ENHANCEMENT OF THE ANTIDIABETIC EFFECT OF GLICLAZIDE BY THE ANTIPEPTIC DRUG OMEPRAZOLE IN ALLOXAN-INDUCED DIABETIC RATS

Assiut University web-site: www.aun.edu.eg

ENHANCEMENT OF THE ANTIDIABETIC EFFECT OF GLICLAZIDE BY THE ANTIPEPTIC DRUG OMEPRAZOLE IN ALLOXAN-INDUCED DIABETIC RATS

MAHMOUD H. ABDELRAHIM ¹; SAFWAT A. MANGOURA¹; SOTOHY A. SOTOHY ²;

SARY KH. ABDELGHAFAR ³ and ASMAA M. SADEK ⁴

¹ Department of Pharmacology, Faculty of Medicine, Assiut University.

² Department of Animal & Poultry Hygiene, Faculty of Veterinary Medicine, Assiut University.

³ Department of Pathology, Faculty of Veterinary Medicine, Assiut University.

⁴ Department of Pharmacology, Faculty of Veterinary Medicine, New Valley University.

Received: 25 August 2019;     Accepted: 5 September 2019

INTRODUCTION

Diabetes mellitus is a disease characterized by hyperglycemia, depletion of antioxidants and alteration in lipid metabolism(Jay et al., 2006). Diabetes is characterized by increased the generation of Reactive oxygen species (ROS) and decreased antioxidant levels in the body(Owu et al., 2012). Moreover, under chronic hyperglycemia, there is an increase in TNF-α production and oxidative stress which mediate diabetic complications (Kandhare      et al., 2012).

Diabetic patients have a higher incidence of peptic ulcer disease than the non-diabetic population(Tseng

Corresponding author: Dr. Asmaa M. Sadek

E-mail address: asmaamsadek92@gmail.com

Present address: Department of Pharmacology, Faculty of Veterinary Medicine, New Valley University

et al., 2012). Diabetes is associated with an increased prevalence of gastrointestinal tract symptom and susceptibility to acute gastric injury and impaired ulcer healing (Takehara et al., 1997).

Peptic ulcer is a break in the lining of the stomach, first part of the small intestine and the lower esophagus (Alshammari et al., 2018).

Omeprazole is an example of proton pump inhibitors (PPIs). It blocks gastric acid secretion by irreversibly inhibiting the hydrogen/potassium adenosine triphosphatase (H⁺/K⁺ ATPase) of the gastric parietal cell(Morjan et al., 2013).

Gliclazide is sulfonylurea used for the treatment of type 2 diabetes mellitus (T2DM). It act by binding to the β-cell sulfonylurea receptor  that blocks the ATP-sensitive potassium  channels, resulting in a decrease in potassium efflux leads to opening of voltage-dependent calcium channels, resulting in exocytosis of insulin containing secretory granules (Inzucchi      et al., 2012). It is preferred in therapy because of its selective inhibitory activity towards K⁺ATP channels, antioxidant property and low incidence of producing severe hypoglycemia (Mastan and Kumar, 2010).

MATERIALS AND METHODS

I- Materials

Animals:

Forty adult male Wistar albino rats weighing 250-300 grams were purchased from the animal house, Faculty of Veterinary Medicine, Assuit University. The animals were transmitted to Faculty of Veterinary Medicine, New Valley University. They were housed under standardized environmental conditions, fed with standard chow diet and tap water ad libitum and kept for 2 weeks to adapt the laboratory conditions before starting the experiment. All the animal experiments were conducted in accordance with the guide of the National Institutes of Health (NIH 1985) for the care of laboratory animals.

Chemicals and kits:

Alloxan monohydrate  was purchased fromLOBA chemie (Mumbai, India), gliclazide and omeprazole were purchased from AK Scientific (Union City, U.S.A.), carboxymethylecellulose (CMC) was purchased from SD Fine-Chem LTD. (Mumbai, India), glucose assay kit and TAC kitwere  purchased fromBiodiagnostic (Egypt), insulin ELISA kitwas purchased from Immunospec Corporation (USA), TNF-α ELISA kitwas purchased from Becton (USA).

II- Methods

Induction of diabetes mellitus: Rats were treated with a single dose of freshly prepared solution of alloxan monohydrate (100mg/kg) intraperitoneally (IP) after overnight fasting to induce diabetes (Mastan et al., 2009). During the first 24h of diabetes induction, alloxan treated animals were allowed to drink 5% glucose solution to overcome alloxan-induced hypoglycemia (Abdel Aziz et al., 2017).

To confirm the induction of diabetes mellitus:The blood glucose of each animal was measured using the glucometer. Diabetes was confirmed 48 hours after alloxan injection. Rats with blood glucose levels of 250 mg/dl and above were considered diabetic and selected for study (Ige and Adewoye, 2013).

Experimental design:

Animal groups:

Animals were randomly divided into five groups (8 animals per group):

Group I (Negative control group): The rats were injected IP with an equivalent volume of normal saline.

Group II (positive control group): The rats were injected IP with alloxan (100mg/kg) dissolved in normal saline to induce DM. Rats were received an equivalent volume of 0.5% CMC solution orally by gastric tube once daily for 28 consecutive days.

Group III (Effect of gliclazide on diabetic rats): Diabetic rats were received gliclazide at a dose 10 mg/kg suspended in 1ml of 0.5% CMC solution orally by a gastric tube once daily for 28 consecutive days.

Group IV (Effect of omeprazole on diabetic rats): Diabetic rats were received omeprazole at a dose 20 mg/kgsuspended in 1ml of 0.5% CMC solution orally by a gastric tube once daily for 28 consecutive days.

Group V (Effect of the combined administration of omeprazole and gliclazide on diabetic rats): Diabetic rats were received omeprazole at a dose 20 mg/kg and gliclazide at a dose 10 mg/kg orally by a gastric tube daily for 28 consecutive days.

Sample collection:

1. Serum samples:

The animals afterovernight fasting were anaesthetized with ether by placing the rat in an anesthetic box filled with ether vapor, which was maintained by periodically applying liquid ether to a cotton wool on the base of the box. When the surgical stage of anesthesia was reached (judged by loss of withdrawal reflexes) the animal was removed and placed on a table. The blood was collected from the retro-orbital plexus in micro centrifuge tube.The collected blood was allowed to clot in an upright position at room temperature for an hour; and then refrigerated for further an hour for clot retraction. Clear serum was separated by centrifugation at 3000 r.p.m. for 10-15 minutes and then collected in Eppendorf’s tubes processed directly for glucose determination, then kept in deep freezer at -20ºC for subsequent biochemical analysis (Hussein et al., 2015).

2. Tissue sample:

After blood samples collection the rats were sacrificed. The Pancreas was removed, rinsed in ice-cold 0.9% sodium chloride solution and prepared for histopathological evaluation (Hussein et al., 2015).

Experimental procedure:

1) Determination of serum glucose level:

Serum glucose level was estimated according to the enzymatic colorimetric method (Trinder, 1969).

2) Determination of serum insulin level:

Serum insulin levels were estimated by rat/mouse ELISA kit (Millipore) according to manufacture’s protocol (Zhang et al., 2008).

3) Determination of serum TAC:  

Serum TAC was determined using TAC colorimetric kit according to the manufacture’s protocol (Koracevic et al., 2001).

4) Determination of serum TNFα:  

Serum TNF-α level was estimated by ELISA kit according to manufacture’s protocol (Beyaert and Fiers, 1998).

5) Histopathological examination:

A small specimen of pancreas was fixed in 10% neutral buffered formalin solution for 24 hours and then washed by running water over night and dehydrated. The dehydrated samples were cleared in xylol for 6 hours. The specimens were placed in a crucible containing soft paraffin and kept in an oven at 56°C for 12 hours. The samples were then blocked in hard paraffin and cut into sections of about 5 microns in thickness. Then, the sections stained by hematoxylene and eosin and were examined under light microscopy at 200 X magnification (DP72, Olympus) (D Bancroft and Stevens, 2018).

Data management and statistical analysis:

The data were presented as means ± standard errors (SE) and analyzed by one-way analysis of variance (ANOVA). For the comparison of statistical significance between two groups, Student’s unpaired t-test was used. A P-value of < 0.05 was adopted as statistically significant. Data analysis was performed by using Graph Pad Prism 7 (Graph Pad software Inc., San Diego, USA).

RESULTS

1-  Effect of gliclazide, omeprazole and their combination on serum glucose level of diabetic rats:

These results are given in Table (1) and graphically illustrated in Figure (1).

