Abstract
Insulin is a peptide hormone that mediates both metabolic and mitogenic effects, and impaired insulin signaling leads to insulin resistance with compensatory hyperinsulinemia.
Insulin resistance and hyperinsulinemia are common attributes to obesity, hypertension, and type 2 diabetes mellitus. All these conditions have been associated with an increased probability of cancer, especially liver, pancreas, prostate, and colorectal cancer. Hyperinsulinemia can drive oncogenesis through an alteration of the activity of several intracellular pathways and increasing cell proliferation. Besides, the inflammatory state elicited by insulin resistance is a determinant in malignization and cancer progression through the overproduction of cytokines and oxygen free radicals that could harm DNA and proteins, contributing to mutagenesis and carcinogenesis. Therefore, sustained high levels of glucose and high levels of reactive oxygen species (ROS) could increase the risk of cancer.
Compared with other types of diabetes treatments, the insulin-sensitizing drug metformin has been shown to decrease cancer incidence. Also, epidemiologic surveys have suggested a relationship between the treatment of insulin resistance and cancer risk; however, these studies are not conclusive, and further evaluation of this relationship is required.
This is a preview of subscription content, log in via an institution to check access.
References
Amin MN, Hussain MS, Sarwar MS et al (2019) How the association between obesity and inflammation may lead to insulin resistance and cancer. Diabet Metab Synd 13(2):1213–1224. https://doi.org/10.1016/j.dsx.2019.01.041
Belfiore A, Malaguarnera R, Vella V et al (2017) Insulin receptor isoforms in physiology and disease: an updated view. Endocr Rev 38(5):379–431. https://doi.org/10.1210/er.2017-00073
Bonomini F, Rodella LF, Rezzani R (2015) Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis 6(2):109–120. https://doi.org/10.14336/ad.2014.0305
Bordeleau L, Yakubovich N, Dagenais GR et al (2014) The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care 37(5):1360–1366. https://doi.org/10.2337/dc13-1468
Brown AK, Webb AE (2018) Regulation of FOXO factors in mammalian cells. Curr Top Dev Biol 127:165–192. https://doi.org/10.1016/bs.ctdb.2017.10.006
Cusi K, Maezono K, Osman A et al (2000) Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105(3):311–320. https://doi.org/10.1172/jci7535
DeFronzo RA, Ferrannini E, Groop L et al (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019. https://doi.org/10.1038/nrdp.2015.19
Deng T, Lyon CJ, Bergin S, Caligiuri MA, Hsueh WA (2016) Obesity, inflammation, and cancer. Annu Rev Pathol 11:421–449. https://doi.org/10.1146/annurev-pathol-012615-044359
Dev R, Bruera E, Dalal S (2018) Insulin resistance and body composition in cancer patients. Ann Oncol 29(Suppl_2):ii18–ii26. https://doi.org/10.1093/annonc/mdx815
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ (Clinical Research ed) 330(7503):1304–1305. https://doi.org/10.1136/bmj.38415.708634.F7
Furer A, Afek A, Sommer A et al (2020) Adolescent obesity and midlife cancer risk: a population-based cohort study of 2.3 million adolescents in Israel. Lancet Diabetes Endocrinol. https://doi.org/10.1016/s2213-8587(20)30019-x
Goodwin PJ, Chlebowski RT (2016) Obesity and cancer: insights for clinicians. J Clin Oncol Off J Am Soc Clin Oncol 34(35):4197–4202. https://doi.org/10.1200/jco.2016.70.5327
Gunter MJ, Hoover DR, Yu H et al (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101(1):48–60. https://doi.org/10.1093/jnci/djn415
