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Address for CorrespondenCe:

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RoLE oF oxIDATIVE STRESS IN FoRMATIoN MECHANISMS oF GASTRoESoPHAGEAL REFLUx DISEASE IN PATIENTS wITH

DIABETES MELLITUS TYPE II AND ITS CoRRECTIoNoparin a.a., oparin a.G., kudriavtSev a.a.*

Department of Therapy, Rheumatology and Clinical Pharmacology, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine

ABSTrAcT

Present study was aimed to investigate the role of oxidative stress in the formation mecha-nisms of gastroesophageal reflux disease in patients with diabetes mellitus type II and to develop methods for its correction.

Two groups of people with mild and moderate severe diabetes mellitus type II with concomi-tant gastroesophageal reflux disease were observed. The first included 28 patients aged 35 to 45 years who received standard treatment and actovegin. The second group consisted of 25 patients of the same sex and age who received only basic therapy. The third experimental group included 27 patients with gastroesophageal reflux disease without concomitant pathology of the same age group. In all patients, the level of antioxidant protection, lipid peroxidation and regional blood flow in the celiac trunk were determined.

In the course of the study, we found that while treating patients with diabetes mellitus type II with concomitant gastroesophageal reflux disease both in patients of the first and second groups, a clear tendency of decreasing the clinical manifestations of the disease was determined, and the glycemic index was normalized.

We found that after a 4-week course of therapy in patients of both treatment groups, the indi-ces of antioxidant protection of esophageal mucosa increased, and the indices of lipid peroxida-tion decreased. In patients the diameter of the celiac trunk increased, and the blood flow velocity in it improved. While in patients of the second control group, who received only the standard treatment, the dynamics of blood flow in the celiac trunk was significantly less.

The introduction of actovegin in the standard treatment regimen of patients with diabetes mel-litus type II with concomitant gastroesophageal reflux disease reduces the timing of the onset of clinical remission of both the underlying disease and concomitant disease, and also increases the activity of antioxidant protection of the esophagus.

KeywordS: gastroesophageal reflux disease, actovegin, diabetes mellitus type II, antioxidant protection, lipid peroxidation.

Anton A. Kudriavtsev, PhD studentDepartment of Therapy, Rheumatology and Clinical Pharmacology58 Amosova Street, Kharkiv 61176, UkraineTel.: (+38095) 633 49 86E-mail: dtdn10@gmail.com

Received 05/001/2018; accepted for printing 18/07/2018

high incidence, severity of complications, dis-ability and heavy mortality. This is due to not only the presence of a large number of comorbid pathologies, but also to a significant deterioration in the life quality.

Every year the mortality rate of diabetic pa-tients steadily increases, the incidence prognosis is about 5-7% per year. According to the Interna-tional Diabetes Federation expert assessment in 2011, there will be 520 million patients with diabe-tes mellitus in the world by 2030, but already in 2015 their number reached 415 million, while 10

iNTroducTioN

Diabetes mellitus is still a serious medical and social problem, since the number of patients suf-fering from this disease continues to increase [Kinekawa F et al., 2008; Fedorchenko Iu, 2013; Krishnan B et al., 2013; Fadeenko H, Hridnev A, 2014; Dedov I et al., 2015]. It is determined by its

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years ago experts predicted that by 2025 the total number of patients with diabetes mellitus would be only 330 million [Moraes-Filho J et al., 2009; Agrawal S et al., 2014; Sun H et al., 2014; Oparin A, Beziazychna N, 2016].

According to modern refined estimates, the number of patients with diabetes mellitus is ex-pected to increase to 642 million worldwide by 2040. In Ukraine, more than 1.3 million people with diabetes mellitus are registered, which makes about 2% of the total population of the country. At the same time, epidemiological studies have shown that the true incidence is 2-3 times higher [Kinekawa F et al., 2007; Natalini J et al., 2015; Korniienko D, Oparin A, Beziazychna N, 2016].

Moreover, in recent years, not only the num-ber of patients with diabetes mellitus, especially type II, has increased, but also the incidence and disability rates have sharply risen among them, they have often been diagnosed with serious complications and concomitant diseases, among which a special place is occupied by gastro-esophageal reflux disease [Thakkar B et al., 2013; Karabouta Z et al., 2008].

According to numerous researchers, the fre-quency of gastroesophageal reflux disease occur-rence with diabetes mellitus (from 18.8 to 26.7%) is significantly higher than in patients without dia-betes mellitus (10 to 17%) [Promberger R et al., 2013; Park S et al., 2016]. These concomitant dis-eases largely predetermine the course of diabetes mellitus and its complications and affect the life expectancy of the patient.

