|Year : 2016 | Volume
| Issue : 1 | Page : 24-30
Protective effect of exenatide (glucagon-like peptide-1 receptor agonist) on renal ischemia–reperfusion injury in diabetic rats
Ola A El-Gohary, Mona A Said
Department of Physiology, Faculty of Medicine, Benha University, Benha, Egypt
|Date of Submission||06-Jun-2015|
|Date of Acceptance||25-Sep-2015|
|Date of Web Publication||28-Nov-2016|
Ola A El-Gohary
Physiology Department, Faculty of Medicine, Benha University, Benha, 13518
Source of Support: None, Conflict of Interest: None
Aim Diabetes mellitus (DM), especially type 2, is a major health problem, and diabetic nephropathy is the main cause of end-stage renal disease. Renal ischemia–reperfusion (I/R) injury is common in diabetic patients. Recent studies reported increased vulnerability of kidneys to I/R injury in diabetic rats. In view of the reported efficacy of glucagon-like peptide-1 (GLP-1) on I/R injury, this study was designed to assess the effect of exenatide (GLP-1) on renal I/R in type 2 DM.
Materials and methods Type 2 DM in rats was induced by administration of nicotinamide (110 mg/kg, intraperitoneal), 15 min before a single dose of streptozotocin (45 mg/kg, intraperitoneal). Renal I/R was performed in both diabetic and normal rats. The protocol comprised ischemia for 30 min followed by reperfusion for 24 h aynd a treatment period with exenatide 2 weeks before induction of ischemia.
Results Renal I/R in diabetic rats induced marked renal dysfunction associated with a significant increase in malondialdehyde, nitric oxide, and tumor necrosis factor α levels. Antioxidant enzymes such as reduced glutathione and superoxide dismutase were significantly reduced. Exenatide treatment significantly normalized these biochemical parameters compared with diabetic I/R rats.
Conclusion In conclusion, exenatide protects renal I/R injury in type 2 DM. These findings have major implication in the treatment of ischemic injury that is prone to develop in DM.
Keywords: diabetes mellitus, exenatide, glucagon-like peptide 1, ischemia– reperfusion, kidney, oxidative stress
|How to cite this article:|
El-Gohary OA, Said MA. Protective effect of exenatide (glucagon-like peptide-1 receptor agonist) on renal ischemia–reperfusion injury in diabetic rats. Benha Med J 2016;33:24-30
|How to cite this URL:|
El-Gohary OA, Said MA. Protective effect of exenatide (glucagon-like peptide-1 receptor agonist) on renal ischemia–reperfusion injury in diabetic rats. Benha Med J [serial online] 2016 [cited 2017 Aug 19];33:24-30. Available from: http://www.bmfj.eg.net/text.asp?2016/33/1/24/194384
| Introduction|| |
Diabetes mellitus (DM) is currently a major health problem all over the world. It is a chronic metabolic disorder resulting from an interaction of hereditary and environmental factors . It is classified into type 1 (insulin-dependent) and type 2 (non-insulin-dependent) DM. Type 2 DM is a heterogeneous disorder characterized by insulin resistance . The incidence of type 2 DM is increasing significantly and is associated with high morbidity and mortality rates . Increased glucose states are associated with many renal complications . The recent studies have demonstrated a higher incidence of nephropathy in type 2 DM than in type 1 DM patients . Diabetic patients are at a higher risk for ischemic problems caused by decreased blood flow . With increasing duration and severity of ischemia, cell damage can develop predisposing to a spectrum of reperfusion-associated pathologies, collectively called reperfusion injury . Imbalance between reactive oxygen species (ROS) and antioxidant capacity as well as nitric oxide (NO) plays an important role in mediating cell damage during ischemia–reperfusion (I/R) injury ,,,. Inflammation also contributes substantially to the pathogenesis of I/R, with a central role for adhesion molecules and cytokines .
