Abstract
Purpose
Vildagliptin has been shown to prevent microvascular complications during diabetes. The aim of this research was to evaluate the antioxidant effects of vildagliptin in diabetic nephropathy.
Methods
The diabetes was induced in the animals by high-fat diet and intraperitoneal injection of 35 mg/kg streptozotocin. After diagnosis of diabetes, the vildagliptin (6 mg/kg/day) was orally administered for one month. The biochemical parameters of blood urea nitrogen, creatinine, insulin, and serum albumin were measured. The levels of stress oxidative markers were detected using spectrophotometry.
Results
Treatment with vildagliptin significantly diminished blood glucose, oxidative stress, and reduced creatinine as well as increased insulin secretion. In addition, the vildagliptin improved renal glomerular and tubule interstitial damages and reduced vascular lesions.
Conclusions
The treatment with vildagliptin can be useful in controlling the renal complications of type 2 diabetes mellitus through inhibiting lipid peroxidation and increasing the antioxidant enzymes.
Keywords: Kidney, Nephropathy, Oxidative stress, Type 2 diabetes, Vildagliptin
Introduction
Type 2 diabetes mellitus (T2DM) is one of the chronic and progressive diseases and a major health concern around the world. The pathology of the disease is known to be abnormal secretion of insulin due to dysfunction of pancreatic beta cell as well as insulin-resistance in peripheral target tissues, which causes hyperglycemia. In addition to hereditary background, the risk of developing T2DM in humans increases with age, obesity and low physical activity. Preventive interventions for dysfunction of pancreatic beta cells are essential for long-term control of blood glucose levels [1].
Oxidative stress is involved in the pathogenesis of lifestyle-related diseases such as diabetes, hypertension and atherosclerosis. The oxidative stress plays a crucial role in diabetes mellitus through the development of microvascular and macrovascular complications caused by the disease. The renal dysfunction is one of the most serious microvascular complications [2]. There are several mechanisms in obesity, which is considered to be a risk factor for T2DM, causing an increase in oxidative stress in the diabetic patients. In obese people, a significant reduction in insulin-mediated glucose uptake can lead to hyperinsulinemia, which in turn leads to an increase in free radical production [3].
A number of pathways for reactive Oxygen Species (ROS) production in the kidney, such as glycolysis, NAD (P) H oxidase and xanthine oxidase, are pivotal in the diabetic nephropathy pathology [4]. Over time, damage to the kidney blood vessels leads to a reduction in filtration and the development of disorders in the kidney parenchyma, thereby reducing glomerular filtration rate [5]. Regarding the above-mentioned issues, inhibiting oxidative stress production in chronic renal dysfunction can be considered as one of the effective therapeutic strategies for lowering the complications of diabetes mellitus. Despite the widespread complications of diabetes, therapies not only should be able to control blood glucose but also should be effective in preventing complications from diabetes. Currently, there are very limited therapies routinely used for T2DM, most of which are associated with hypoglycemia. In addition, existing drugs are not as effective as controlling the complications of the disease [6].
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin-releasing peptide or gastric inhibitory polypeptide (GIP) are involved in the regulation of glucose homeostasis [5]. In experimental studies, continuous infusion of GLP-1 or long-term injections of GLP-1 mimetics such as exendin-4 has had significant effects on reducing glucose levels and enhancing beta-cell neogenesis, decreasing apoptosis, and secreting glucagon from alpha cells [7, 8]. The DPP-4 inhibitors (known as gliptins) are a series of new anti-hyperglycemic agents that have a broad biological effect on incretin hormones and impede their degradation [9]. The gliptins not only can control blood sugar but also have renoprotective role against complications of chronic diabetes due to various potentials, including anti-apoptotic and anti-oxidant effects. The vildagliptin is one of the newest gliptins that by inhibiting DPP-4 enhances the level of active incretins, the response of pancreatic beta cells to glucose, the secretion and insulin sensitivity and lipoprotein metabolism as well as reduces the aberrant glucagon secretion, fasting blood glucose, hemoglobin A1C and postprandial glucose [10]. The vildagliptin controls the blood glucose without causing hypoglycemia [11].