Moreover, among patients with diabetes mellitus type II, the frequency of gastroesophageal reflux dis-ease occurrence (in 31.1%) is much higher than among patients with diabetes mellitus type I – in 18.6% of patients [Kinekawa F et al., 2008; Becker C et al., 2013; Duggan C et al., 2013; Promberger R et al., 2013; Park S et al., 2016; Kostitska I, 2017].

However, many issues related to the formation of this co-morbid pathology are still not fully dis-closed, and, accordingly, the methods of treating such patients with diabetes mellitus with concom-itant gastroesophageal reflux disease have not been fully developed and require further research [Duggan C et al., 2013].

At the heart of the development mechanisms of gastroesophageal reflux disease in diabetes melli-

tus is diabetic polyneuropathy, which leads to a decrease and lag of gastric secretion, inadequate work of gastric motility, when peristaltic waves become asynchronous, low-amplitude and ineffec-tive, slowing down gastric emptying. These mech-anisms lead to a reflux of gastric contents into esophageal lumen.

Also, intractable hyperglycemia provokes an increase in the relaxation time of the lower esopha-geal sphincter, which also contributes to the devel-opment of gastroesophageal reflux [Vertkin A et al., 2013; Standarts of medical care in diabetes, 2015; Wang X et al., 2015; Medical care in diabe-tes, 2016; Oparin A, Beziazychna N, 2016; Shesta-kova M et al., 2016].

we need to take into account the fact that the intake of pelleted antihyperglycemic medicines, in particular, sulfanylurea derivatives (glipizide, gliquidone, glimepiride) and postprandial regula-tors (nateglinide, metformin), can induce dyspep-sia, which is one of the symptoms of gastroesopha-geal reflux disease [Duggan C et al., 2013].

All these facts of a few studies devoted to the investigation of the gastroesophageal reflux dis-ease formation mechanisms with underlying dia-betes mellitus type 2 have not been fully clarified, and therefore require further investigation, which conditions this study.

This study aimed to investigate the role of oxi-dative stress in the formation mechanisms of gas-troesophageal reflux disease in patients with dia-betes mellitus type II and to develop methods for its correction.

mATeriAl ANd meThodS

To achieve the set goal, we conducted a study in two treatment groups of patients with mild and moderate severe diabetes mellitus type II with con-comitant gastroesophageal reflux disease (GERD).

The I group (main) included 28 patients – 18 men and 10 women (35.7%) aged 35 to 45 years (mean age 39.4 ± 3.54 years) who received stan-dard treatment – metformin at a dose defined tak-ing into account blood sugar level, omeprazole 20 mg twice a day, domperidone 10 mg thrice a day and, additionally, actovegin 200 mg twice a day during 4 weeks.

The II group (control) consisted of 25 patients of the same age (38.2 ± 3.68 years) and sex – 16

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(64%) men and 9 (36%) women, who received only basic treatment – metformin at a dose defined taking into account blood sugar level, omeprazole 20 mg twice a day and domperidone 10 mg thrice a day during 4 weeks.

The III group (experimental) included 27 pa-tients with GERD without concomitant pathology of the same age group (37.4 ± 4.12 years), 18 (66.6%) men and 9 (33.3%) women, who received omeprazole 20 mg twice a day and domperidone 10 mg thrice a day during 4 weeks.

The studies were carried out in accordance with the Declaration of Helsinki [Rickham PP., 1964]; the procedures were approved by the local ethics committee. Informed consent for the participation was obtained from all patients.

At admission, prior to the prescribed therapy, all patients of both first and second groups with symptoms characteristic of diabetes mellitus had equal clinical implications of gastroesophageal re-flux disease – a moderate acid regurgitation (in 84% and in 82.2% of patients respectively), occa-sional inflammation (in 60.4% and in 60.0% of pa-tients respectively), as well as dysphagia (in 72% and in 71.4% of patients respectively).

The diagnosis of diabetes mellitus type II is confirmed in accordance with the criteria proposed by wHO experts, including the definition of com-pensation ratio of carbohydrate metabolism by the level of glycosylated hemoglobin HbA1c using af-finity chromatography.

The diagnosis of gastroesophageal reflux dis-ease was established according to the Montreal Consensus [Vakil, N.et al., 2006] taking into ac-count the clinical presentation and the data of fi-brogastroduodenoscopy, in which all patients of both first and second groups had oedema and hy-peremia of the esophageal mucosa. Along with this, in 5 patients of the first group, single cases of erosions of the esophageal mucosa were revealed. In other words, both groups of patients were ho-mogeneous by sex, age and clinical presentation, and practically did not differ from each other.

The state of lipid peroxidation was assessed by defining malondialdehyde and diene conjugates in blood, determined spectrofluorometrically using a standard set of reagents produced by IBL (Germany).