Various drug therapies are used in the treatment of type 2 DM and its complications . Of the currently available oral antidiabetic agents, sulfonylureas are widely used by many diabetic patients. However, sulfonylureas potently and persistently stimulate insulin secretion irrespective of blood glucose levels, thereby causing hypoglycemia, which is a common undesirable side effect . As such, there is a need to develop efficient new therapeutic strategies for the treatment of type 2 DM. During the investigation of new antidiabetic drugs that do not have the disadvantages of sulfonylureas, glucagon-like peptide 1 (GLP-1), an incretin analog, attracted attention. The insulinotropic action of GLP-1 is glucose dependent; therefore, the risk for hypoglycemia is minimized .
Recent evidence has demonstrated the beneficial effects of GLP-1-associated drugs in the treatment of type 2 DM . GLP-1 is a 30-amino acid hormone secreted by the small intestine in response to nutrient ingestion and degraded by the enzyme dipeptidyl peptidase-IV. GLP-1 acts through the GLP-1 receptor, which is a G-coupled protein receptor expressed not only in the gastrointestinal tract but also in the nervous system, heart, vascular smooth muscles, proximal tubules, and glomeruli of the kidney ,. GLP-1 increases insulin secretion from pancreatic β-cells and reduces glucagon release from a-cells through induction of adenylate cyclase and cyclic adenosine monophosphate production ,.
GLP-1 receptor agonists extend the effects of endogenous GLP-1 by resisting enzymatic degradation . The GLP-1 receptor agonist exendin-4 is a 39-amino acid peptide that was originally isolated from the salivary secretions of the Gila monster lizard . A synthetic version of exendin-4, exenatide, is currently used for the treatment of type 2 DM . The administration of GLP-1 receptor agonists results in greater improvements in glycemic control when administered as monotherapy or in combination with one or two oral antidiabetic drugs in patients with type 2 DM. Moreover, these drugs seem to exert a number of other pleiotropic effects on diabetic nephropathy ,. GLP-1 have reported efficacy in I/R injury ,. Thus, this study was designed to assess the effect of exenatide (GLP-1 receptor agonist) on renal I/R in type 2 DM.
| Materials and methods|| |
This study was conducted on 40 adult Wistar albino male rats, 6–8 weeks old, weighing between 170 and 200 g. The animals were housed in the Animal Laboratory at the Medical Research Center of Benha Faculty of Medicine. They were housed at room temperature (25°C) and 12/12 h light/dark cycle. All rats were fed a standard diet and water.
Groups of the experiment
The animals were randomly divided into five groups of eight rats each.
Group I (the control group) included normal sham-operated rats (underwent all surgical procedures without I/R in normal rats).
Group II (the diabetic group) included diabetic sham-operated rats (underwent all surgical procedures without I/R in diabetic rats).
Group III (the I/R group) included IR-induced normal rats. On day 28, ischemia was produced for 30 min, followed by reperfusion for 24 h.
Group IV (the DM+I/R group) included IR-induced diabetic rats. After induction of diabetes, on day 28, I/R was induced.
Group V (the exenatide+DM+I/R group) included exenatide-treated rats. In diabetic rats, on day 14, exenatide was injected at a dose of 10 mcg, subcutaneously, twice a day for 2 weeks . On day 28, I/R was induced.
It was purchased from Sigma-Aldrich Chemical Co., St. Louis, Mo, USA. It was dissolved in freshly prepared sodium citrate buffer pH 4.5.
It was purchased from Sigma-Aldrich Chemical Co. It was dissolved in normal physiological saline.
It was purchased from Sigma-Aldrich Chemical Co. It was supplied as a sterile solution for subcutaneous injection (250 μg/ml).
Induction of diabetes mellitus
Type 2 DM was induced in rats by administering nicotinamide (110 mg/kg, intraperitoneal) 15 min before a single dose of streptozotocin (45 mg/kg, intraperitoneal) . The animals were allowed to drink 5% glucose solution overnight to overcome drug-induced hypoglycemia. Control rats were injected with the buffer alone. Diabetes was verified 72 h later by measuring blood glucose levels (after an overnight fasting) with the use of glucose oxidase reagent strips. Rats having blood glucose level of 250 mg/dl or greater were considered to be diabetic. Four weeks elapsed between the induction of diabetes and ischemic injury.
Renal ischemia–reperfusion injury
Diabetic and normal rats were anesthetized with ketamine (60 mg/kg, intraperitoneal) and diazepam (5 mg/kg, intraperitoneal). After anesthesia, the animal was fixed in supine position on the operating table and the abdominal skin was shaved and disinfected with povidone–iodine solution. All rats underwent surgical exposure of the left and right renal pedicles through midline incision. To induce renal ischemia, both renal pedicles were occluded for 30 min using a nontraumatic vascular clamp. After 30 min of occlusion, the clamps were removed and the kidneys were subjected to reperfusion. The abdomen was properly irrigated with isotonic saline, and then the abdominal incision was closed by means of continuous stitches using vicryl 2/0 sutures.
Urine sample collection
Urine samples were collected for 24 h (at the end of the reperfusion periods) after placing each rat in a metabolic cage, and, to avoid urea degradation, urine samples were maintained frozen. Urinary albumin was measured by means of quantitative reaction using a Sigma Diagnostic Kit (Sigma-Aldrich Chemical Co., St. Louis, Mo, USA).
Blood sample collection
Blood samples were taken 24 h after ischemia (reperfusion period). A craniocaudal incision of about 2 cm was made, parallel and slightly to the left of the sternum through the skin and pectoral muscles to expose the ribs. A blunt curved forceps was then inserted between the fifth and sixth ribs, through the intercostals muscles. The gap was widened so that the rapidly beating heart becomes visible, and then the blood samples were taken from the right ventricle.
Blood samples were allowed to clot at room temperature and sera were separated by means of centrifugation at 3000 rpm for 15 min. Sera were used for biochemical assessment of serum glucose using the glucose oxidase–peroxidase method (GOD–POD Kit, Accurex Biomedicals Pvt. Ltd., Mumbai, India), blood urea nitrogen (BUN) (Jaffe’s method), creatinine (the DAM method), and aspartate aminotransferase (AST), using standard diagnostic Kits (Sigma-Aldrich Chemical Co.); serum tumor necrosis factor a (TNF-α) was determined using an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota, USA).
The previous incision was continued through the animal’s anterior abdominal wall. The abdominal cavity was entered by cutting the muscles and peritoneum. The kidneys were exposed and then freed from the surrounding tissue. Kidneys were quickly excised and portions of kidney tissues were homogenized in a saline solution (0.9%), centrifuged at 3000 rpm for 15 min, and the supernatant was kept at −20°C and used for the determination of antioxidant parameters such as malondialdehyde (MDA) , superoxide dismutase (SOD) , and reduced glutathione (GSH) ; however, NO was estimated using the method described by Lepoivre et al. .
| Results|| |
Effect of exenatide on serum glucose concentration
Administration of nicotinamide (110 mg/kg, intraperitoneal) followed by STZ (45 mg/kg, intraperitoneal) resulted in a significant elevation of serum glucose level in the DM group compared with the control group (P < 0.05), but no significant difference was found on comparing the I/R group and the control group. On performing renal I/R to diabetic rats, they produced a significant increase in serum glucose concentration as compared with both diabetic animals (P < 0.05) and I/R animals (P < 0.05). Moreover, pretreatment of rats with exenatide (10 μg/kg) produced a significant hypoglycemic effect (P < 0.05) as compared with the DM+I/R group ([Table 1]).
|Table 1 Effect of exenatide on serum glucose concentration and renal function after renal ischemia–reperfusion in normal and diabetic rats|
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Effect of exenatide on renal function
There was a significant increase in BUN and serum creatinine in both the DM group (P < 0.05) and the I/R group (P < 0.05) compared with the normal control group. In addition, serum level of AST was found to be significantly increased in the I/R group compared with the normal control group (P < 0.05), whereas this increase did not reach statistical significance on comparing the DM group and the control group. Diabetic animals that underwent renal I/R exhibited a significant increase in the serum concentrations of BUN, creatinine, and AST as compared with DM animals (P < 0.05), suggesting a significant degree of glomerular dysfunction. Serum concentrations of BUN, creatinine, and AST were also significantly increased in the DM+I/R group compared with the I/R group (P < 0.05). Pretreatment of rats with exenatide produced a significant reduction in the serum levels of these parameters as compared with the DM+I/R group (P < 0.05). As regards urine albumin, the results showed a significant increase in 24-h urine albumin in both the DM group (P < 0.05) and the I/R group (P < 0.05) compared with the normal control group. Performing renal I/R to diabetic rats was associated with a significant increase in urine albumin as compared with the DM group (P < 0.05) and the I/R group (P < 0.05). Exenatide supplementation resulted in a significant reduction in 24-h urine albumin (P < 0.05), compared with the DM+I/R group ([Table 1]).
Effect of exenatide on lipid peroxidation and antioxidant enzymes
MDA content of the renal tissue was found to be significantly increased in both the DM group (P < 0.05) and the I/R group (P < 0.05) compared with the normal control group. Moreover, the renal MDA content in diabetic rats was elevated after induction of I/R injury, compared with the DM group (P < 0.05) and the I/R group (P < 0.05). However, the exenatide-treated group significantly decreased the I/R-induced elevation in renal MDA level as compared with the DM+I/R group (P < 0.05) ([Table 2]).
|Table 2 Effect of exenatide on lipid peroxidation and antioxidant enzymes after renal ischemia–reperfusion in normal and diabetic rats|
Click here to view
As regards the antioxidant enzyme activity, the renal tissue SOD and GSH contents were significantly decreased in both the DM group (P < 0.05) and the I/R group (P < 0.05) compared with the normal control group. Moreover, I/R in diabetic rats demonstrated a significant decrease in renal tissue SOD and GSH contents in comparison with DM animals (P < 0.05) and I/R animals (P < 0.05), whereas in the exenatide-treated group, renal SOD and GSH contents were found to be significantly increased (P < 0.05), compared with the DM+I/R group.
The serum TNF-α level was significantly increased in the DM group (P < 0.05) and the I/R group (P < 0.05) compared with the normal control group. In DM+I/R rats, serum TNF-α level was significantly higher compared with the DM group (P < 0.05) and the I/R group (P < 0.05). The exenatide-treated group had significantly lower serum TNF-α level (P < 0.05) compared with the DM+I/R group.
The levels of NO were increased in the DM group (P < 0.05) and the I/R group (P < 0.05) as compared with the normal control group. In addition, NO levels showed a significant increase in diabetic animals that underwent renal I/R, compared with either the DM group (P < 0.05) or the I/R group (P < 0.05). The exenatide-treated group demonstrated a significant decrease in NO level (P < 0.05) as compared with the DM+I/R group.
| Discussion|| |
DM, especially type 2, causes organ dysfunction and increases the sensitivity of organs to damages. DM and hyperglycemia render the kidney more susceptible to ischemic injury . Ischemia of the kidney starts a series of incidents including cellular dysfunction and necrosis . However, reperfusion can paradoxically create more tissue injury. It seems that the effects of I/R injury on renal cells are multifactorial, involving hypoxia, free radical damage, and inflammatory responses . There is growing evidence that treatment with GLP-1 receptor agonists may be effective in decelerating the progression of I/R injury ,. Therefore, in the present study, we examined the effect of renal ischemia for 30 min on renal functions, proinflammatory cytokines TNF-α, and oxidant markers in STZ–nicotinamide-induced diabetic rats and the possible role of exenatide in these changes.
In the present study, diabetic rats showed a significant increase in serum blood glucose, BUN, serum creatinine, urine albumin, TNF-α, NO, and MDA, as well as a significant decrease in antioxidant enzymes (SOD and GSH). Induction of I/R in diabetic rats caused significant increase in serum blood glucose, BUN, serum creatinine, urine albumin, TNF-α, NO, MDA and AST as well as significant decrease in SOD and GSH, as compared with diabetic rats. At the same time, there was a negative correlation between exenatide and these parameters. These findings suggest the possible role of proinflammatory cytokines, TNF-α, and oxidative markers in the pathogenesis of ischemic injury in diabetic kidney.
The present study showed a significant increase in the blood glucose in diabetic rats, with a further increase by induced renal I/R injury. These results are in agreement with those reported by Mohamed et al. .
As regards kidney functions, diabetic rats showed impaired renal function in the form of significant increase in BUN and serum creatinine levels associated with increased 24-h urinary albumin excretion as compared with normoglycemic ones. These findings, which are in agreement with several studies ,, are considered as an indicator of deteriorated renal function ,. In addition, the data of the current work confirmed the findings of Yousef et al.  and Gabr et al. , who found that the combination of renal ischemia with diabetes raised the renal dysfunction more than did diabetes alone, leading to a marked increase in serum urea, creatinine, AST, and urine albumin, suggesting a significant impairment of the glomerular function. These results emphasize the hypothesis of Melin et al. , who stated that the combination of both diabetes and renal ischemia plays a major role in the development of diabetic nephropathy. Type 2 diabetes can cause increased sensitivity to renal I/R as observed experimentally through several mechanisms. One possible mechanism was hyperglycemia and its secondary effects such as formation of advanced glycosylated end products and increased oxidative stress. Hemodynamic alterations could be a contributing factor. Formation of NO could also be involved. Moreover, shortage of insulin could play a role in the increased sensitivity to I/R .
In addition, both diabetic rats and rats exposed to renal I/R exhibited an increase in oxidative stress product including tissue MDA. There was a depletion of the antioxidant enzyme pool, demonstrated by the declined activity of SOD and GSH in kidney tissues. This notion was confirmed by Vaghasiya et al. , who emphasized that the oxidative stress is implicated both in the complications of type 2 diabetes and renal I/R and that the combined oxidative stress from these two sources may, thus, increase the total level of ROS. Kakadiya et al.  documented that during renal I/R much of the tubular and glomerular dysfunction occurs during the reperfusion period following anoxia. Generation of ROS has been postulated as one of the major factors, contributing to this reperfusion injury . In renal I/R injury, ROS react with lipids, leading to lipid peroxidation of biological membranes , which in turn impacts enzymatic processes, such as ion pump activity, that inhibit transcription and repair of DNA ,.
The present study showed a significant rise in serum TNF-α level in diabetic rats and in ischemic rats when compared with normal control rats. However, the marked rise was found in diabetic ischemic rats. These findings are in agreement with several investigations that demonstrated a significant rise in the serum level of TNF-α in renal I/R injury as well as in diabetic rats ,. The enhanced TNF-α production in ischemic diabetic rats may result from the hyperglycemia  and the increased generation of ROS . Hyperglycemia-induced oxidative stress and products of lipid peroxidation likewise serve as activators of transcription factors, leading to induction of gene expression of proinflammatory cytokines and release of many inflammatory cytokines, such as TNF-α and IL-6 . TNF-α may produce a renal injury, inducing apoptosis, necrotic cell death, alterations of intraglomerular blood flow, and glomerular filtration rate as a result of the hemodynamic imbalance between the vasoconstrictive and vasodilatory mediators . Impairment of the barrier function of the glomerular capillary wall leads to the enhanced albumin permeability . At the molecular level, TNF-α augments the release of many inflammatory factors from renal mesangial cells . These findings are in agreement with those of Araki et al.  and Kher et al. , who reported that the oxidative stress and the inflammatory response might play a pathophysiological role in renal I/R injury in type 2 diabetes. This may confirm the results of the present study in which there was a significant positive correlation between serum TNF-α and renal tissue content of MDA.
Another point of interest in the present study was to investigate the involvement of NO in the development of renal I/R injury in DM. NO was significantly elevated in renal tissue in diabetic ischemic rats. This result is in agreement with the findings of many authors who documented that inducible nitric oxide synthase is activated in the kidney of rats, soon after the induction of diabetes ,. The NO system may be involved in the increased sensitivity to I/R in DM. The reaction of NO with O2 results in peroxynitrite formation, a potent and aggressive cellular oxidant, and causes the formation of 3-nitro-l-tyrosine. Nitrite/nitrate levels, as the end products of NO conversion, were increased in blood plasma and aortic tissue in diabetic animals compared with nondiabetic ones , which was confirmed by elevated NO level in the current study.
Exenatide treatment in diabetic I/R rats reduced the oxidative stress and the biomarkers of the inflammation, which are determinant factors in the course of renal disease. Treatment with exenatide prevented renal I/R-induced lipid peroxidation and protected the kidneys from severe attenuation of antioxidant enzyme activity in rats exposed to the renal I/R. In addition, it improved the functional renal parameters such as BUN and creatinine, AST, and urine albumin.
Several mechanisms might be responsible for the renoprotective effects of exenatide against renal I/R. First, the restoration of normoglycemia, because glucose metabolism is stimulated over fatty acid metabolism . An increased sensitivity to ischemia has been demonstrated when blood glucose level was raised by dextrose infusion or intraperitoneal glucose injection in combination with renal I/R in dogs . In our study, we found that glucose controlled by means of exenatide pretreatment could have a protective effect against renal I/R in type 2 DM.
In addition, exenatide might reduce apoptosis and oxidative stress. Timmers et al  demonstrated that the activity of the antioxidant enzymes was higher in animals treated with exenatide and nuclear oxidative stress was reduced. In the current study, decreased MDA activity and increased SOD and GSH in the treatment with exenatide demonstrated the reduction in nuclear oxidative stress. The results of the present study are in agreement with those performed by others, which have been suggesting an antioxidant and anti-inflammatory effect of incretin modulators, due to attenuation of the deleterious effects of oxidative stress and protection against the cytokine-induced apoptosis and necrosis ,. Therefore, the protection afforded by exenatide reflects improved glucose metabolism as well as anti-inflammatory, antioxidant, and antiapoptotic effects.
In conclusion, type 2 diabetes provoked an exaggerated renal I/R injury in STZ–nicotinamide-treated rats. Exenatide treatment attenuated renal I/R in diabetic rats by modifying the oxidative stress and the inflammation processes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Daisy P, Balasubramanian K, Rajalakshmi M, Eliza J, Selvaraj JInsulin mimetic impact of catechin isolated from Cassia fistula on the glucose oxidation and molecular mechanisms of glucose uptake on Streptozotocin-induced diabetic Wistar ratsPhytomedicine2010172836
Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao PCombination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screeningPharmacol Res200552313320
Leong A, Dasgupta K, Chiasson JL, Rahme EEstimating the population prevalence of diagnosed and undiagnosed diabetesDiabetes Care20133630023008
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al.
Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)Diabetes Care20123513641379
Yokoyama H, Okudaira M, Otani T, Sato A, Miura J, Takaike H et al.
Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in JapanKidney Int200058302311
Hokama JY, Ritter LS, Davis-Gorman G, Cimetta AD, Copeland JG, McDonagh PFDiabetes enhances leukocyte accumulation in the coronary microcirculation early in reperfusion following ischemiaJ Diabetes Complications20001496107
Yellon DM, Baxter GFProtecting the ischaemic and reperfused myocardium in acute myocardial infarction: distant dream or near reality?Heart2000834381387
Basireddy M, Isbell TS, Teng X, Patel RP, Agarwal AEffects of sodium nitrite on ischemia–reperfusion injury in the rat kidneyAm J Physiol Renal Physiol2006290F779F786
Erdogan H, Fadillioglu E, Yagmurca M, Uçar M, Irmak MKProtein oxidation and lipid peroxidation after renal ischemia–reperfusion injury: protective effects of erdosteine and N-acetylcysteineUrol Res2006344146
Yildirim A, Gumus M, Dalga S, Sahin YN, Akcay FDehydroepiandrosterone improves hepatic antioxidant systems after renal ischemia/reperfusion injury in rabbitsAnn Clin Lab Sci200333459464
Noiri E, Nakao A, Uchida K, Tsukahara H, Ohno M, Fujita T et al.
Oxidative and nitrosative stress in acute renal ischemiaAm J Physiol Renal Physiol2001281F948F957
Ysebaert DK, De Greef KE, De Buef A, Van Rompay AR, Vercauteren S, Persy VP, De Broe MET cells as mediators in renal ischemia/reperfusion injuryKidney Int200466491496
Sheikh-Ali M, Raheja P, Borja-Hart NMedical management and strategies to prevent coronary artery disease in patients with type 2 diabetes mellitusPostgrad Med20131251733
Stahl M, Berger WHigher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureasDiabet Med199916586590
MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MBThe multiple actions of GLP-1 on the process of glucose-stimulated insulin secretionDiabetes200251Suppl 3S434S442
Simsek S, Galan BECardiovascular protective properties of incretin-based therapies in type 2 diabetesCurr Opin Lipidol201223540547
Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain MCardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathwaysCirculation200811723402350
Bullock BP, Heller RS, Habener JFTissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptorEndocrinology199613729682978
Burgmaier M, Heinrich C, Marx NCardiovascular effects of GLP-1 and GLP-1-based therapies: implications for the cardiovascular continuum in diabetes?Diabet Med201330289299
Geelhoed-Duijvestijn PHIncretins: a new treatment option for type 2 diabetes?Neth J Med2007656064
Neumiller JJClinical pharmacology of incretin therapies for type 2 diabetes mellitus: implications for treatmentClin Ther201133528576
Wheeler MB, Lu M, Dillon JS, Leng XH, Chen C, Boyd AEIIIFunctional expression of the rat glucagon-like peptide-I receptor, evidence for coupling to both adenylyl cyclase and phospholipase-CEndocrinology19931335762
Nauck MAA critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risksDiabetes Care20133621262132
Monami M, Dicembrini I, Marchionni N, Rotella CM, Mannucci EEffects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysisExp Diabetes Res 20122012672658
Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DMGlucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injuryDiabetes200554146151
Bose AK, Mocanu MM, Carr RD, Yellon DMMyocardial ischemia/reperfusion injury is attenuated by intact glucagon-like peptide-1 (GLP-1) in the in vitro rat heart and may involve the p70s6K pathwayCardiovasc Drugs Ther200721253256
Vaghasiya J, Sheth N, Bhalodia Y, Shailesh M, Jivani NExenatide protects renal ischemia reperfusion injury in type 2 diabetes mellitusInt J Diab Dev Ctries201030217225
Pari L, Suman SEfficacy of naringin on hepatic enzymes of carbohydrate metabolism in streptozotocin-nicotinamide induced type 2 diabetic ratsInt J Pharm Biol Arch20101280286
Mihara M, Uchiyama MDetermination of malonaldehyde precursor in tissues by thiobarbituric acid testAnal Biochem197886271278
Das S, Vasishat S, Snehalata R, Das N, Srivastava LMCorrelation between total antioxidant status and lipid peroxidation in hypercholesterolemiaCurr Sci200078486487
Moron MS, Depierre JW, Mannervik BLevels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liverBiochim Biophys Acta19795826778
Lepoivre G, Iwanejko J, Dembińska-Kieć A, Pankiewicz J, Wanat A, Anna P et al.
Determination of nitrite/nitrate in human biological material by the simple Griess reactionClin Chim Acta1998274177188
Mohamed M, Hammadi S, Abd-El Hamid MThe possible role of the incretin enhancer sitagliptin, in renal ischemic reperfusion injury in type 2 diabetes mellitusJ Endocr Metab Dis20144181196
Sivarajah A, Chatterjee PK, Patel NS, Todorovic Z, Hattori Y, Brown PA et al.