The results showed that, serum glucose level was significantly increased (p < 0.001) in +ve control) in comparison with –ve control rats.

In diabetic rats treated with gliclazide 10 mg/kg orally for 28 consecutive days, serum glucose level was significantly decreased (p < 0.001) in comparison with diabetic rats (+ve control).

On the other hand, serum glucose level in diabetic rats treated with omeprazole 20 mg/kg orally for 28 consecutive days was significantly decreased (p < 0.001) in comparison with diabetic rats.

In diabetic rats treated with a combination of gliclazide 10 mg/kg and omeprazole 20 mg/kg orally for 28 consecutive days, serum glucose level was significantly decreased (p < 0.001) in comparison with diabetic rats.

Table 1: Effect of gliclazide (10 mg/kg), omeprazole (20 mg/kg) and their combination on serum glucose level, serum insulin level, serum TAC, serum TNF-α level in diabetic rats.

Data represent the mean ± SE of each group (n=8). ***:  significant difference at p < 0.001in comparison with –ve control. ###:  significant difference at p < 0.001in comparison with diabetic rats (+ve control) .

Figure (1): Effect of gliclazide (10 mg/kg), omeprazole (20 mg/kg) and their combination on serum glucose level of diabetic rats.

Data represents the mean ± SE of each group (n=8).

***: significant difference at p < 0.001 in comparison with –ve control.

###: significant difference at p < 0.00 in comparison with diabetic rats (+ve control).

2- Effect of gliclazide, omeprazole and their combination on serum insulin level of diabetic rats:

These results are given in Table (1) and graphically illustrated in Figure (2).

The results showed that, serum insulin level was significantly decreased (p < 0.001) in  diabetic rats in comparison with –ve control rats.

In diabetic rats treated with gliclazide 10 mg/kg orally for 28 consecutive days, serum insulin level was significantly increased (p < 0.001) in comparison with diabetic rats.

On the other hand, serum insulin level in diabetic rats treated with omeprazole 20 mg/kg orally for 28 consecutive days was significantly increased (p < 0.001) in comparison with diabetic rats.

In diabetic rats treated with a combination of gliclazide 10 mg/kg and omeprazole 20 mg/kg orally for 28 consecutive days, serum insulin level was significantly increased (p < 0.001) in comparison with diabetic rats.

Figure (2): Effect of gliclazide (10mg/kg), meprazole (20mg/kg) and their combination on serum insulin level of diabetic rats.

Data represents the mean ± SE of each group (n=8).

***: significant difference at p < 0.001 in comparison with –ve control .

 ###: significant difference at p < 0.001  in comparison with diabetic rats (+ve control).

3- Effect of gliclazide, omeprazole and their combination on serum TAC of diabetic rats:

These results are given in Table (1) and graphically illustrated in Figure (3).

The results showed that, serumTAC was significantly decreased (p < 0.001) in alloxan-induced diabetic rats (+ve control) in comparison with –ve control rats.

In diabetic rats treated with gliclazide 10 mg/kg orally for 28 consecutive days, serumTAC was significantly increased (p < 0.001) in comparison with untreated diabetic rats (+ve control).

On the other hand, serum TAC in diabetic rats treated with omeprazole 20 mg/kg orally for 28 consecutive days was significantly increased (p < 0.001) in comparison with untreated diabetic rats.

 In diabetic rats treated with a combination of gliclazide 10 mg/kg and omeprazole 20 mg/kg orally for 28 consecutive days, serumTAC was significantly increased (p < 0.001) in comparison with untreated diabetic rat.

Figure (3): Effect of gliclazide (10mg/kg), omeprazole (20mg/kg) and their combination on serum TAC of diabetic rats.

Data represents the mean ± SE of each group (n=8).

***: significant difference at p < 0.001 in comparison with –ve control.

###: significant difference at p < 0.001  in comparison with +ve control.

4- Effect of gliclazide, omeprazole and their combination on serum TNF-α level in diabetic rats.

These results are given in Table (1) and graphically illustrated in Figure (4).

The results showed that, serum TNF-α was significantly increased (p < 0.001) in alloxan-induced diabetic rats (+ve control) in comparison with –ve control rats.

In diabetic rats treated with gliclazide 10 mg/kg orally for 28 consecutive days, serum TNF-α was significantly decreased (p < 0.001) in comparison with untreated diabetic rats (+ve control).

On the other hand, serum TNF-α  in diabetic rats treated with omeprazole 20 mg/kg orally for 28 consecutive days was significantly decreased (p < 0.001) in comparison with untreated diabetic rats (+ve control).

In diabetic rats treated with a combination of gliclazide 10 mg/kg and omeprazole 20 mg/kg orally for 28 consecutive days, serum TNF-α was significantly increased (p < 0.001) in comparison with untreated diabetic rats (+ve control).

Figure (4): Effect of gliclazide (10mg/kg), omeprazole (20mg/kg) and their combination on TNFα of diabetic rats.

Data represents the mean ± SE of each group (n=8).

 ***: significant difference at p < 0.001 in comparison with –ve control.

 ###: significant difference at p < 0.001 in comparison with +ve control.

5- Effect of gliclazide, omeprazle and their combination on histopathological changes of pancreatic tissues in diabetic rats:

Examined sections of pancreas of -ve control rats showed the normal histopathological structure of β-cells at the islets of Langerhans and normal pancreatic acini (Figure 5A). The pancreas of alloxan-induced diabetic rats showed damaged β-cells due to   necrosis leading to decreased its number and degeneration of pancreatic acini (Figure 5B).  Diabetic rats treated with gliclazide revealing regenerating β-cells and pancreatic acini (Figure 5C). Examined sections of the pancreas of diabetic rats treated with omeprazole showed an increase number of β-cells with mild hyalinosis of some β-cells and normal acini (Figure 5D). The pancreas of diabetic rats  treated with combination of gliclazide and omeprazole showed nearly normal histopathological structure of β-cells at the islets of Langerhans and normal pancreatic acini (Fiure 5E).

Figure (5): Histopathological changes in pancreatic  tissue from rats of the studied groups x200:

A) -ve control rats showed the normal histopathological structure of β-cells in the islets of Langerhans (arrowhead) and normal pancreatic acini (arrow) H&E, X200. B) Alloxan-induced diabetic rats showed damaged β-cells due to necrosis leading to decreased its number (arrow) and degeneration of pancreatic acini (arrowhead) H&E, X200. C) Diabetic rats treated with gliclazide revealing regenerating β-cells (arrow head) and pancreatic acini (arrow) H&E, X200. D) Diabetic rats treated with omeprazole showed an increase number of β-cells with mild hyalinosis of some β-cells (arrowhead) and normal acini (arrow) H&E, X200. E) Diabetic rats  treated with a combination of gliclazide and omeprazole showed nearly normal histopathological structure of β-cells at the islets of Langerhans (arrowhead) and normal pancreatic acini (arrow) H&E, X200.

DISCUSSION

Experimental DM was induced, according to Mastan et al. (2009)by injecting of alloxan monohydrate 100mg/kg  IP as a single dose. Alloxan monohydrate induces diabetes by destroying the insulin-producing β-cells of the pancreas (Oberley, 1988). This action is mediated by ROS with a simultaneous massive increase in intracellular calcium concentration leading to a rapid destruction of β cells(Szkudelski, 2001).

As regarding serum glucose level, results of this study showed that serum glucose level significantly increased in alloxan-induced diabetic rats in comparison with –ve control rats. This reults are consistent with Mastan et al. (2009).

The present study investigated  that serum glucose level was significantly decreased in diabetic rats treated with gliclazide 10 mg/kg for 28 consecutive days, in comparison with diabetic rats. This was similar to results reported by Agrawal and Gupta (2013) who reported that gliclazide has a glucose lowering effect in diabetic rats.

Gliclazide is a second generation sulfonylurea and it acts on β-cells of pancreas and stimulate insulin secretion by reducing the permeability of K⁺ ion channels. In addition, it increases the sensitivity of peripheral tissue to insulin and reduces insulin resistance (Nasry et al., 2013).

Treatment of diabetic rats with omeprazole 20 mg/kg for 28 consecutive days cause significant reduction in serum glucose level in comparison with diabetic rats. This results similar to  recent retrospective electronic medical record examination indicated that patients with T2DM taking PPIs (omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole) showed improved glycaemic control compared with a group of patients not taking a PPIs (Lin et al., 2016).

The explanation is PPIs have been shown to increase endogenous gastrin levels in animals and humans. It has also been suggested that gastrin may exert functional role in stimulating insulin secretion which in turn is responsible for its hypoglycemic effect (Takebayashi and Inukai, 2015).

