Diabetes as the risk of cancer: a literature review

Theodore Dharma Tedjamartono


Cancer is a non-communicable disease with high mortality and morbidity rates. Data recorded by GLOBOCAN in 2018 shows the number of cancer patients is reached 18 million people with a death rate of 9 million people and predicted to increase every year. Diabetes is known to affect morbidity and mortality in cancer patients through increasing cancer cell proliferation and the risk of metastasis. This literature study not only explains the epidemiology, but also the mechanisms underlying the association of diabetes to cancer in general. Literature search was done using four search engines from PubMed, ProQuest, Science Direct and Google Scholar in the last 5 year, but relevant older articles were included. Cancer occurs due to the carcinogenesis process. This process is complex, where normal cells do not immediately mutate and become cancer cells but through several stages. The possible mechanisms underlying carcinogenesis in diabetic patients are hyperglycaemia, hyperinsulinemia, chronic inflammation, genetic variation, obesity, and hyperlactatemia. Examination of sugar levels in cancer patients, as well as cancer screening in patients with diabetes need to be done to detect early events and reduce morbidity and mortality.


Insulin resistance, Hyperglycaemia, Carcinogenesis, Malignancy

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Bao C, Pedersen NL, Yang R, Marseglia A, Xu W, Wang Y, et al. Diabetes in midlife and risk of cancer in late life: A nationwide Swedish twin study. Int J Cancer. 2018;143(4):793-800.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.

Hua F, Yu JJ, Hu ZW. Diabetes and cancer, common threads and missing links. Cancer Lett. 2016;374(1):54-61.

International Diabetes Federation [Internet]. IDF Diabetes Atlas, 9th edn. 2019 [cited 2020 Dec 23]. Available at:

Care D, Suppl SS. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43:S14-31.

Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: A consensus report. Diabetes Care. 2010;33(7):1674-85.

Scappaticcio L, Maiorino MI, Bellastella G, Giugliano D, Esposito K. Insights into the relationships between diabetes, prediabetes, and cancer. Endocrine. 2017;56(2):231-9.

Wojciechowska J, Krajewski W, Bolanowski M, Krecicki T, Zatoński T. Diabetes and Cancer: A Review of Current Knowledge. Exp Clin Endocrinol Diabetes. 2016;124(5):263-75.

Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer. 2009;16(4):1103-23.

Lega IC, Wilton AS, Austin PC, Fischer HD, Johnson JA, Lipscombe LL. The temporal relationship between diabetes and cancer: A population-based study. Cancer. 2016;122(17):2731-8.

Saarela K, Tuomilehto J, Sund R, Keskimäki I, Hartikainen S, Pukkala E. Cancer incidence among Finnish people with type 2 diabetes during. Eur J Epidemiol. 2019;34(3):259-65.

Ballotari P, Vicentini M, Manicardi V, Gallo M, Ranieri CS, Greci M, et al. Diabetes and risk of cancer incidence: Results from a population-based cohort study in northern Italy. BMC Cancer. 2017;17(1):1-8.

Pitot HC. The molecular biology of carcinogenesis. Cancer. 1993;72(3 S):962-70.

Sutandyo N. Diabetes Mellitus as One of the Risk Factors Contribute to Carcinogenesis. Indones J Cancer. 2020;14(2):64.

Wang M, Yang Y, Liao Z. Diabetes and cancer: Epidemiological and biological links. World J Diabetes. 2020;11(6):227-38.

Huxley R, Ansary-Moghaddam A, Berrington De González A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: A meta-analysis of 36 studies. Br J Cancer. 2005;92(11):2076-83.

Jing W, Jin G, Zhou X, Zhou Y, Zhang Y, Shao C, et al. Diabetes mellitus and increased risk of cholangiocarcinoma: a meta-analysis. Eur J Cancer Prev. 2012;21(1):24-31.

Luo S, Li JY, Zhao LN, Yu T, Zhong W, Xia ZS, et al. Diabetes mellitus increases the risk of colorectal neoplasia: An updated meta-analysis. Clin Res Hepatol Gastroenterol. 2016;40(1):110-23.

Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121(4):856-62.

Person P. Otto warburg: “on the origin of cancer cells.” Oral Surgery, Oral Med Oral Pathol. 1957;10(4):412-21.

Bellier J, Nokin MJ, Lardé E, Karoyan P, Peulen O, Castronovo V, et al. Methylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer. Diabetes Res Clin Pract. 2019;148:200-11.

Ryu TY, Park J, Scherer PE. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J. 2014;38(5):330-6.

Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T. Zinc homeostasis and signaling in health and diseases. J Biol Inorg Chem. 2011;16(7):1123-34.

Pirola L, Balcerczyk A, Okabe J, El-Osta A. Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol. 2010;6(12):665-75.

Xu J, Ye Y, Wu H, Duerksen-Hughes P, Zhang H, Li P, et al. Association between markers of glucose metabolism and risk of colorectal cancer. BMJ Open. 2016;6(6).

Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646-74.

Li Zyue, Yang Y, Ming M, Liu B. Mitochondrial ROS generation for regulation of autophagic pathways in cancer. Biochem Biophys Res Commun. 2011;414(1):5-8.

Godsland IF. Insulin resistance and hyperinsulinaemia in the development and progression of cancer. Clin Sci. 2010;118(5):315-32.

Denley A, Carroll JM, Brierley GV, Cosgrove L, Wallace J, Forbes B, et al. Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors. Mol Cell Biol. 2007;27(10):3569-77.

Vigneri R, Goldfine ID, Frittitta L. Insulin, insulin receptors, and cancer. J Endocrinol Invest. 2016;39(12):1365-76.

Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4(7):505-18.

Wong KK, Engelman JA, Cantley LC. Targeting the PI3K pathway in cancer. Curr Opin Genet Dev. 2009;8(8):627-44.

Zoncu R, Efeyan A, Sabatini DM. MTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35.

Lega IC, Lipscombe LL. Review: Diabetes, Obesity, and Cancer-Pathophysiology and Clinical Implications. Endocr Rev. 2020;41(1):33-52.

Clemmons DR, Maile LA, Ling Y, Yarber J, Busby WH. Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycaemic stress. Growth Horm IGF Res. 2007;17(4):265-70.

Fuchs O, Sheiner E, Meirovitz M, Davidson E, Sergienko R, Kessous R. The association between a history of gestational diabetes mellitus and future risk for female malignancies. Arch Gynecol Obstet. 2017;295(3):731-6.

Park YMM, O’Brien KM, Zhao S, Weinberg CR, Baird DD, Sandler DP. Gestational diabetes mellitus may be associated with increased risk of breast cancer. Br J Cancer. 2017;116(7):960-3.

Bejaimal SAD, Wu CF, Lowe J, Feig DS, Shah BR, Lipscombe LL. Short-term risk of cancer among women with previous gestational diabetes: A population-based study. Diabet Med. 2016;33(1):39-46.

Powe CE, Tobias DK, Michels KB, Chen WY, Eliassen H, Manson JE, et al. HHS Public Access. 2018;1-15.

Van Den Brandt PA, Spiegelman D, Yaun SS, Adami HO, Beeson L, Folsom AR, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol. 2000;152(6):514-27.

Xie C, Wang W, Li X, Shao N, Li W. Gestational diabetes mellitus and maternal breast cancer risk: a meta-analysis of the literature. J Matern Neonatal Med. 2019;32(6):1022-32.

Lori M. Millner, Mark W. Linder and RVJ. HHS Public Access. Physiol Behav. 2019;176(3):139-48.

Crusz SM, Balkwill FR. Inflammation and cancer: Advances and new agents. Nat Rev Clin Oncol. 2015;12(10):584-96.

Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019;120(1):6-15.

Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, et al. IL-23/IL-17-mediated tumour growth. Nature. 2013;491(7423):254-8.

Purrington KS, Slager S, Eccles D, Yannoukakos D, Fasching PA, Miron P, et al. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. Carcinogenesis. 2014;35(5):1012-9.

