The impact of obesity on the development of certain cancers in patients with type 2 diabetes

Abstract

The impact of obesity on the development of certain cancers in patients with type 2 diabetes. Mechanisms of association. Vatseba T.S., Sokolova L.K., Tronko M.D., Churpiy I.K., Vatseba M.O., Derpak V.V. The aim of the study was to investigate the effect of obesity on the development of cancer of certain localizations in patients with type 2 diabetes mellitus (T2D) and to explain the association mechanisms of obesity in diabetes and cancer. The study included retrospective analysis of first time diagnosed cancer cases in patients with T2D in 2012-2016 in IvanoFrankivsk region. Analysis of the data was carried out using Statistica 12.0 (StatSoft Inc., USA) program. The data are presented in the tables as M±SD (M± standard deviation). Differences between the studied parameters were determined using the ANOVAtest, taking into account the Bonferroni correction. The relationship between the studied data was evaluated using the criterion of chi-square with Yates correction (χ2). The odds ratio (OR), 95% confidence interval, the positive and negative predictive value were calculated to determine the association between two events. The differences were considered significant at p<0.05. According to the results, 533 cases of the first time diagnosed cancer were detected in patients with T2D. It was found that obesity is inherent in women with breast, uterine, ovarian and colorectal cancer; for men with prostate cancer and with colorectal cancer. According to the criterion of χ2, the effect of obesity on the incidence of breast cancer in women (x=8.46; p<0.05), and prostate cancer (x=7.02; p<0.05) and colorectal cancer (x=7.94; p<0.05) in men was proven. OR revealed an increased risk of breast cancer in women [OR=2.06; 95% CI (1.28-3.29); p<0.05], and prostate cancer [OR=2.94; 95% CI (1.37-6.32); p<0.05] and colorectal cancer [OR=2.87; 95% CI (1.42-5.82); p<0.05] in men associated with obesity. Thus, among patients with T2D, obesity increases the risk of breast cancer in women, prostate cancer and colorectal cancer in men. The mechanisms of association of obesity and cancer in patients with T2D are hyperglycemia, hyperinsulinemia, cytokine imbalance, hyperestrogenism (in estrogen-dependent cancer), and intestinal dysbiosis (in colorectal cancer). Реферат. Вплив ожиріння на розвиток певних видів раку у хворих на цукровий діабет 2 типу. Механізми асоціації. Вацеба Т.С., Соколова Л.К., Тронько М.Д., Чурпій І.К., Вацеба М.О., Дерпак В.В. Метою дослідження було вивчити вплив ожиріння на розвиток раку певних локалізацій у пацієнтів з цукровим діабетом (ЦД) 2 типу та пояснити механізми асоціації ожиріння та онкологічних захворювань у хворих з діабетом. Дослідження включало ретроспективний аналіз медичних карт хворих на ЦД 2 типу, жителів Івано-Франківської області, з уперше діагностованими онкологічними захворюваннями впродовж 2012-2016 років. Для аналізу даних використовували програму Statistica 12.0 (StatSoft Inc., США). Дані представлені в таблицях у вигляді M±SD (M± стандартне відхилення). Відмінності між досліджуваними показниками визначали за допомогою тесту ANOVA, з урахуванням поправки Бонфероні. Взаємозв язок між досліджуваними даними оцінювали за критерієм хі-квадрат з корекцією Йєтса (χ2). Коефіцієнт шансів (OR), 95% довірчий інтервал, позитивне та негативне прогноcтичне значення були розраховані для визначення асоціації між явищами. Відмінності вважалися достовірними при p<0,05. Виявлено 533 випадки вперше діагностованих МЕДИЧНІ ПЕРСПЕКТИВИ / MEDICNI PERSPEKTIVI 89 21/ Том XXVI / 2 онкологічних захворювань у пацієнтів з ЦД 2 типу. Встановлено, що ожиріння притаманне жінкам з раком молочної залози, тіла матки, яєчників і товстого кишечнику, для чоловіків – зі злоякісними новоутвореннями передміхурової залози та колоректальним раком. За критерієм χ2 виявлений вплив ожиріння на частоту злоякісних пухлин молочної залози в жінок (x=8,46; p<0,05), раку передміхурової залози (x=7,02; p<0,05) та колоректального раку (x=7,94; p<0,05) у чоловіків. За методом відношення шансів у хворих на ЦД 2 типу виявлений асоційований з ожирінням підвищений ризик раку молочної залози в жінок [OR=2,06; 95% CI (1,283,29); p<0,05], передміхурової залози [OR=2,94; 95% CI (1,37-6,32); p<0,05] та колоректальної локалізації [OR=2,87; 95% CI (1,42-5,82); p<0,05] у чоловіків. Таким чином, у хворих на ЦД 2 типу із ожирінням виявлений підвищений ризик