Agonists of peroxisome-proliferator activated receptor-gamma reduce renal ischemia/reperfusion injuryAm J Nephrol201323267276
Sancaktutar AA, Bodakci MN, Hatipoglu NK, Soylemez H, Basarılı K, Turkcu GThe protective effects of pomegranate extracts against renal ischemia–reperfusion injury in male ratsUrol Ann201464650
Tawfik MKRenoprotective activity of telmisartan versus pioglitazone on ischemia/reperfusion induced renal damage in diabetic ratsEur Rev Med Pharmacol Sci201216600609
Chen H, Brahmbhatt S, Gupta A, Sharma ACDuration of streptozotocin induced diabetes differentially affects p38-mitogen-activated protein kinase (MAPK) phosphorylation in renal and vascular dysfunctionCardiovasc Diabetol20054113
Kuhad A, Chopra KAttenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathwayLife Sci200984296301
Yousef WM, Omar AH, Ghanayeem NM, Abd El-Wahed MM, Morsy MDEffect of some calcium channel blockers in experimentally induced diabetic nephropathy in ratsInt J Diab Metab2005143949
Gabr MM, Sherif IO, Ali SI, Mohamed HERenal ischemia/reperfusion injury in type II DM: possible role of proinflammatory cytokines, apoptosis, and nitric oxideEur J Sci Res201047632648
Melin J, Hellberg O, Fellström BHyperglycaemia and renal ischaemia-reperfusion injuryNephrol Dial Transplant200318460462
Vaghasiya JD, Sheth NR, Bhalodia YS, Jivani NPExaggerated liver injury induced by renal ischemia reperfusion in diabetes: effect of exenatideSaudi J Gastroenterol201016174180
Kakadiya J, Brambhatt J, Shah NRenoprotective activity of pioglitazone on ischemia/reperfusion induced renal damage in diabetic ratsRec Res Sci Technol201029297
Vaghasiya J, Sheth N, Bhalodia Y, Manek RSitagliptin protects renal ischemia reperfusion induced renal damage in diabetesRegul Pept20111664854
Molitoris BA, Sutton TAEndothelial injury and dysfunction: role in the extension phase of acute renal failureKidney Int200466496499
Tuğtepe H, Sener G, Biyikli NK, Yüksel M, Cetinel S, Gedik N, Yeğen BCThe protective effect of oxytocin on renal ischemia/reperfusion injury in ratsRegul Pept2007140101108
Liu R, Bal HS, Desta T, Behl Y, Graves DTTumor necrosis factor-alpha mediates diabetes-enhanced apoptosis of matrix-producing cells and impairs diabetic healingAm J Pathol2006168757764
Bonventre JV, Zuk AIschemic acute renal failure: an inflammatory disease?Kidney Int200466480485
Yamagishi S, Fukami K, Ueda S, Okuda SMolecular mechanisms of diabetic nephropathy and its therapeutic interventionCurr Drug Targets20078952959
Koike N, Takamura T, Kaneko SInduction of reactive oxygen species from isolated rat glomeruli by protein kinase C activation and TNF-αlpha stimulation, and effects of a phosphodiesterase inhibitorLife Sci20078017211728
Yeboah MM, Xue X, Duan B, Ochani M, Tracey KJ, Susin M, Metz CNCholinergic agonists attenuate renal ischemia–reperfusion injury in ratsKidney Int2008746269
Araki K, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu HTelmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese miceHypertension2006485157
Kher A, Meldrum KK, Wang M, Tsai BM, Pitcher JM, Meldrum DRCellular and molecular mechanisms of sex differences in renal ischemia–reperfusion injuryCardiovasc Res200567594603
Umrani DN, Goyal RKFenoldopam treatment improves peripheral insulin sensitivity and renal function in STZ-induced type 2 diabetic ratsClin Exp Hypertens200325221233
Zheng L, Du Y, Miller C, Gubitosi-Klug RA, Ball S, Berkowitz BA, Kern TSCritical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetesDiabetologia20075019871996
Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T et al.
Hyperglycemic pseudohypoxia and diabetic complicationsDiabetes199342801813
Moursi M, Rising CL, Zelenock GB, D’Alecy LGDextrose administration exacerbates acute renal ischemic damage in anesthetized dogsArch Surg1987122790794
Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P et al.
Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injuryJ Am Coll Cardiol200953501510
Matsui T, Nishino Y, Takeuchi M, Yamagishi SVildagliptin blocks vascular injury in thoracic aorta of diabetic rats by suppressing advanced glycation end product-receptor axisPharmacol Res201163383388
Zhang X, Wang Z, Huang Y, Wang JEffects of chronic administration of alogliptin on the development of diabetes and cell function in high fat diet/streptozotocin diabetic miceDiabetes Obes Metab201113337347
[Table 1], [Table 2]