THE IMPACT OF OBESITY ON THE DEVELOPMENT OF CERTAIN CANCERS IN PATIENTS WITH TYPE 2 DIABETES. MECHANISMS OF ASSOCIATION

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

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 retro-spective 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 На умовах ліцензії CC BY 4.0 altered cells. In old age, the system of maintenance and restoration of genetic stability weakens that contributes to the survival of damaged cells, which acquire additional properties: the ability to survive in uncomfortable conditions and to avoid apoptosis [23].
The association between obesity and cancer in diabetes is explained by a change in the regulation of metabolic processes and apoptosis at the level of intracellular signaling pathways. The predisposition of patients with T2D with obesity to cancer is connected with insulin resistance, secondary hyperinsulinemia, increasing bioavailability of IGF-1. In hyperinsulinemia, insulin cross-reacts with IGF-1 receptors (IGF-1R) and, conversely, IGF-1 with insulin receptors (IR). The effect of insulin and IGF-1 is accomplished through the stimulation of the PI3K/Akt/mTOR and MAPK/mTOR signalling pathways, which are involved in metabolism control and in oncogenesis [13,18].
Obesity is recogized to be potent factor of cancer of reproductive organs through the influence of dysmetabolic and dyshormonal disorders. Excessive conversion of androgen precursors into oestradiol in adipose tissue causes hyperestrogenemia, a major factor in oncogenesis at these localizations. Prolonged hyperestrogenemia and progesterone deficiency contribute to the development of endometrial cancer. Oestradiol not only accelerates cell proliferation and inhibits apoptosis, but also stimulates local IGF-1 synthesis. Recent studies have shown the ability of insulin and IGF-1 to stimulate endometrial proliferation directly, even without the involvement of oestrogens. Synergistic proliferative effect of IGF-1 and oestrogen has been demonstrated. In addition, increased levels of sex hormones in patients with obesity are due to a decrease in levels of sex hormone-binding globulin (SHBG) due to hyperinsulinemia. Peripheral oestrogen synthesis in adipose tissue is predominant exactly in postmenopausal women with obesity [20]. Scientific studies have proved the mitogenic and mutagenic effects of oestrogens that cause direct or indirect DNA damage, inducing genetic instability and mutations in normal and neoplastic cells of the mammary gland [21].
The effect of obesity on the development of the prostate and colorectal cancer probably has a different explanation than in the case of the organs of the reproductive system. The effects of cytokine imbalance and oxidative stress can be the mechanisms of carcinogenesis. Due to obesity, the increasing of adipocyte size leads to insufficient vascularization of adipose tissue, hypoxia, infiltration of the tissue by macrophages and lymphocytes, which produce many cytokines with proinflammatory effects, including tumor necrosis fac-tor α (TNF-α), interleukin 6 (IL-6), IL-8, IL-18, and others. Each of these factors influences the malignant transformation and progression of cancer [19].
It is proved that hypogonadism, caused by hyperestrogenemia, is inherent for obese men, it reduces the pro-oncogenic effects of testosterone on the cells of prostate. However, the results of a recent study of Céline Lavalette et al. have shown an increased risk of prostate cancer in men with a waist circumference >94.0 cm [(OR=1.20, 95% CI (0.92-1.56)] [4]. In study Francesca Cirillo and co-authors presented data on the dysregulation of microRNAs as potential molecular link between the metabolic changes associated with obesity and the development of colorectal cancer [11].
An additional factor of oncogenesis in colorectal cancer is intestinal dysbiosis, a change in the gut microbiota that is involved in the metabolism of proteins, poly-and oligosaccharides, in endogenous synthesis and in the recirculation of macro-and micronutrients and signaling molecules. Obesity affects the interaction of the microflora with the host, increases intestinal permeability, leads to the leakage of lipopolysaccharides from the gramnegative intestinal bacteria, which promote the development of low-level inflammation and carcinogenesis. These lipopolysaccharides activate the nuclear factor (NF-κB) of the large intestine epitheliocytes, which controls the expression of genes of the immune response, apoptosis, and cell cycle. Gram-positive bacteria, whose amount is low in DM can suppress NF-κB due to their butyrate-producing properties.
Butyrate is one of the short-chain fatty acids (SCFAs) with the prominent anti-inflammatory abilities. The additional value of SCFAs is due to their ability to regulate intestinal motility, facilitating the elimination of products of metabolism, toxins, and carcinogens. The change of qualitative composition of the gut microbiota and the content of SCFAs causes increased concentration of bacterial endotoxins, which leads to the metabolic endotoxicity and to the chronic systemic inflammation [10].
In addition, current studies prove the crucial role of the gut microbiota in the formation of the correct immunological response and immunological response of the body to epigenetic external and internal influences [15]. That is, both diabetes and obesity negatively affect the oncoprotective function of the gut microbiota.
Chronic hyperglycemia, a major manifestation of diabetes, is also a strong factor in oncogenesis in T2D, regardless of BMI. Due to oxidative stress oxidation of intracellular structures takes place, causing DNA damage and changes in genetic control and regulation of cellular apoptosis and survival. In obese patients with insulin resistance, hyperglycemia 21/ Том XXVI / 2 stimulates additional insulin production, which contributes to both hyperinsulinemia and obesity and prooncogenic effects associated with them [5].
Based on the results of the medical records, 533 first diagnosed OD cases were detected in patients with T2D in the period of 2012-2016.
According to the results of the study in patients with T2D, different types of cancer were identified. Most often breast, uterine, pancreatic, skin, and colorectal cancer were diagnosed (Table 1). Age characteristics and body mass index (BMI) of patients with T2D with the most common types of cancer were determined. According to data of Table  2, cancer is most often diagnosed in patients over 60 years of age.