раку молочної залози в жінок, простати та колоректального раку в чоловіків. Механізмами асоціації ожиріння та раку у хворих на ЦД 2 типу є гіперглікемія, гіперінсулінемія, дисбаланс цитокінів, гіперестрогенія (при естроген-залежних пухлинах) та дисбіоз кишечнику (при колоректальному раку). Effective treatment of patients with diabetes mellitus (DM) and oncological diseases (OD) remains a priority of scientific and practical medicine. As of 2019, 463 million patients with diabetes have been identified worldwide [8]. Given the rate of spread, experts from the World Health Organization (WHO) estimate that the number of patients with diabetes will increase to 625 million by 2040 [22]. Along with the increase in the incidence of diabetes, a progressive increase in the frequency of OD is noted [6]. According to the National Cancer Institute in Ukraine, for the last ten years, the number of patients with malignant neoplasms has increased by 25%. According to the data of the cancer registry in Ukraine in 2017, a statistically significant increase in general morbidity in men by 1.6% and in women – by 1.2% was registered [16]. Recent studies prove an increased risk of cancer in patients with type 2 diabetes (T2D) [9]. Pathogenetic factors of diabetes (hyperglycemia, hyperinsulinemia, obesity, cytokine imbalance, oxidative stress) are recognized as potential factors of oncogenesis [17]. Dysmetabolic disorders change the activity of intracellular regulatory systems-signalling pathways that, in addition to metabolism, control the processes of cell apoptosis and survival. Obesity is an important pathogenetic factor of T2D, which significantly increases risk of cancer. The understanding of the mechanisms of the association of T2D, obesity with cancer is important for the prevention and treatment of both diseases. The research is aimed to study the effects of obesity on the development of cancer of certain localizations in patients with T2D and to explain the association mechanisms of obesity, cancer and diabetes. MATERIALS AND METHODS OF RESEARCH The study was conducted following the guidelines of the Declaration of Helsinki (1975) and its revised version of 1983. The study included the selection and analysis of clinical records of patients with T2D (inpatient and outpatient), who were first diagnosed with cancer in 2012-2016 in Ivano-Frankivsk region of Ukraine. The bases of the retrospective epidemiological study were: Precarpathian Clinical Oncology Center, Ivano-Frankivsk Regional Clinical Hospital and medical institutions in the Ivano-Frankivsk region. Selection of persons was carried out in accordance with the requirements for epidemiological studies [3]. The results of scientific research and own data were used to explain the mechanisms of association of obesity in diabetes with cancer. Analysis of the data was carried out using Statistica 12.0 program [14]. The data are presented in the tables as M±SD (M± standard deviation). Differences between the studied parameters were determined using the test One-way ANOVA, taking into account the Bonferroni correction. The relationship between the study data was investigated by Yates-corrected chi-square (χ2). The odds ratio (OR), 95% confidence interval, the positive and negative predictive values were calculated to determine the risk of predicted events. The differences were considered significant at p<0.05 [1, 7]. RESULTS AND DISCUSSION The results of scientific studies prove the high incidence of different types of cancer in obese patients with T2D at age over 60 [2, 9]. It was proved that aging and carcinogenesis are interrelated [12]. The prevalence of cancer in older people can be associated with the processes of cellular aging. Aging, on the one hand, is a process of protection against cancer, but on the other hand, the age is recognized to be a major risk factor for cancer. There is a theory that the genes that are responsible for protection against cancer exhaust their useful effects during the reproductive age and are not effective enough in the elderly. DNA damage is a major factor that triggers oncogenesis. Reactive oxygen species and oxidative stress in diabetes are endogenous factors of DNA damage. The physiological response to DNA damage is manifested in the activation of cascades of specific kinases and genes that ultimately affect the cell cycle, either slowing it down (to allow time to repair the damage) or, if repair is not possible, leading to apoptosis of