The level of antioxidant protection of the esophageal mucosa was assessed by the content of

catalase (K) in the blood serum determined by Revin’s method, as well as by the diameter of the celiac trunk and the blood flow velocity deter-mined by the pulsed wave Doppler sonography with color mapping performed on the Ultima pro-30 (Ukraine).

The criteria for excluding patients from the study were: the presence of other diseases of the internal organs and the neuroendocrine system, as well as the patient’s refusal to participate in the study.

The average indices of 20 healthy persons of the same age and sex were taken as a norm.

Statistical processing of the data was carried out using the windows Statistica 6.0 program. Comparison of the indices in the groups was car-ried out by the method of parametric statistics (Student’s t-test).

The interrelation between the indices in the groups was estimated using the Pearson correla-tion analysis (r is the correlation coefficient). Dif-ferences were rated with p<0.05 for all types of analysis of statistical significance.

The work was carried out in accordance with the research work of the Department of Therapy, Rheumatology and Clinical Pharmacology of Kharkov Medical Academy of Postgraduate Edu-cation: “Pathogenetic mechanisms of formation of comorbid pathology in students suffering from gastroesophageal reflux disease and their correc-tion” (state registration No 0110U002441).

reSulTS

In the course of the study, we found that while treating patients with diabetes mellitus type II with concomitant gastroesophageal reflux disease both of the first (primary) and the second groups, starting from the first days of the treatment, there was a clear tendency to decrease episodes of inflammation, re-gurgitation and the phenomenon of dyspepsia, the blood sugar level became lower and more stable.

Moreover, in patients additionally receiving ac-tovegin, these terms were 2-3 days shorter, and on average made 5.2±0.48 days, while in patients of the control group, that was only on a standard treatment regimen, these terms of the onset of clinical remis-sion were extended by 3-5 days, and on average, the periods of clinical symptoms reversal (8.4±0.92 days) were statistically significantly (p<0.05) longer than in the patients of the main group.

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In patients suffering from both isolated gastro-esophageal reflux disease and gastroesophageal reflux disease with concomitant diabetes mellitus type II, there is a significant increase in the level of malondialdehyde and diene conjugates compared to the control group at the norm of 3.0±0.21 and 57.5±1.73 mcmole/ml respectively. Simultane-ously, there was also a significant difference be-tween patients of both treatment groups (Table 1).

Thus, both in patients with isolated gastro-esophageal reflux disease and in patients with gas-troesophageal reflux disease with concomitant pa-thology, oxidative stress is observed, which mani-fests itself in a significant increase in lipid peroxi-dation indices and a decrease in antioxidant activ-ity. Moreover, in patients with gastroesophageal reflux disease with concomitant pathology, there is a significant increase in the products of lipid per-oxidation and a significant decrease in antioxidant activity products not only in comparison with the control group, but also with the patients with iso-lated gastroesophageal reflux disease.

At the same time, we found that after a 4-week course of therapy, the indices of antioxidant pro-tection of the esophageal mucosa increased and lipid peroxidation indices decreased in patients of both treatment groups. However, in patients re-ceiving Actovegin, they were significantly higher than in patients who did not take it.

Furthermore, the diameter of the celiac trunk in-creased in patients, and the blood flow velocity in it improved. However, in patients of the main group who additionally received Actovegin, the diameter of the celiac trunk increased from 0.59±0.05 cm to 0.92±0.08 cm, and the blood flow velocity in it in-creased from 6.9±0.82 to 12.9±0.75 cm/s, and on average, practically (p>0.05) approached the pa-rameters of healthy individuals of the control group – 13.5±0.92 cm/s and 0.93±0.07 cm/s (respectively).

while in the patients of the second control group, who was only on the standard treatment regimen, the dynamics of the blood flow in the ce-liac trunk was much smaller, and on average their blood flow velocity increased from 6.9±0.74 cm/s to 10.9±0.96 cm/s (p>0.05), and the diameter of the celiac trunk widened from 0.59±0.06 cm to 0.79±0.04 cm. However, on average, these param-eters remained after the treatment, not only lower than the norm (p<0.05), but also lower than the av-

erage indices of the main group of patients (p<0.05) who additionally received actovegin (Table 2).

Concurrently, in patients of both groups after the course of treatment, the catalase activity level in-creased. However, in the patients of the main group, this increase was more significant, from 44.5±4.26 mg/ml to 80.1±3.75 mg/ml (p<0.001), while in the patients of the control group the dynamics of the in-crease was less evident – from 44.8±4.56 mg/ml to 69.7±6.1 mg/ml (at a rate of 83.1±3.67 mg/ml) and, when compared after the treatment, the level re-mained statistically significantly (p<0.05) not only below the norm, but also below the average level (p<0.05) of I group patients.

Moreover, in 5 patients of this control group, after a 4-week course of treatment, the blood sugar level was raised occasionally, although insignifi-cantly, and this rising was accompanied by inflam-mation and acid regurgitation, which was not ob-served in the patients of the main group who addi-tionally received actovegin.

