ZWIĄZEK POMIĘDZY GRELINĄ A GASTRYNĄ U PACJENTÓW Z PRZEWLEKŁYM ZAPALENIEM ŻOŁĄDKA I WSPÓŁWYSTĘPUJĄCĄ CUKRZYCĄ TYPU 2

Elizaveta S. Sirchak, Silviya V. Patskun

UZHHOROD NATIONAL UNIVERSITY, UZHHOROD, UKRAINE

Abstract

Introduction: Ghrelin is 28-amino-acid peptide that is produced by X/A-like cells present in the stomach. Gastrin is a hormone that stimulates gastric acid secretion and mucosal cell growth.

The aim: to study the interrelation between ghrelin and gastrin levels in patients with combination of chronic gastritis and type 2 diabetes mellitus.

Materials and methods: 60 Helicobacter pylori positive patients with a combination of chronic gastritis and type 2 diabetes mellitus were examined. The diagnosis of type 2 diabetes mellitus is based on the recommendations of the International Diabetes Federation (IDF, 2005). Gastric acid secretion function was studied by intra-stomach express-pH-metry (method of prof. V.N. Chernobrov). Serum gastrin was determined using ELISA using Gastrin-EIA test kit Cat. No. CS 001 030. Serum ghrelin was determined by immunoassay analysis using the Human Ghrelin ELISA Kit from RayBiotech No. 1.03930005306

Results: The obtained data testify to the existence of a feedback between the level of ghrelin and gastrin in the blood of patients with chronic gastritis and type 2 diabetes mellitus. That is, with increasing levels of gastrin in the blood, the level of ghrelin in the blood decreases and vice versa with a decrease in the level of gastrin in the blood, the level of ghrelin – increases.

Conclusions: A significantly higher level of ghrelin was found in patients with type 2 diabetes mellitus and chronic gastritis compared with control group. The reverse association between gastrin and ghrelin levels in patients with combination of chronic gastritis and type 2 diabetes mellitus has been obtained.

 

Wiad Lek 2018, 71, 2 cz. I, -314

 

Introduction

Gastrin is a hormone that stimulates gastric acid secretion and mucosal cell growth. It is released from G cells and it acts through the cholecystokinin -2 receptor. It is believed that gastrin stimulates the enterochromaffinlike cells to release histamine, which, in turn, binds to H-2 receptors on parietal cells and stimulate acid secretion. Both chemical and mechanical stimuli increase gastrin secretion. These stimuli act directly on the G cell and/or indirectly through the adjacent neuroendocrine cells and neurons. [1] The pituitary gland adenylate cyclase-activating protein, bombesin, sucralose, glucose, caffeine, and bacterial lipopolysaccharide also stimulate gastrin release [2]. Such causes as gastrinoma, predominant Helicobacter pylori associated gastritis, gastric outlet obstruction; renal failure, retained antrum, atrophic gastritis, and antisecretory therapy can lead to increase in the serum gastrin concentration [3].

Ghrelin is 28-amino-acid peptide that is produced by X/A-like cells present in the stomach and also throughout the entire gastrointestinal tract ghrelin expression has been described. Thirty percent of the circulating ghrelin levels are acylated and remaining 70% circulates as unacylated ghrelin. The ghrelin-circulating levels were decreased after gastrectomy, suggesting that the stomach is the main source of ghrelin in the organism. Such tissues as hypothalamus, pituitary, ovary, testis, heart and placenta are responsible for ghrelin release [4].

After feeding, low levels of ghrelin can be seen and in food deprivation conditions plasma ghrelin levels are elevated. The mechanism that directly regulates ghrelin production in the stomach remained unclear, leading to the assumption that any changes in plasma ghrelin reflect changes in gastric ghrelin release. Changes in plasma ghrelin levels that are mediated by food provided due to variations in ghrelin release by the stomach. The ghrelin secretion directly from the stomach is regulated not only by the direct mechanical contact with the gastric wall, digestion or absorption of nutrients. It can be stimulated and modify without real food intake, in the same way as true feeding. This fact indicates that a relevant factors involved in this process are the central nervous system, including ghrelin as a neural-mediated integrative factor that constitutes as a link between the sensory qualities of food, neural activation and nutrient metabolism. [5]

Ghrelin has orexigenic and lipogenic effects and also plays significant role in glucose regulation. While acylated ghrelin can lead to insulin resistance, the unacylated ghrelin counters hyperglycemia and enhances insulin sensitivity [6].

THE AIM

Aim: to study the interrelation between ghrelin and gastrin levels in patients with combination of chronic gastritis (CG) and type 2 diabetes mellitus (DM).