Haeusler RA, McGraw TE, Accili D (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19(1):31–44. https://doi.org/10.1038/nrm.2017.89
Harding JL, Andes LJ, Gregg EW et al (2020) Trends in cancer mortality among people with vs without diabetes in the USA, 1988–2015. Diabetologia 63(1):75–84. https://doi.org/10.1007/s00125-019-04991-x
Hoxhaj G, Manning BD (2020) The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 20(2):74–88. https://doi.org/10.1038/s41568-019-0216-7
Hurrle S, Hsu WH (2017) The etiology of oxidative stress in insulin resistance. Biom J 40(5):257–262. https://doi.org/10.1016/j.bj.2017.06.007
Imai K, Takai K, Hanai T, Suetsugu A, Shiraki M, Shimizu M (2019) Homeostatic model assessment of insulin resistance for predicting the recurrence of hepatocellular carcinoma after curative treatment. Int J Mol Sci 20(3). https://doi.org/10.3390/ijms20030605
Kashyap SR, Defronzo RA (2007) The insulin resistance syndrome: physiological considerations. Diab Vasc Dis Res 4(1):13–19. https://doi.org/10.3132/dvdr.2007.001
Keane K, Newsholme P (2014) Metabolic regulation of insulin secretion. Vitam Horm 95:1–33. https://doi.org/10.1016/b978-0-12-800174-5.00001-6
Keane KN, Cruzat VF, Carlessi R, de Bittencourt PI Jr, Newsholme P (2015) Molecular events linking oxidative stress and inflammation to insulin resistance and β-cell dysfunction. Oxidative Med Cell Longev 2015:181643. https://doi.org/10.1155/2015/181643
Kim HJ, Lee S, Chun KH et al (2018) Metformin reduces the risk of cancer in patients with type 2 diabetes: an analysis based on the Korean National Diabetes Program Cohort. Medicine 97(8):e0036. https://doi.org/10.1097/md.0000000000010036
Kobliakov VA (2019) The mechanisms of regulation of aerobic glycolysis (Warburg effect) by Oncoproteins in carcinogenesis. Biochemistry (Mosc) 84(10):1117–1128. https://doi.org/10.1134/s0006297919100018
Kulas JA, Weigel TK, Ferris HA (2020) Insulin resistance and impaired lipid metabolism as a potential link between diabetes and Alzheimer’s disease. Drug Dev Res. https://doi.org/10.1002/ddr.21643
Kwon HJ, Park MI, Park SJ et al (2019) Insulin resistance is associated with early gastric cancer: a prospective multicenter case control study. Gut and Liver 13(2):154–160. https://doi.org/10.5009/gnl17556
Li A, Qiu M, Zhou H, Wang T, Guo W (2017) PTEN, insulin resistance and cancer. Curr Pharm Des 23(25):3667–3676. https://doi.org/10.2174/1381612823666170704124611
Maciejczyk M, Żebrowska E, Chabowski A (2019) Insulin resistance and oxidative stress in the brain: what’s new? Int J Mol Sci 20(4). https://doi.org/10.3390/ijms20040874
Madariaga A, Goodwin PJ, Oza AM (2020) Metformin in gynecologic cancers: opening a new window for prevention and treatment? Clin Cancer Res 26(3):523–525. https://doi.org/10.1158/1078-0432.ccr-19-3645
Maynard G (1910) A statistical study in cancer death-rates. Biometrika 7:276–304
Melvin A, O’Rahilly S, Savage DB (2018) Genetic syndromes of severe insulin resistance. Curr Opin Genet Dev 50:60–67. https://doi.org/10.1016/j.gde.2018.02.002
Nitulescu GM, Van De Venter M, Nitulescu G et al (2018) The Akt pathway in oncology therapy and beyond (review). Int J Oncol 53(6):2319–2331. https://doi.org/10.3892/ijo.2018.4597
Onyango AN (2018) Cellular stresses and stress responses in the pathogenesis of insulin resistance. Oxidative Med Cell Longev 2018:4321714. https://doi.org/10.1155/2018/4321714
Perry RJ, Shulman GI (2020) Mechanistic links between obesity, insulin, and cancer. Trends Cancer 6(2):75–78. https://doi.org/10.1016/j.trecan.2019.12.003