Vincent EE, Yaghootkar H. Using genetics to decipher the link between type 2 diabetes and cancer: shared aetiology or downstream consequence? Diabetologia. 2020;63(9):1706-17.

Folsom AR, Pankow JS, Peacock JM, Bielinski SJ, Heiss G, Boerwinkle E. Variation in TCF7L2 and Increased Risk of Colon Cancer: The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 2008;31(5):905-9.

Freeman. HHS Public Access. Physiol Behav. 2018;176(1):139-48.

Zhang B, Jia W, Matsuda K, Kweon S, Matsuo K, Xiang B, et al. HHS Public Access. 2014;46(6):533-42.

Burwinkel B, Shanmugam KS, Hemminki K, Meindl A, Schmutzler RK, Sutter C, et al. Transcription factor 7-like 2 (TCF7L2) variants is associated with familial breast cancer risk: A case-control study. BMC Cancer. 2006;6:7-10.

Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Milne RL, Schmidt MK, et al. NIH Public Access. 2014;45(4):353-61.

Agalliu I, Suuriniemi M, Prokunina-Olsson L, Johanneson B, Collins FS, Stanford JL, et al. Evaluation of a variant in the transcription factor 7-like 2 (TCF7L2) gene and prostate cancer risk in a population-based study. Prostate. 2008;68(7):740-7.

Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and cancer: Local and systemic mechanisms. Annu Rev Med. 2015;66:297-309.

Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk: New mechanistic insights from epidemiology. Nat Rev Cancer. 2015;15(8):484-98.

Van Kruijsdijk RCM, Van Der Wall E, Visseren FLJ. Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009;18(10):2569-78.

Somasundar P, Yu AK, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res. 2003;113(1):50-5.

Wu Y, Dong Y, Atefi M, Liu Y, Elshimali Y, Vadgama JV. Lactate, a Neglected Factor for Diabetes and Cancer Interaction. Mediators Inflamm. 2016;2016.

Romero-Garcia S, Moreno-Altamirano MMB, Prado-Garcia H, Sánchez-García FJ. Lactate contribution to the tumor microenvironment: Mechanisms, effects on immune cells and therapeutic relevance. Front Immunol. 2016;7.

Thorburn AW, Gumbiner B, Bulacan F, Wallace P, Henry RR. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. J Clin Invest. 1990;85(2):522-9.

Bokhari S, Emerson P, Israelian Z, Gupta A, Meyer C. Metabolic fate of plasma glucose during hyperglycemia in impaired glucose tolerance: Evidence for further early defects in the pathogenesis of type 2 diabetes. Am J Physiol - Endocrinol Metab. 2009;296(3):440-4.

DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: The missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-87.

Feichtinger RG, Lang R. Targeting L-Lactate Metabolism to Overcome Resistance to Immune Therapy of Melanoma and Other Tumor Entities. J Oncol. 2019.

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 - J Am Med Assoc. 2008;300(23):2754-64.

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.

Gallagher EJ, LeRoith D. Obesity and diabetes: The increased risk of cancer and cancer-related mortality. Physiol Rev. 2015;95(3):727-48.

Ranc K, Jørgensen ME, Friis S, Carstensen B. Mortality after cancer among patients with diabetes mellitus: Effect of diabetes duration and treatment. Diabetologia. 2014;57(5):927-34.

Baena-Díez JM, Peñafiel J, Subirana I, Ramos R, Elosua R, Marín-Ibañez A, et al. Risk of cause-specific death in individuals with diabetes: A competing risks analysis. Diabetes Care. 2016;39(11):1987-95.

Tancredi M, Rosengren A, Svensson AM, Kosiborod M, Pivodic A, Gudbjörnsdottir S, et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med. 2015;373(18):1720-32.

Ge XJ, Du YX, Zheng LM, Wang M, Jiang JY. Mortality trends of liver cancer among patients with type 2 diabetes at the global and national level. J Diabetes Complications. 2020;34(8):107612.