Activation of intracellular enzyme systems under the influence of pathogenetic factors of oncogenesis in patients with type 2 diabetes mellitus
Keywords:diabetes mellitus, hyperinsulinemia, risk of cancer, signaling pathways
Background. It is proved that patients with diabetes mellitus (DM) have an increased risk of cancer. The main factors of oncogenesis in DM are obesity, cytokine imbalance, hyperinsulinemia (HI), hyperglycemia. These disorders cause dysfunction of the intracellular regulatory signaling pathways, the main of which is PI3K/Akt/mTOR. The purpose of the work was to study the role of phosphorylated Akt-protein kinase (phospho-Akt) in the oncogenesis processes in patients with type 2 DM. Materials and methods. Seventy-five people were examined. Patients were divided into groups: І — healthy, ІІ — persons with DM type 2, ІІІ — patients with cancer, IV — patients with cancer and DM type 2. Patients with breast, endometrial, pancreatic and intestinal cancer were included in the study. The levels of insulin, insulin-like growth factor 1 (IGF-1) and phospho-Akt were determined. Results. Patients of groups II and IV had a decompensated DM with HbA1c level > 8.0 %. Reliable HI was found in patients with DM in groups II and IV (p < 0.05), IGF-1 level was increased in all study groups (p < 0.05). Levels of phospho-Akt in patients from groups II and III were elevated (p < 0.05) and in group IV — reduced (p < 0.05). In the third group, HI in patients with breast, endometrial and intestinal cancer (p < 0.05) was detected, as well as elevation of IGF-1 regardless of localization (p < 0.05). In group IV, increased content of insulin and IGF-1 were detected in patients with breast and endometrial cancer (p < 0.05). In women from group III with breast and endometrial cancer, the level of IGF-1 was higher than that of group IV (p < 0.05). In patients treated with metformin monotherapy, phospho-Akt level was significantly lower (p < 0.05). There was a direct correlation between phospho-Akt and IGF-1 in patients of group II (r = 0.50; p < 0.05) and between phospho-Akt and insulin in group III (r = 0.45; p < 0.05). Conclusions. HI and IGF-1 are common pathogenetic factors of type 2 DM and cancer. The elevated level of phospho-Akt can serve as a laboratory indicator of cancer risk in healthy individuals. The combination of type 2 DM and cancer causes a decrease in phospho-Akt due to the competitive interaction of intracellular signaling pathways. Metformin therapy helps to reduce phospho-Akt level and can be considered as one of the ways to prevent cancer.
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 Feb;38(2):264-70. doi: 10.2337/dc14-1996.
Oberaigner W, Ebenbichler C, Oberaigner K, Juchum M, Schönherr HR, Lechleitner M. Increased cancer incidence risk in type 2 diabetes mellitus: results from a cohort study in Tyrol/Austria. BMC Public Health. 2014 Oct 10;14:1058. doi: 10.1186/1471-2458-14-1058.
Vatseba TS, Sokolova LK. Pathogenegenetic mechanisms of oncogenesis in diabetes mellitus and analysis of cancer incidence in patients with diabetes mellitus in the Precarpathian region. Endokrynologia. 2018;2(23):128-136. (in Ukrainian).
Li ZJ, Yang XL, Yao Y, Han WQ, Li BO. Circulating adiponectin levels and risk of endometrial cancer: Systematic review and meta analysis. Exp Ther Med. 2016 Jun;11(6):2305-2313. doi: 10.3892/etm.2016.3251.
Sun XF, Shao YB, Liu MG, et al. High-concentration glucose enhances invasion in invasive ductal breast carcinoma by promoting Glut1/MMP2/MMP9 axis expression. Oncol Lett. 2017 May;13(5):2989-2995. doi: 10.3892/ol.2017.5843.
Gristina V, Cupri MG, Torchio M, Mezzogori C, Cacciabue L, Danova M. Diabetes and cancer: А critical appraisal of the pathogenetic and therapeutic links. Biomed Rep. 2015 Mar;3(2):131-136. doi: 10.3892/br.2014.399.
Pushkarev VM, Sokolova LK, Pushkarev VV, Tronko MD. The role of AMPK and mTOR in the development of insulin resistance and type 2 diabetes. The mechanism of metformin action (literature review). Problemi endokrinnoi patologii. 2016;(57):77-90. (in Russsian).
Farese RV, Sajan MP. Metabolic functions of atypical protein kinase C: "good" and "bad" as defined by nutritional status. Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E385-94. doi: 10.1152/ajpendo.00608.2009.
Ong PS, Wang LZ, Dai X, Tseng SH, Loo SJ, Sethi G. Judicious toggling of mTOR activity to combat insulin resistance and cancer: current evidence and perspectives. Front Pharmacol. 2016 Oct 25;7:395. doi: 10.3389/fphar.2016.00395.
How to Cite
Copyright (c) 2019 T.S. Vatseba
This work is licensed under a Creative Commons Attribution 4.0 International License.