Qi J, He P, Yao H et al (2019) Cancer risk among patients with type 2 diabetes: a real-world study in Shanghai, China. J Diabetes 11(11):878–883. https://doi.org/10.1111/1753-0407.12926
Rani V, Deep G, Singh RK, Palle K, Yadav UC (2016) Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies. Life Sci 148:183–193. https://doi.org/10.1016/j.lfs.2016.02.002
Roden M, Shulman GI (2019) The integrative biology of type 2 diabetes. Nature 576(7785):51–60. https://doi.org/10.1038/s41586-019-1797-8
Scapin G, Dandey VP, Zhang Z et al (2018) Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis. Nature 556(7699):122–125. https://doi.org/10.1038/nature26153
Sciacca L, Vella V, Frittitta L et al (2018) Long-acting insulin analogs and cancer. Nutr Metab Cardiovasc Dis 28(5):436–443. https://doi.org/10.1016/j.numecd.2018.02.010
Shaw LM (2011) The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer. Cell Cycle (Georgetown, Tex) 10(11):1750–1756. https://doi.org/10.4161/cc.10.11.15824
Shlomai G, Neel B, LeRoith D, Gallagher EJ (2016) Type 2 diabetes mellitus and cancer: the role of pharmacotherapy. J Clin Oncol Off J Am Soc Clin Oncol 34(35):4261–4269. https://doi.org/10.1200/jco.2016.67.4044
Soeters MR, Soeters PB (2012) The evolutionary benefit of insulin resistance. Clin Nutr (Edinburgh, Scotland) 31(6):1002–1007. https://doi.org/10.1016/j.clnu.2012.05.011
Tangvarasittichai S (2015) Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 6(3):456–480. https://doi.org/10.4239/wjd.v6.i3.456
Tatulian SA (2015) Structural dynamics of insulin receptor and transmembrane signaling. Biochemistry 54(36):5523–5532. https://doi.org/10.1021/acs.biochem.5b00805
Tini G, Sarocchi M, Tocci G et al (2019) Arterial hypertension in cancer: the elephant in the room. Int J Cardiol 281:133–139. https://doi.org/10.1016/j.ijcard.2019.01.082
Tokarz VL, MacDonald PE, Klip A (2018) The cell biology of systemic insulin function. J Cell Biol 217(7):2273–2289. https://doi.org/10.1083/jcb.201802095
Ugwueze CV, Ogamba OJ, Young EE, Onyenekwe BM, Ezeokpo BC (2020) Metformin: a possible option in cancer chemotherapy. Anal Cell Pathol (Amst) 2020:7180923. https://doi.org/10.1155/2020/7180923
Vella V, Milluzzo A, Scalisi NM, Vigneri P, Sciacca L (2018) Insulin receptor isoforms in cancer. Int J Mol Sci 19(11). https://doi.org/10.3390/ijms19113615
Vigneri R, Goldfine ID, Frittitta L (2016) Insulin, insulin receptors, and cancer. J Endocrinol Investig 39(12):1365–1376. https://doi.org/10.1007/s40618-016-0508-7
Yaribeygi H, Farrokhi FR, Butler AE, Sahebkar A (2019) Insulin resistance: review of the underlying molecular mechanisms. J Cell Physiol 234(6):8152–8161. https://doi.org/10.1002/jcp.27603
Zatterale F, Longo M, Naderi J et al (2019) Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol 10:1607. https://doi.org/10.3389/fphys.2019.01607
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Singapore Pte Ltd.
About this entry
Cite this entry
Monroy, A., Gómez-Laguna, L., Aranda-Flores, C.E., Alavez, S. (2021). Insulin Resistance and Cancer. In: Chakraborti, S., Ray, B.K., Roychowdhury, S. (eds) Handbook of Oxidative Stress in Cancer: Mechanistic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-15-4501-6_147-1
Download citation
DOI: https://doi.org/10.1007/978-981-15-4501-6_147-1
Received:
Accepted:
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-15-4501-6
Online ISBN: 978-981-15-4501-6
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences