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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 44  |  Issue : 4  |  Page : 163-169

The impact of ghrelin on oxidative stress and inflammatory markers on the liver of diabetic rats


Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Al-Gharbia, Egypt

Date of Submission01-Aug-2016
Date of Acceptance20-Sep-2016
Date of Web Publication8-Mar-2017

Correspondence Address:
Elsayed Emara
Department of Physiology, Faculty of Medicine, Tanta University, El-Geish street, Tanta
Egypt
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DOI: 10.4103/1110-1415.201723

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  Abstract 

Background On the basis of the antioxidant and anti-inflammatory effects of ghrelin on the liver of diabetic rats.
Aim This research was designed to investigate its supposed improving role against histochemical alterations induced in the liver by diabetes.
Materials and methods This study was carried out on 21 male albino rats that were divided into three equal groups. Group I included seven male rats and was used as a control group. In the remaining 14 rats, diabetes was induced through an intraperitoneal injection of streptozotocin. The diabetic rats were chosen and randomly divided into two groups. Group II included untreated diabetic rats, and group III included diabetic rats treated with subcutaneous administration of unacylated ghrelin (UAG). At the end of the experimental period, the blood samples were collected and liver tissues were excised for chemical and histopathological investigations.
Results The results showed that the plasma level of glucose and inflammatory cytokines were increased and that of insulin and total ghrelin were significantly decreased in diabetic rats. Moreover, serum levels of aspartate aminotransferase and alanine aminotransferase were significantly elevated, whereas there was a significant decrease in lactate dehydrogenase. Furthermore, hepatic tissue malondialdehyde was significantly increased, and the levels of serum superoxide dismutase and glutathione peroxidase were significantly decreased in the diabetic group. However, their treatment with UAG significantly opposed the levels of the previously mentioned parameters toward the normal levels. Finally, liver histopathology of the diabetic animals showed several alterations, which were ameliorated through the administration of UAG.
Conclusion It could be concluded that ghrelin administration has an improving effect against histochemical alterations induced in the diabetic liver.

Keywords: anti-inflammatory, antioxidant, cytokines, diabetes, ghrelin, liver


How to cite this article:
Elsawy M, Emara E. The impact of ghrelin on oxidative stress and inflammatory markers on the liver of diabetic rats. Tanta Med J 2016;44:163-9

How to cite this URL:
Elsawy M, Emara E. The impact of ghrelin on oxidative stress and inflammatory markers on the liver of diabetic rats. Tanta Med J [serial online] 2016 [cited 2017 Jun 22];44:163-9. Available from: http://www.tdj.eg.net/text.asp?2016/44/4/163/201723


  Introduction Top


Ghrelin is a 28-amino acid peptide hormone produced mainly by the cells lining the fundus of the stomach. It is involved in the regulation of lipid and glucose metabolism. Two major forms of ghrelin can be found in circulation: an acylated (AG) form and an unacylated (UAG) form, which circulates in amounts far greater than those of AG [1]. Many researchers have generally focused upon this peptide’s role in growth and energy metabolism. Recently, studies investigating ghrelin’s effect on inflammation and immune response have gained importance [2]. Further studies have revealed that ghrelin may be an antioxidant and anti-inflammatory agent [2].

Diabetes mellitus (DM) is an endocrinological and/or metabolic disorder with an increasing global prevalence and incidence. The association between diabetes and liver disease has relevance to diabetologists, hepatologists, and primary care physicians. The finding of an excess prevalence of chronic liver disease in type 2 diabetic patients has stimulated interest in this association and on exploration of pathogenesis that promise to shed light on the relationship between hepatic metabolism and glucose homeostasis [3]. Abnormal liver function results are more common among diabetes patients. Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the markers for associated nonalcoholic fatty liver disease in diabetes patients [3].

Plasma ghrelin concentration is decreased in type 2 diabetic patients compared with nondiabetic individuals [4]. Human studies showed a positive relationship between insulin sensitivity and diacylglycerol (DAG) [5],[6], and treatment with DAG improves insulin sensitivity [6].

Interestingly, AG has been shown to stimulate glucose output by primary hepatocytes, whereas UAG mediates an inhibitory effect [7]. Moreover, it counteracts the stimulatory effect of AG on glucose release [8]. For this reason, we prefer UAG and not AG in the current study.

Oxidative stress is considered to play a prominent causative role in the development of various hepatic disorders. There are several pieces of evidence indicating that oxidative stress is increased in diabetes. Overproduction of reactive oxygen species (ROS) and decreased efficiency of antioxidant occur as a result of hyperglycemia [9]. Numerous pieces of evidence suggested that hyperglycemia is associated with oxidative stress, and the free radical-generating system is the main reason for the development of diabetes and its complications [9]. Many researchers reported the relationship between oxidative stresses and the expression or function of ghrelin [10]. Moreover, previous studies have reported that ghrelin has an anti-inflammatory action on the oxidative injury of the diverse organs, such as the heart, pancreas, kidney, and small intestine [11].

The gradual increase in the number of studies on the anti-inflammatory effectiveness of ghrelin has brought an enthusiasm to investigators, in terms of using ghrelin for therapeutic purposes. For this purpose, the present study was designed to assess the effects of the administration of exogenous ghrelin on oxidative stress and inflammation markers in the liver of diabetic rats.


  Materials and methods Top


Experimental animals

This study was carried out on 21 male albino rats weighing 200–250 g. The animals were obtained from the animal house of the Faculty of Science, Tanta University (Tanta, Egypt). The handling of the animals was carried out in accordance with the ethical guidelines for investigations and approved by the local ethical committee for the care and use of laboratory animals.

The rats were handled daily, housed in isolated animal cages, and kept under a 12-h light–dark cycle at room temperature.

Experimental design

The animals were maintained on standard commercial rat chow and tap water ad libitum for the whole period of the experiment. Before the start of the work, all animals underwent 2 weeks of acclimatization period.

At the start of our study, seven male rats were separated and used as a control group (group I). The animals in group I were injected with vehicle alone.

In the other 14 rats, diabetes was induced with an intraperitoneal injection of streptozotocin (STZ) (40 mg/kg in freshly prepared citrate buffer pH 4.5) according to Haidara et al. [12]. Diabetes mellitus was verified 3 days later by measuring blood glucose levels. Fasting blood samples were collected from tail vein and analyzed for blood glucose using a glucometer (Accu-Chek Extra Care, Roche Diabetes Care India Pvt. Ltd.). Animals showing fasting blood glucose of at least 250 mg/dl were considered as diabetic and used for the study.

The diabetic rats were chosen and randomly divided into two groups (groups II and III). Group II included STZ-induced, untreated diabetic rats.

Group III included the diabetic rats treated with UAG. The rats were given 100 μg/kg/day of UAG (Sigma) by means of subcutaneous injection for 4 weeks [13].

The study period lasted for 4 weeks, a period which has been proved to induce detectable diabetic complications in different organs [14].

Blood and liver sampling

At the end of 4 weeks, blood samples of the fasted rats were collected from the medial retro-orbital venous plexus under light ether anesthesia. Thereafter, the blood was centrifuged at 3000 rpm for 15 min to separate plasma for different biochemical assays. The animals were then decapitated under ether anesthesia and liver tissue samples were rapidly excised and stored at −60°C for subsequent biochemical assays and histopathological examination.

Biochemical assays

Total ghrelin in plasma was measured using enzyme-linked immuno sorbent assay (ELISA) kit according to manufacturers’ instructions (Phoenix Pharmaceuticals, Belmont, California, USA) [4].

Serum AST, ALT, and lactate dehydrogenase (LDH) levels were determined as indicators of liver function and damage using AST, ALT, and LDH (Roche Diagnostic, Mannheim, Germany) commercial kits in a Roche − Hitachi Modular Auto analyzer (Roche Diagnostic) [14].

Plasma level of interleukin-6 (IL-6) was determined using commercially available ELISA kits according to manufacturers’ instructions (R&D Systems, Minneapolis, Minnesota, USA). Plasma level of C-reactive protein and tumor necrosis factor-α (TNF-α) level were assessed using commercially available ELISA kits according to the manufacturer’s instructions (TiterZyme EIA kit; Assay Designs Inc., Ann Arbor, Michigan, USA) [11].

The malondialdehyde (MDA) content in the liver, a measure of lipid peroxidation, was determined using the thiobarbituric acid method [15]. The activity of superoxide dismutase (SOD) was assayed using the method of Marklund and Marklund [16]. The activity of glutathione peroxidase (GPx) was assayed using the method of Lawrence and Burk [17].

Histopathological examination

Liver tissues were fixed in 10% formalin, dehydrated with 50–100% ethanol solution, and embedded in paraffin. Sections of 3–5 µm thickness were prepared and routinely stained with basic dye haematoxylin and acidic dye eosin and then examined under light microscope.

Statistical analysis

Data are presented as means±SD. The determinations were performed on 10 animals per group and the differences were examined using the one-way analysis of variance, followed by the Fisher test (Stat View), and the significance was accepted at P<0.05.