Spectrum and incidence of cancer of different localizations in patients with T2D
Using Bonferoni correction, it was found that BMI of women with cancer of the pancreas was lower than in women with breast, uterine, ovarian, and colorectal cancer (p<0.05). In women with gastric cancer, BMI was lower than in those with breast cancer (p<0.05). In men with prostate cancer and colorectal cancer BMI was higher than in patients with skin (p<0.05), lung (p<0.05) and pancreatic cancer (p<0.05), in men with colorectal cancer BMI was also higher than in patients with gastric cancer (p<0.05) ( Among 322 women, 189 were obese and 133 were not obese; among 211 men, 90 were obese and 121 were not obese. The analysis of differences in the frequency of obesity in patients with T2D with most common localizations of cancer was performed by Yatescorrected χ² (Table 3).
According to the results obtained, the effect of obesity on the incidence of breast cancer in women (x 2 =8.46; p<0.05), prostate cancer (x 2 =7.02; p<0.05) and colorectal cancer (x 2 =7.94; p<0.05) in men was proven, but it does not affect the incidence of cancer of the pancreas, skin, lung and stomach (p<0.05) ( На умовах ліцензії CC BY 4.0 Considering the higher frequency of obesity in patients with breast cancer, prostate cancer and colorectal cancer, the risk of this malignant neoplasms (associated with obesity) was evaluated using the statistical method of the Odds ratio (Table 4).

T a b l e 4
Assessment of cancer risk associated with obesity in patients with T2D  Table 4).
The results of our study proved the prevalence of cancer in elderly patients, as well as the association of obesity with the development of cancer in some localizations.
The results of our study coincide with the data of other scientific studies.
Patients with T2D with obesity require screening to identify mentioned forms of cancer. Normalization of BMI is one of the methods of cancer prevention in patients with T2D.

CONCLUSIONS
1. Among patients with type 2 diabetes, obesity increases the risk of breast cancer in women, prostate cancer and colorectal cancer in men.
2. The mechanisms of association of obesity in diabetes with cancer are hyperglycemia, hyperinsulinemia, cytokine imbalance, hyperestrogenism (in estrogen-dependent cancer), and intestinal dysbiosis (in colorectal cancer).
Further scientific research will be directed to the study of the effect of anti-diabetic drugs of different groups on the development of oncological diseases.
The study is a fragment of the research project "Epidemiology of oncological diseases in patients with diabetes mellitus and the effect of antihyperglycemic drugs on oncogenesis markers" (registration number 0117U005263), included into the complex research work of theIvano-Frankivsk National Medical University -"Pathogenetic mechanisms of development of changes in organs of the respiratory, endocrine, nervous systems in the modeled pathological conditions and their correction" (registration number 0117U001758), without special funding.
Conflict of interests. The authors declare no conflict of interest.