This study indicated that gliclazide at 10 mg/kg or omeprazole at 20 mg/kg was to some extent reduce the serum glucose level, while serum glucose level was pointedly decreased with a combination of gliclazide 10 mg/kg and omeprazole 20 mg/kg indicating that interaction of PPIs with antidiabetic occurred by therapeutic doses. This is in accordance with previous study of kumar et al. (2000) that reported that omeprazole significantly enhanced the hypoglycaemic activity of sulfonylureas in albino rabbits.

The literature reports reveal that sulfonylureas are metabolized mainly by CYP2C9 and CYP3A. PPIs probably inhibits CYP isoenzymes that are responsible for metabolism of sulfonylureas. It may be concluded that during concomitant administration of sulfonylureas and omeprazole at therapeutic doses, drug–drug interaction does occur (Schelleman et al., 2014).

In disagree with this results, Mrudula et al. (2017) reported that in vivo studies conducted on alloxan-induced diabetic rats showed that there are no interactions at therapeutic doses with PPIs but at higher doses it enhanced the anti-diabetic potential of sulfonylureas like glipizide and glibenclamide. They explained that sulfonylureas are mainly metabolized by CYP3A4 and CYP2C9, the weak inhibitory effect of the PPI's on the same enzyme shows significant interaction only at higher doses, but is safe to be administered concomitantly at therapeutic doses.

As regarding insulin, the present study noted that serum insulin level was significantly decreased in diabetic rats in comparison with –ve control rats. This reults are consistent with Ryle et al. (1984).

Sustained hyperglycemia has been identified as a principle mediator of increased ROS generation in diabetes (Santakumari et al.,2003). This might be the result of suppression of β-cell proliferation and inhibition of insulin gene transcription (Robertson     et al., 2003) that caused impairment of insulin release.

Data of the present investigation showed that gliclazide significantly increase the serum insulin level, same as the study conducted by Dachicourt     et al. (1998) who have examined the effects of gliclazide treatment on the severity of diabetes in  rats. In the gliclazide-treated rats, plasma glucose levels declined progressively and their  insulin levels decreased to values similar to those in non-diabetic rats. They concluded that gliclazide improves β-cell function through improvement of the insulin content per individual β-cell. sulfonylurea is a direct insulin secrectagogue; indirectly it also increase insulin secretion in response to fuels such glucose (Röder    et al., 2016).

In diabetic rats treated with omeprazole, serum insulin level was significantly increased in comparison with diabetic rats. There results are similar to the results of Bödvarsdóttir et al. (2010) who showed that the PPIs increase endogenous gastrin levels and insulin content of the pancreas and the level of insulin in the blood are increased.

In contrast, no differences in glucose levels or insulin secretion were found in another study that examined the effects of treatment with PPIs in  patients with T2DM, despite a 9-fold increase in endogenous gastrin levels (Dupre et al., 1969).

Data of the current study revealed that combined administration of gliclazide and omeprazole cause significant increase in serum insulin levels in comparison with diabetic rats. The percent of increase is more than each single administration. In agreement with this results, Phadatare et al. (2011) stated that Sulfonylurea and PPIs combination therapy produced hypoglycemia or antihyperglycemia and increased the serum insulin level in normal and diabetic rats.

Sulfonylurea produced hypoglycemia in normal/ diabetic rats, omeprazole is metabolized by hepatic CYP2C19 and CYP3A4 and there is more possibility that omeprazole inhibit the metabolism of gliclazide, which is metabolized by CYP3A4 and CYP2C9 (Gökalp et al., 2011). Furthermore, the presence of interaction was supported by an increase in serum insulin levels with omeprazole treatment.

As redarding TAC, The present data showed that serum TAC was significantly decreased in alloxan-induced diabetic rats in comparison with –ve control rats. This finding further supports and thus confirms the previous result that diabetes is associated with impaired antioxidant defences (Vicentini et al., 2011).The resultsof the present study corroborate the finding that shows a decline in the activities of antioxidant enzymes in diabetic rats (Das and Sil, 2012).

During diabetic state, increased generation of ROS occur and cause an imbalance between the oxidant and antioxidant status (Noda et al., 2000).

The marked increase in serum TAC level noticed in this study in the diabetic rats treated with gliclazide, is in accordance with Mourya et al. (2018) who reported that administration gliclazide to patients with T2DM resulted in an increase in the antioxidant parameters, TAC, MDA, SOD and thiols.