Recent studies have looked at the protective effects of vildagliptin on some tissues, including the heart tissue. However, there is still no study to examine the possible effects of vildagliptin and its mechanisms of action in various tissues (including the kidney tissue) in which structural and functional changes occur following the diabetes. Thus, the purpose of this study was to investigate the effect of long-term treatment of Vildagliptin on the antioxidant status of the body and the biochemical and pathological parameters of the kidney in diabetic rats.
Materials and methods
Animals
A total of 26 male Wistar rats (weighing 250–300 g) were obtained from the Animal Centre of Tabriz University of Medical Sciences, Iran. According to Guideline for Laboratory Animal Care, the rats were kept four per cage at a 12/12 hours light/dark cycle, 50% humidity, 25 °C, and had unlimited access to standard lab chow and tap water. The principles of working with animals were approved by the Ethics Committee of the Tabriz University of Medical Sciences (code number is IR.TBZMED.REC.1395.583).
Induction of type 2 diabetes and drug administration
After a week of acclimatization period, 26 rats were randomly assigned to three groups (control, diabetic, and diabetic + vildagliptin). In each group, 6 rats (n = 06) were considered. An additional number was due to death in the diabetic group. The duration of the diabetic period was 12 weeks. The diabetes was induced in the animals by high-fat diet (HFD) (containing 35% normal rat diet, 30% sheep fat, 4% sucrose, 24% casein, 1% cholesterol, 0.3% DL-methionine) for 6 weeks. After overnight fasting, the animals were injected with single intraperitoneal injection low dose streptozotocin (STZ, 30 mg/kg dissolved in citrate buffer with pH 4.5) at the end of the sixth [12]. Animals in the control group were fed normal diet. The weight of all rats and food intake was recorded weekly. One week after STZ injection (end of seventh week), all groups were tested for oral glucose tolerance test (OGTT) by rat-tail lancing and glucometry. The rats having blood glucose greater than 250 mg/dL and impaired OGTT (indicative of T2DM initiation phase) were considered as diabetic animals [13]. After diagnosis of definite diabetes, the diabetic + vildagliptin group was received 6 mg/kg/day of vildagliptin through gavage from the end of the seventh week to the end of the diabetic period for 5 weeks (Novartis, Basel, Switzerland) [14].
Oral glucose tolerance test
At the end of the seventh week, oral glucose tolerance test (OGTT) was performed in all groups as gavage after the diabetic period, before treatment, and after 8 h of overnight fasting. By rat-tail lancing, small scratch was done to measure fasting blood glucose (FBS) using the glucometer. Then, about 2 g of oral glucose powder per kg body weight of the rat (2 g/kg) was dissolved in distilled water and gavaged to the animal. The blood glucose level was checked at 30, 60, 90 and 120 min after receiving oral glucose, from the same scratch created in the tail of the animals [13].
The biochemical parameters
The animals were euthanized by decapitation under ketamine/xylazine (60 and 10 mg/kg, respectively) anesthesia and the blood samples (2 cc) were taken from inferior vena cava for biochemical evaluation, and the left kidney was dissected from the rat body [14]. The serum levels of urea nitrogen (BUN), creatinine (Cr) and albumin (Alb) were assessed for the evaluation of renal function and measured using a colorimetry in accordance with the corresponding kit (Sigma-Aldrich, St Louis, MO). The serum insulin level was obtained using ELISA kit (Cayman chemical, Ann Arbor, Michigan).
Assessment of lipid peroxidation and antioxidant activity
The lipid peroxidation levels (MDA: Malondealdehyde) in kidney supernatant were estimated by measuring thiobarbituric acid-reactive substances (TBARS). The reaction mixture’s absorbance was read at 535 nm [15].
The superoxide dismutase (SOD) activity was determined using RASOD kit (Randox, Crumlin, UK) according to the method of Delmas-Beauvieux et al. [16]. The kidney tissue was homogenized to prepare supernatant and required solutions. The absorbance was assayed spectrophotometrically at 505 nm (Pharmacia Biotech, England).
The glutathione peroxidase (GPx) activity was measured using the RANSEL kit (Randox Crumlin, UK) according to Paglia and Valentine [17]. Glutathione reductase at a concentration equal to or greater than 0.5 unit/l and of NADPH solutions at 0.28 mmol/l were prepared to convert the oxidized glutathione instantly to its reduced form. The reduction in absorbance at 340 nm (37 °C) was measured spectrophotometrically. The concentration of GSH-px was obtained. The catalase (CAT) level was obtained according to Aebi method. The results were expressed as U/mg of sample protein.