  Results Top


Effect of unacylated ghrelin on plasma levels of glucose, insulin, and total ghrelin in streptozotocin-induced diabetic rats

[Table 1] shows that the plasma level of glucose was significantly (P<0.05) increased and plasma levels of insulin and total ghrelin were significantly decreased (P<0.05) in diabetic rats compared with normal control rats. However, treatment of the diabetic rats with UAG significantly lowered (P<0.05) plasma glucose and significantly increased plasma levels of insulin and total ghrelin compared with untreated diabetic rats.
Table 1 Changes in plasma levels of glucose, insulin, and total ghrelin in the control, diabetic, and unacylated ghrelin-treated diabetic groups

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Effect of unacylated ghrelin on cytokine concentrations

[Table 2] shows that plasma levels of proinflammatory cytokines (CRP, TNF-α, and IL-6) were significantly (P<0.05) higher in diabetic rats compared with normal control animals. UAG treatment in the diabetic group showed significant elevations in the levels of those cytokines (P<0.05).
Table 2 Changes in plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α in the control, diabetic, and unacylated ghrelin-treated diabetic groups

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Effect of unacylated ghrelin on liver function

[Table 3] shows that serum levels of ALT and AST were significantly (P<0.05) higher in diabetic rats when compared with normal control rats, indicating impairment of liver functions. Similarly, LDH activity, as an index of generalized tissue damage was also found to be significantly increased (P<0.05) compared with controls. Meanwhile, in diabetic rats treated with UAG the enzyme levels were reversed significantly (P<0.05).
Table 3 Changes in serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in the control, diabetic, and unacylated ghrelin-treated diabetic groups

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Effect of unacylated ghrelin on lipid peroxidation and antioxidant enzymes

[Table 4] shows that hepatic tissue MDA was significantly (P<0.05) increased, and the antioxidant levels of SOD and GPx were significantly decreased (P<0.05) in the diabetic group when compared with the control one. UAG treatment for diabetic rats significantly (P<0.05) decreased the elevated MDA and increased (P<0.05) the reduced antioxidant enzyme activities.
Table 4 Changes in hepatic tissue levels of malondialdehyde and enzyme activities of serum superoxide dismutase and glutathione peroxidase in the control, diabetic, and unacylated ghrelin-treated diabetic groups

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Histological results

The histopathological findings of this study revealed the following:



  • Group I: Liver biopsy of the animals of the control group showed no pathological abnormality. Liver parenchyma was in good morphology and hepatocytes were arranged around the central vein. The hepatic lobules appeared normal with polygonal hepatocytes having regular nucleus and cytoplasm. No congestion and inflammation were observed in the sinusoids ([Figure 1]a).
    Figure 1 Histological results of liver tissues stained with hematoxylin and eosin under light microscope (×200 magnification). (a) Normal control group; (b) diabetic group; and (c) unacylated ghrelin-treated group.

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  • Group II: In the diabetic animals, the liver showed several alterations, including a mild degree of fatty changes and cloudy swelling with mild infiltration of lymphocytes. Hepatocytes were marked with vacuolization, striped necrosis, and inflammatory cells arranged around the necrotic tissue. Congestion in liver sinusoids was significant with scattered infiltration of inflammatory cells including neutrophil leukocytes ([Figure 1]b).


  • Group III: In the UAG-treated group, the area and extent of necrosis attenuated and the immigration of inflammatory cells markedly reduced. Liver parenchyma was well preserved with radially arranged hepatocytes around the central vein. Regular sinusoidal structures were seen without congestion. Moreover, the apoptotic nuclei were significantly reduced in the ghrelin-treated group compared with the diabetic one ([Figure 1]c).



  Discussion Top


Ghrelin is a multifunctional peptide hormone with pleiotropic effects. It exhibits novel protective effects, such as anti-inflammatory, antiapoptotic, and antifibrotic effects in many organs [7]. The aim of the present study was to investigate the impact of ghrelin on oxidative stress and inflammation markers in the liver of diabetic rats. Diabetes raises the risk for nonalcoholic fatty liver disease by developing liver inflammation, scarring or cirrhosis, and cancer. Rats with diabetes mellitus showed obvious hepatic histological changes, elevated serum enzyme ALT and AST levels, increased formation of oxidative stress and lipid peroxidation markers, and upregulated levels of proinflammatory cytokines and apoptotic cells in the liver [2],[12],[14]. All previously mentioned changes were documented by the current results, as shown in group II diabetic rats ([Table 1],[Table 2],[Table 3],[Table 4] and [Figure 1]b).

It has been shown in the current and other studies that ghrelin concentrations are reduced in different pathophysiological conditions including diabetes [4],[18]. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin [18],[19].

The present study demonstrated that treatment with UAG counteracted all STZ diabetogenic effects by reducing glucose and enhancing insulin levels, and improved the liver functions and decreased the elevations in serum LDH activity and proinflammatory cytokine levels. Furthermore, increased hepatic lipid peroxidation level and decreased activity of antioxidant enzymes that were observed as the consequences of oxidative injury were also reversed with UAG treatment. Histopathologic findings also supported the anti-inflammatory effects of UAG in hyperglycemia-induced hepatic damage.

Treatment with UAG improved glucose metabolism and preserved insulin secretion. STZ causes diabetes by inducing β-cell destruction, partly through the stimulation of apoptosis [20]. Granata et al. [21] reported that UAG increased the antiapoptotic protein BCL2 in STZ-treated rats, suggesting that they may prevent β-cell death by enhancing the activity of the antiapoptotic cell machinery. Indeed, several studies have demonstrated the requirement of BCL2 in protection against β-cell apoptosis [22],[23]. Moreover, Granata et al. [21] added that UAG even upregulated insulin mRNA in STZ-treated animals, suggesting that increased insulin secretion may be due to either enhanced β-cell survival and/or regeneration, de novo insulin production, or both. Tam et al. [24] reported that UAG restored insulin and autophagic signaling in the skeletal muscle of diabetic mice. Restoration of insulin signaling in the skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose.

Reports suggested that diabetes and obesity are linked with a relative DAG deficiency or an increased AG : DAG ratio [25],[26]. DAG administration might lead to an improvement in postprandial glucose levels in obese diabetic humans. This effect might be attributed to the reduction in AG levels [8].

Hyperglycemia may trigger a generalized vascular inflammatory process contributing to atherogenesis [27],[28]. This process may involve an increased expression of proinflammatory cytokines such as IL-1b, IL-6, and TNF-α, possibly through an increase in oxidative stress status [28] or a decrease in antioxidant defense systems [29].

The present study showed that UAG administration significantly reduced plasma levels of proinflammatory cytokines in diabetic rats when compared with untreated diabetic rats. This improvement in cytokine profile in the present study is supported by previous studies [30],[31]. Barazzoni et al. [31] demonstrated that ghrelin attenuated TNF α-induced nuclear translocation NF-kB, indicating that blockade for activation of the transcription factor NF-kB could be a potential mechanism whereby ghrelin modulates inflammatory responses.

Lipid peroxidation is initiated by free radical attack on membrane lipids, generating large amounts of reactive products, which have been implicated in diabetes and its complications. The increased lipid peroxidation levels in progression of diabetes may have a role in tissue damage associated with diabetes [32]. The results of the present study showed that MDA formation, the index of lipid peroxidation, was significantly increased in the liver of STZ-diabetic animals. Significant increases in lipid peroxidation during diabetes showed the occurrence of oxidative damage in diabetic animals. This observation is in agreement with previous studies [33],[34]. Treatment with UAG reduced lipid peroxidation levels, indicating that ghrelin may inhibit oxidative damage of the liver.

Oxidative stress is the imbalance between production and removal of reactive oxygen species. Increased oxidative stress, which contributes substantially to the pathogenesis of diabetic complications, is the consequence of either enhanced ROS production or attenuated ROS scavenging capacity. The antioxidative defense system enzymes such as SOD and GPx showed lower activities in various tissues during diabetes [7],[9]. The decreased activities of SOD and GPx may be in response to an increased production of hydrogen peroxide and superoxide by the auto-oxidation of excess glucose and nonenzymatic glycation of proteins [35]. SOD and GPx activities were decreased in diabetic rats, and administration of UAG to diabetic rats increased the activities of SOD and GPx and may help in controlling free radicals.

Moreover, serum ALT, AST, and LDH levels were significantly increased in diabetic rats, indicating impairment of liver functions and generalized tissue damage, respectively. Treatment of the diabetic rats with UAG could significantly inhibit an increase in serum ALT, AST, and LDH levels in comparison with the untreated diabetic rats.

Our findings were also confirmed by histological observation. The area and extent of necrosis attenuated and the immigration of inflammatory cells reduced. Liver parenchyma was well preserved with radially arranged hepatocytes around the central vein. Regular sinusoidal structures were seen without congestion.


  Conclusion and recommendations Top


UAG can be capable of reducing the diabetic-induced liver oxidative injury through its anti-inflammatory and antioxidative effects. Although its antidiabetogenic action requires further investigation, the results obtained in this study suggested that UAG may be a promising therapeutic molecule for prevention or early treatment of diabetic disorders.

Acknowledgements

The authors gratefully acknowledge Prof. Essam Elshweehy, Assistant Professor of Histology, Faculty of Medicine, Tanta University, for his kind help in the histopathological part of the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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