Data of the current study showed that administration of omeprazole to diabetic rats significantly increased TAC in comparison with untreated diabetic rats. There results were similar to that of previous authors Abdelzaher et al. (2017)who reported that omeprazole significantly improved tissue oxidative stress parameters (MDA, CAT, SOD, NO) in diabetic rats compared to the non-treated diabetic rats.

Biswas and his workers (2003) stated that PPIs exhibit anti-oxidant effects of ROS by blocking membrane lipid peroxidation and protein oxidation, omeprazole have gastro-protective effects via inhibition of oxidative tissue damage and a direct scavenging activity against the hydroxyl radical.

In the present study, the elevated serum TNF-α level in diabetic rats, is in accordance withSwaroop et al. (2012) who recently reported that uncontrolled diabetes significantly enhanced TNF-α level.

Inflammatory cytokines as TNF-α has been involved in the pathogenesis of DM (Lushchak et al., 2018), it catalyzes multiple signaling cascades which resulted in β-cell apoptosis. TNF-α destroy the pancreatic β-cells and created DM via enhancing the formation of free radicals, lipid peroxides and aldehydes (El-Hadidy et al., 2015).

The serum TNFα level was significantly decreased in diabetic rats treated with gliclazide in comparison with untreated diabetic rats. This observed decrease in TNF-α level is in agreement with the findings ofMourya et al. (2018)who found that the administration of gliclazide in patient with T2DM inhibit the enhanced production of TNF-α.

This could be attributed to that gliclazide possesses a unique azabicyclo-octyl ring act as a general free radical scavenger (Palsamy and Subramanian, 2010) which inhibit TNF-α production (Drzewoski and Zurawska-Klis, 2006).TNF-α exacerbate diabetic complications by promoting tissue ischemia so, suppression of increased TNF-α may ameliorate diabetic complications(Yan et al., 2018).

Administration of omeprazole to diabetic rats significantly decreased the level of TNF-α, this result is in accordance with the study of Abdelzaher et al. (2017)who reported that omeprazole significantly decreased the level of serum TNFα in diabetic rats and the work of Onda et al., 2017 who showed that PPIs decreased cytokine secretion.

The histopathological data of this study also support the results of biochemical markers. In pancreas of alloxan-induced diabetic rats, There were atrophy and necrosis of β-cells and decreasing in β-cells number. These data were in agreement withShah and Khan (2014)and El-Esawy et al. (2016)who demonstrated that diabetic rats show damaged β cells due to necrosis and a decreased number of β cells and  Yagihashi (2017)who reported that β-cell massis reduced in diabetic patients.

Alloxan induces hyperglycemia by specific cytotoxic impact on pancreatic β-cells leading to its damage. One of the intracellular phenomena for its cytotoxicity is through the production of free radicals (Yadav et al., 2002).

Treatment of diabetic rats with gliclazide showed a significant protection of islets of Langerhans and acinar cells in comparison to that of the diabetic group. Our results are similar to the results of  Kimoto et al. (2003) who demonstrated that gliclazide could protect pancreatic β-cells from oxidative damage. Thier results suggest that gliclazide reduces oxidative stress of beta-cells by H₂O₂ probably due to its radical scavenging activity and results of Parim et al. (2016)who investigated that treatment of diabetic rats with gliclazide lead to regeneration of β-cells.

The present information expresses that omeprazole showed significant reduction of histopathological changes and increased β-cells number  in comparison with diabetic rats. This results similar to the results of Beamish et al. (2017)who reported that PPIs lead to endogenous hypergastrinaemia. Gastrin has been shown to promote beta-cell proliferation in rodents. Also, Rooman et al. (2002) noticed an increase in the number of single, extra-insular β-cells and small beta-cell clusters after gastrin treatment following pancreatic duct ligation in rats, suggesting increased β-cell neogenesis.

However, this showed disagreement with the results reported by the study of Breuer et al. (2016) who showed that PPIs treatment was not associated with changes in glucose control, islet morphology or new β-cell formation.

CONCLUSION

Finally, it can be concluded that, in the treatment of DM associated with peptic ulcer, application of  antidiabetic agent gliclazide in combination with omeprazole would have drug-drug interaction. The antidiabetic action of gliclazide was enhanced by omeprazole as regard our data obtained by  laboratory and histopathological results.

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