC et al. Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus. J Clin Endocrinol Metab 2012; 97: E1170-E1175
    CrossrefPubMedGoogle Scholar
  • 118 Hsieh MC, Lee TC, Cheng SM et al. The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. Exp Diabetes Res 2012; 2012: 413782
    PubMedGoogle Scholar
  • 119 Yang X, So WY, Ma RC et al. Use of sulphonylurea and cancer in type 2 diabetes-The Hong Kong Diabetes Registry. Diabetes Res Clin Pract 2010; 90: 343-351
    CrossrefPubMedGoogle Scholar
  • 120 Pasello G, Urso L, Conte P et al. Effects of sulfonylureas on tumor growth: a review of the literature. Oncologist 2013; 18: 1118-1125
    CrossrefPubMedGoogle Scholar
  • 121 Monami M, Lamanna C, Balzi D et al. Sulphonylureas and cancer: a case-control study. Acta Diabetol 2009; 46: 279-284
    CrossrefPubMedGoogle Scholar
  • 122 Gonzalez-Perez A, Garcia Rodriguez LA. Prostate cancer risk among men with diabetes mellitus (Spain). Cancer Causes Control 2005; 16: 1055-1058
    CrossrefPubMedGoogle Scholar
  • 123 Buchs AE, Silverman BG. Incidence of malignancies in patients with diabetes mellitus and correlation with treatment modalities in a large Israeli health maintenance organization: a historical cohort study. Metabolism 2011; 60: 1379-1385
    CrossrefPubMedGoogle Scholar
  • 124 Blin P, Lassalle R, Dureau-Pournin C et al. Insulin glargine and risk of cancer: a cohort study in the French National Healthcare Insurance Database. Diabetologia 2012; 55: 644-653
    CrossrefPubMedGoogle Scholar
  • 125 Dejgaard A, Lynggaard H, Rastam J et al. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia 2009; 52: 2507-2512
    CrossrefPubMedGoogle Scholar
  • 126 Karlstad O, Starup-Linde J, Vestergaard P et al. Use of insulin and insulin analogs and risk of cancer – systematic review and meta-analysis of observational studies. Curr Drug Saf 2013; 8: 333-348
    CrossrefPubMedGoogle Scholar
  • 127 Colmers IN, Bowker SL, Tjosvold LA et al. Insulin use and cancer risk in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies. Diabetes Metab 2012; 38: 485-506
    CrossrefPubMedGoogle Scholar
  • 128 Ruiter R, Visser LE, van Herk-Sukel MP et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia 2012; 55: 51-62
    CrossrefPubMedGoogle Scholar
  • 129 Teng JA, Hou RL, Li DL et al. Glargine promotes proliferation of breast adenocarcinoma cell line MCF-7 via AKT activation. Horm Metab Res 2011; 43: 519-523
    Article in Thieme ConnectPubMedGoogle Scholar
  • 130 Aizen D, Sarfstein R, Bruchim I et al. Proliferative and signaling activities of insulin analogues in endometrial cancer cells. Mol Cell Endocrinol 2015; 406: 27-39
    CrossrefPubMedGoogle Scholar
  • 131 Qin J, Teng JA, Zhu Z et al. Glargine Promotes Human Colorectal Cancer Cell Proliferation via Upregulation of miR-95. Horm Metab Res 2015;
    PubMedGoogle Scholar
  • 132 Stammberger I, Essermeant L. Insulin glargine: a reevaluation of rodent carcinogenicity findings. Int J Toxicol 2012; 31: 137-142
    CrossrefPubMedGoogle Scholar
  • 133 Lim S, Stember KG, He W. Electronic medical record cancer incidence over six years comparing new users of glargine with new users of NPH insulin. PLoS One 2014; 9: e109433
    CrossrefPubMedGoogle Scholar
  • 134 Bordeleau L, Yakubovich N, Dagenais GR et al. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care 2014; 37: 1360-1366
    CrossrefPubMedGoogle Scholar
  • 135 Govindarajan R, Ratnasinghe L, Simmons DL et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 2007; 25: 1476-1481
    CrossrefPubMedGoogle Scholar
  • 136 Monami M, Dicembrini I, Mannucci E. Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials. Acta Diabetol 2014; 51: 91-101
    CrossrefPubMedGoogle Scholar
  • 137 Wei S, Yang J, Lee SL et al. PPARgamma-independent antitumor effects of thiazolidinediones. Cancer Lett 2009; 276: 119-124
    CrossrefPubMedGoogle Scholar
  • 138 Weng JR, Chen CY, Pinzone JJ et al. Beyond peroxisome proliferator-activated receptor gamma signaling: the multi-facets of the antitumor effect of thiazolidinediones. Endocr Relat Cancer 2006; 13: 401-413
    CrossrefPubMedGoogle Scholar
  • 139 Shiau CW, Yang CC, Kulp SK et al. Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARgamma. Cancer Res 2005; 65: 1561-1569
    CrossrefPubMedGoogle Scholar
  • 140 Colmers IN, Bowker SL, Johnson JA. Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2012; 38: 475-484
    CrossrefPubMedGoogle Scholar
  • 141 Feng YH, Velazquez-Torres G, Gully C et al. The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med 2011; 15: 825-836
    CrossrefPubMedGoogle Scholar
  • 142 Frohlich E, Wahl R. Chemotherapy and Chemoprevention by Thiazolidinediones. Biomed Res Int 2015; 2015: 845340
    PubMedGoogle Scholar
  • 143 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
    CrossrefPubMedGoogle Scholar
  • 144 Ferwana M, Firwana B, Hasan R et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med 2013; 30: 1026-1032