MATERIALS AND METHODS

60 Helicobacter pylori positive patients with a combination of CG and type 2 DM, who were treated in the endocrinology department in Transcarpathia Regional Clinical hospital named after A. Novak in Uzhhorod. The average age of patients was 57.6 ± 2.3 years. Among patients there are 35 (58.3%) women and 25 (41.7%) men. Patients underwent general clinical examinations according to local protocols. The diagnosis of type 2 DM is based on the recommendations of the International Diabetes Federation (IDF, 2005), that is, determining the level of glucose in serum on the empty stomach and 2 hours after glucose administration using the oxidant method. The severity of diabetes was assessed by the level of glycosylated hemoglobin (HbA1c,%), which was determined using a chromogenic assay on Sysmex 560 (Japan) using Siemens reagents.

Gastric secretion`s function was studied by intra-stomach express-pH-metry, using a computer system by the method of prof. V.N. Chernobrov. In the computer analysis of the results, the functional interval of pH (FI pH) from 0 to 5 (in the direction of greater acidity of the stomach) was taken into account:

pH 7.0 – 7.5 (FI-pH0 – anacidity);

pH 3.6-6.9 (FI pH1 – hypoacidity expressed);

pH 2,3 – 3,5 (FI pH2 – moderate hypoacidity);

pH 1.6 – 2.2 (FI pH3 – normoacidity);

pH 1.3 – 1.5 (FI pH4 – moderate hyperacidity);

pH 0.9 – 1.2 (FI pH5 – hyperacidity expressed).

HP was confirmed by detection of its fecal antigens (CITO TEST H.Pylori Ag, Pharmasco, Ukraine).

Serum gastrin was determined using ELISA using Gastrin-EIA test kit Cat. No. CS001 030.

Serum ghrelin was determined by immunoassay analysis using the Human Ghrelin ELISA Kit from RayBiotech No. 1.03930005306, according to the application method. Reading the results was carried out at a wavelength of 450 nm.

The criteria for inclusion of patients in this study were:

Patients with type 2 DM and CG with HP infection;

Criteria for exclusion of patients from this study:

Patients with type 1 DM;

Patients who have already received anti-helicobacter therapy.

All studies were conducted with the consent of patients, and its method corresponded to the Helsinki Declaration of 1975 and its revision in 1983.

Scientific research is a fragment of the SB topic 851 “Mechanisms of the complications formation in the liver and pancreas, methods of their treatment and prevention” (state registration number 0115U001103).

The analysis and processing of the results of the patient examination was carried out using the computer program STATISTICA 10.0 (firm StatSoftInc, USA).

RESULTS

According to the results of intra-stomach pH-metry, patients were divided into 2 groups depending on the degree of pH change. In 75% (45) patients, there was a pronounced gastric hyperacidity, and these patients were included in group І. In 25% (15) patients moderate gastric hyperacidity was detected; these patients were included into II group. The control group included 20 practically healthy people. We measured the level of ghrelin and gastrin in these patient groups. The obtained data are listed in Table I below as the arithmetic mean of the values of the examined patients.

The obtained data testify to the existence of a feedback between the level of ghrelin and gastrin in the blood of patients with CG and type 2 DM. That is, with increasing levels of gastrin in the blood, the level of ghrelin in the blood decreases and vice versa with a decrease in the level of gastrin in the blood, the level of ghrelin – increases.

One of the functions of ghrelin is to increase tissue sensitivity to insulin and increase insulin secretion in response to hyperglycemia. Thus, as the main pathogenic component of type 2 diabetes is insulin resistance, the reduction of the ghrelin level in patients with this pathology is natural. The data of our study, partly confirm the effect of insulin resistance to the level of ghrelin, but according to Table II, we can conclude that not only this factor affects the secretion of the hormone, since when comparing two groups with a difference in pH of gastric juice; increase in the ghrelin level in falling pH was seen.

DISCUSSION

In present study, decrease in the serum`s ghrelin level was observed in patients with combination of CG and DM compared with the control group, and the difference was statistically significant (p<0,05). On the contrary, the result of a prospective study carried out by Bennettet al. showed that no association between the baseline ghrelin level and the incidence of type 2 DM was found. [7] The others clinical studies have identify the interrelation between serum ghrelin, glucose and insulin, but the physiological mechanisms of this relationship remain unclear. [8,9] Previous studies were concentrating only on the changes in ghrelin level in patients with type 2 DM, but the main organ of the body that is responsible for the ghrelin secretion is stomach. It is known that such disease as CG affects the production of gastric juice and also influence on its chemical composition.