The obtained data indicate that oxidative stress is one of the factors not only weighting the course of gastroesophageal reflux disease and diabetes mellitus type II, but also taking a direct part in the formation of gastroesophageal reflux disease itself with diabetes mellitus type II.

The latter is carried out by reduction of trophism and absorption of esophageal and gastric mucosa, disorders of the production of hydrochloric acid, asynchrony and reduction of esophageal and gastric motility, that is, those basic factors that underpin the formation of gastroesophageal reflux disease.

Thus, the results of our studies clearly show that the inclusion of actovegin in the standard treatment regimen of patients with diabetes melli-tus type II with concomitant gastroesophageal re-flux disease has an apparent positive effect on re-

TABle 1Indices of lipid peroxidation in patients with diabetes mellitus type II with concomitant gastroesophageal reflux disease and with isolated gastroesophageal reflux disease

Indices Isolated GERD

Concomitant GERD Norm

Malondialdehyde (mcmole/ml) 4.35±0.34 7.03±0.47 3.0±0.21

Diene conjugates (mcmole/ml) 120.3±3.5 144.8±5.2 57.5±1.73

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ducing the timing of the onset of clinical remission of both diabetes mellitus type II and concomitant gastroesophageal reflux disease with simultaneous increase of the level of antioxidant protection of the esophageal mucosa (increase of the level of catalase in blood, increase of the diameter of the celiac trunk and increase of the blood flow veloc-ity in it), which allow us to recommend the use this medication in the treatment of diabetes mellitus with concomitant gastroesophageal reflux disease, not only for the treatment of diabetes mellitus, but also for the purpose of secondary prevention of complications of diabetes mellitus and, above all, gastroesophageal reflux disease.

coNcluSioN

It has been shown that in patients suffering from both isolated gastroesophageal reflux disease and patients suffering from gastroesophageal re-flux disease with concomitant diabetes mellitus type II, oxidative stress is observed, which is man-ifested in a significant increase in lipid peroxida-

tion and a decrease in antioxidant activity, not only in patients and persons of the control group, but also in patients with isolated gastroesophageal re-flux disease and gastroesophageal reflux disease with concomitant diabetes mellitus type II.

The obtained data indicate that oxidative stress is one of the pathogenetic mechanisms that take part in the formation of gastroesophageal reflux disease in diabetes mellitus type II, which indi-cates the necessity for its pathogenetic correction.

The inclusion of actovegin in the standard treat-ment regimen of patients with diabetes mellitus type II with concomitant gastroesophageal reflux disease shortens the terms of clinical remission of both the underlying disease and the concomitant gastroesophageal reflux disease, contributing to a significant increase in antioxidant activity, a de-crease in lipid peroxidation and an improvement in the regional blood flow that makes it possible to use it not only for treatment, but also for secondary prevention of complications of diabetes mellitus, and, above all, gastroesophageal reflux disease.

TABle 2. Dynamics of blood flow indices, catalase activity and lipid peroxidation in patients with diabetes

mellitus type II with concomitant GERD and isolated GERD before and after the treatment

Indices I group II group III group Norm р

Celiac trunk diameter (cm)

before 0.57±0.05 0.59±0.06 0.77±0.11

0.93±0.07 p2<0.001p3>0.05after 0.92±0.08 0.74±0.04 0.82±0.09

p1 <0.001 <0.05 <0.05

Blood flow velocity in celiac trunk (сm/s)

before 6.8±0.82 6.9±0.74 9.3±0.06

13.5±0.92 p2<0.001p3>0.05after 12.9±0.75 9.8±0.96 10.2±0.04

p1 <0.001 <0.05 <0.05

Catalase ( mg/ml)

before 44.5±4.25 44.8±4.56 59.5±5.231

83.1±3.65 p2<0.001p3>0.05after 80.1±3.75 69.7±6.1 72.1±6.5

p1<0.001 <0.05 <0.05

Malondialdehyde (mcmole/ml)

before 7.03±0.43 6.95±0.43 5.8±0.34

3.0±0.21 p2<0.001p3>0.05

after 3.32±0.08 4.9±0.10 4.2±0.8p1 <0.001 <0.05 <0.05

Diene conjugates (mcmole/ml)

before 139±4.8 142±5.2 107±6.7

57.5±1.73 p2<0.001p3>0.05after 72.5±1.55 94.8±3.8 97.3±4.1

p1<0.001 <0.05 <0.05

NoTe: p1 – measure of confidence of the difference in data before and after treatment; p2 – measure of confidence of the difference between the data of I group patients after treatment and the norm; p3 – measure of confidence of the difference between the data of II group patients after treatment and the norm.

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