    CrossrefPubMedGoogle Scholar
  • 145 Jin SM, Song SO, Jung CH et al. Risk of bladder cancer among patients with diabetes treated with a 15 mg pioglitazone dose in Korea: a multi-center retrospective cohort study. J Korean Med Sci 2014; 29: 238-242
    CrossrefPubMedGoogle Scholar
  • 146 Turner RM, Kwok CS, Chen-Turner C et al. Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis. Br J Clin Pharmacol 2014; 78: 258-273
    CrossrefPubMedGoogle Scholar
  • 147 Ferrara A, Lewis JD, Quesenberry Jr CP et al. Cohort study of pioglitazone and cancer incidence in patients with diabetes. Diabetes Care 2011; 34: 923-929
    CrossrefPubMedGoogle Scholar
  • 148 Chang CH, Lin JW, Wu LC et al. Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology 2012; 55: 1462-1472
    CrossrefPubMedGoogle Scholar
  • 149 Joshi H, Pal T, Ramaa CS. A new dawn for the use of thiazolidinediones in cancer therapy. Expert Opin Investig Drugs 2014; 23: 501-510
    CrossrefPubMedGoogle Scholar
  • 150 Kumagai T, Ikezoe T, Gui D et al. RWJ-241947 (MCC-555), a unique peroxisome proliferator-activated receptor-gamma ligand with antitumor activity against human prostate cancer in vitro and in beige/nude/X-linked immunodeficient mice and enhancement of apoptosis in myeloma cells induced by arsenic trioxide. Clin Cancer Res 2004; 10: 1508-1520
    CrossrefPubMedGoogle Scholar
  • 151 Yamaguchi K, Lee SH, Eling TE et al. A novel peroxisome proliferator-activated receptor gamma ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells. Mol Cancer Ther 2006; 5: 1352-1361
    CrossrefPubMedGoogle Scholar
  • 152 Min KW, Zhang X, Imchen T et al. A peroxisome proliferator-activated receptor ligand MCC-555 imparts anti-proliferative response in pancreatic cancer cells by PPARgamma-independent up-regulation of KLF4. Toxicol Appl Pharmacol 2012; 263: 225-232
    CrossrefPubMedGoogle Scholar
  • 153 Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32: 193-203
    CrossrefPubMedGoogle Scholar
  • 154 Samson SL, Garber A. GLP-1R agonist therapy for diabetes: benefits and potential risks. Curr Opin Endocrinol Diabetes Obes 2013; 20: 87-97
    CrossrefPubMedGoogle Scholar
  • 155 Hegedus L, Moses AC, Zdravkovic M. Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 2011; 96: 853-860
    CrossrefPubMedGoogle Scholar
  • 156 Nauck MA, Friedrich N. Do GLP-1-based therapies increase cancer risk?. Diabetes Care 2013; 36 (Suppl. 02) S245-252
    CrossrefPubMedGoogle Scholar
  • 157 Tella SH, Rendell MS. DPP-4 inhibitors: focus on safety. Expert Opin Drug Saf 2015; 14: 127-140
    CrossrefPubMedGoogle Scholar
  • 158 Tseng CH, Lee KY, Tseng FH. An updated review on cancer risk associated with incretin mimetics and enhancers. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2015; 33: 67-124
    CrossrefPubMedGoogle Scholar
  • 159 Zhao H, Wang L, Wei R et al. Activation of glucagon-like peptide-1 receptor inhibits tumourigenicity and metastasis of human pancreatic cancer cells via PI3K/Akt pathway. Diabetes Obes Metab 2014; 16: 850-860
    CrossrefPubMedGoogle Scholar
  • 160 Chalmer T, Almdal TP, Vilsboll T et al. Adverse drug reactions associated with the use of liraglutide in patients with type 2 diabetes – focus on pancreatitis and pancreas cancer. Expert Opin Drug Saf 2015; 14: 171-180
    CrossrefPubMedGoogle Scholar
  • 161 Nomiyama T, Kawanami T, Irie S et al. Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth. Diabetes 2014; 63: 3891-3905
    CrossrefPubMedGoogle Scholar
  • 162 Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells. Endocrinology 2011; 152: 3362-3372
    CrossrefPubMedGoogle Scholar
  • 163 Ligumsky H, Wolf I, Israeli S et al. The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat 2012; 132: 449-461
    CrossrefPubMedGoogle Scholar
  • 164 Gokhale M, Buse JB, Gray CL et al. Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study. Diabetes Obes Metab 2014; 16: 1247-1256
    CrossrefPubMedGoogle Scholar
  • 165 Farag SS, Srivastava S, Messina-Graham S et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev 2013; 22: 1007-1015
    CrossrefPubMedGoogle Scholar
  • 166 Femia AP, Raimondi L, Maglieri G et al. Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats. Int J Cancer 2013; 133: 2498-2503
    CrossrefPubMedGoogle Scholar
  • 167 Itou M, Kawaguchi T, Taniguchi E et al. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol 2013; 19: 2298-2306
    CrossrefPubMedGoogle Scholar
  • 168 Kissow H, Hartmann B, Holst JJ et al. Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice. Regul Pept 2012; 179: 91-100
    CrossrefPubMedGoogle Scholar
  • 169 Chen YL, Cheng KC, Lai SW et al. Diabetes and risk of subsequent gastric cancer: a population-based cohort study in Taiwan. Gastric Cancer 2013; 16: 389-396
    CrossrefPubMedGoogle Scholar
  • 170 Lai SW, Liao KF, Lai HC et al. Kidney cancer and diabetes mellitus: a population-based case-control study in Taiwan. Ann Acad Med Singapore 2013; 42: 120-124
    PubMedGoogle Scholar