Other findings suggest that hyperinsulinemia associated with insulin resistance decreases serum ghrelin levels in type 2 DM and obese subjects. The present study was in the favor that there is an inverse relationship between fasting glucose and ghrelin level. The study also demonstrated that hyperglycemia due to disturbance in glucose metabolism may result in suppression of ghrelin level in type 2 DM and obesity. [10]

Ghrelin suppresses glucose-induced insulin secretion, without significantly influencing insulin secretion at basal and lower glucose concentrations. This glucose-dependence can be explained by the action of ghrelin to counteract cAMP signaling inβ-cells, which is well known to glucose-dependently promote insulin secretion. [11]

In this study interrelation between gastrin and ghrelin levels were observed in patients with combination of CG and type 2 DM. In all previous studies only interrelation between ghrelin serum level, glucose, and insulin were examined in patients with different metabolic diseases. Level and effect of gastrin were examined only in connection with the stomach disorders. The present study combines both hormones evaluation in patients with combination of CG and type 2 DM. Still the mechanism of interrelation between gastrin and ghrelin level in pathological states remain unknown.

CONCLUSIONS

A significantly higher level of ghrelin was found in patients with type 2 DM and CG compared with control group. The reverse association between gastrin and ghrelin levels in patients with combination of CG and type 2 DM has been obtained.

REFERENCES

1. Ericsson P, Hakanson R, Rehfeld JF et al. Gastrin release: antrum microdialysis reveals a complex neural control. Regul Pept. 2010;161:22–32.

2 Kidd M, Hauso O, Drozdov I et al. Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells. Gastroenterology. 2009;137:231–241.

3. Murugesan SVM, Varro A, Pritchard DM. Review article: strategies to determine whether hypergastrinaemia is due to Zollinger –Ellison syndrome rather than a more common benign cause. Aliment Pharmacol Ther. 2009;29:1055–1068.

4. Al Massadi O, Tschop MH, Tong J. Ghrelin acylation and metabolic control. Peptides. 2011;32:2301–2308.

5. Seoane LM, Al-Massadi O, Caminos JE et al. Sensory stimuli directly acting at the central nervous system regulates gastric ghrelin secretion. An ex vivo organ culture study. Endocrinology. 2007;148:3998–4006.

6. Collden G., Tschop MH, Muller TD. Therapeutic potential of targeting the ghrelin pathway. International Journal of Molecular Sciences. 2017;18(4):798.

7. Bennett NR, Boyne MS, Cooper RS et al. Impact of adiponectin and ghrelin on incident glucose intolerance and on weight change. Clin Endocrinol (Oxf). 2009;70:408–414.

8. Purnell JQ, Weigle DS, Breen P et al. Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans. J Clin Endocrinol Metab. 2003;88:5747–5752.

9. Vartiainen J, Rajala U, Jokelainen J et al. Serum ghrelin and the prediction of the development of impaired glucose regulation and Type 2 diabetes in middle-aged subjects. J Endocrinol Invest. 2010;33:496–500.

10. Jawed M, Saeed MS, Shahid A et al. Ghrelin Level in Type 2 Diabetes Mellitus and Obesity. Annals of King Edward Medical University. 2017;23(3):312-319.

11. Yada T, Damdindorj B, Rita RS et al. Ghrelin signalling in β-cells regulates insulin secretion and blood glucose. Diabetes, Obesity and Metabolism. 2014;16(S1):111-117.

Scientific research is a fragment of the SB topic 851 “Mechanisms of the complications formation in the liver and pancreas, methods of their treatment and prevention” (state registration number 0115U001103).

ADDRESS FOR CORRESPONDENCE

Patskun Silviya Viktorivna

8 March st. 3/59, 88015, Uzhhorod, Ukraine,

tel. +380990857328

e-mail: silvika121191@gmail.com

Received: 20.02.2018

Accepted: 10.04.2018

Table I. Gastrin level in patients with combination of CG and type 2 DM, depending on the acid-forming function of the stomach.

Gastric acid secretion function of the stomach

Gastrin level (pg/ml)

І group (hyperacidity expressed)

n= 40

123,7±4,7*

ІІ group (moderate hyperacidity)

n= 15

98,4±2,4

Control group

n= 20

72,4±3,4*

*p<0,05 – data are reliable.

Table II. Ghrelin level in patients with a combination of CG and type 2 DM, depending on the acid-forming function of the stomach.

Gastric acid secretion function of the stomach

Ghrelin level (mmol/l)

І group (hyperacidity expressed)

n= 40

91,195±3,8*

ІІ group (moderate hyperacidity)

n= 15

234,983±5,7

Control group

n= 20

365,657±6,5*

*p<0,05 – data are reliable.