The histological examinations
For histological studies, the left kidney was taken from the body of animals after anesthesia. Subsequently, the fats around the renal capsule and the central portion of the medulla were removed and the remaining kidney tissue (the kidney cortex) was placed in 10% neutral buffered formalin solution, dehydrated in ethanol, and placed in paraffin. The tissue was sectioned to a thickness of 5 micrometers. Finally, from each paraffinated block, at least 10 thin sections were selected and stained with the standard H & E staining method. The histological examinations were performed using systematic uniform random sampling principle, using optical microscopy (Olympus BH-2, Tokyo, Japan). Structural changes were investigated among different groups and compared with each other.
Statistical analysis
All results of the study are expressed as mean + SEM (standard error of the mean). SPSS version 16 software was used to analyze the data. One-way ANOVA was utilized to analyze the variables between different groups, and Tukey’s post hoc test for the significant difference of means. The mean difference between the two groups was analyzed by t-student test. Non-parametric Kruskal-Wallis test was applied to compare the intensity or degree of tissue changes among groups. p < 0.05 was considered statistically significant in all tests.
Results
OGTT, FBS and insulin
After 12 weeks of diabetic period, FBS was increased significantly in the diabetic rats when compared to control rats, despite strengthening of insulin secretion (p < 0.001). The treatment of diabetic rats with vildagliptin significantly improved hyperglycemia (p < 0.001) (Fig. 1) and increased insulin levels (p < 0.01) as compared with the diabetic group (Fig. 2). At 7th week, the impaired OGTT was detected in the diabetic animals and the blood glucose level in the diabetic animals was increased significantly in fasting time (or zero time), and 30, 60, 90 and 120 min after oral administration of glucose in comparison to the control animals (for all times, P < 0.001) (Fig. 3).
Fig. 1.
Fasting blood glucose. Each bar represents mean ± SEM (n = 06). ***p < 0.001 vs. control group: ### p < 0.001 vs. diabetic group
Fig. 2.
Serum insulin level. Each bar represents the mean ± SEM (n = 06). ***p < 0.001 vs. control group; vs. diabetic group: ##p < 0.01
Fig. 3.
Oral glucose tolerance test (OGTT). The data were expressed as mean ± SEM (n = 06). ***p < 0.001 vs. control group
Changes in renal function
Kidney function was evaluated by albumin, BUN, and serum creatinine. Post-hoc analysis revealed that the serum creatinine levels were significantly decreased by vildagliptin treatment in the diabetic animals (p < 0.05) (Table 1).
Table 1.
The effect of vildagliptin on renal function evaluated by albumin, blood urea nitrogen, and creatinine
| Parameters Groups |
Albumin | Blood urea nitrogen | Creatinine |
|---|---|---|---|
| Control | 3.67 ± 0.08 | 27.2 ± 1.36 | 0.73 ± 0.047 |
| Diabetic | 2.3 ± 0.19 | 30.5 ± 2.98 | 0.83 ± 0.031 |
| Diabetic + vildagliptin | 3.35 ± 0.11 | 26.5 ± 1.49 | 0.67 ± 0.053# |
The data were expressed as mean ± SEM (n = 06).
#p < 0.05 vs. diabetic group.
Changes in renal oxidative stress
As seen in Fig. 4, the activity level of SOD and GPx enzymes of renal tissue was significantly decreased in the diabetic rats (p < 0.001). The treatment of diabetic rats with vildagliptin significantly increased (p < 0.001) enzyme activities of SOD and GPx as well as CAT in comparison with diabetic group (Fig. 4a-c). In addition, the treatment of diabetic rats with vildagliptin reduced the MDA level significantly (p < 0.001) in comparison with the diabetic group (Fig. 4d).
Fig. 4.
Effect of vildagliptin on the oxidative stress markers in the rat renal following diabetes. a catalase (CAT) level, b superoxide dismutase (SOD) activity, c malondialdehyde (MDA) content, and d glutathione oxidase (GPx) enzyme activity. Each bar represents mean ± SEM (n = 06). ***p < 0.001 and**p < 0.01 vs. control group, ###p < 0.001 vs. diabetic group
Histopathological examinations
The control group (Fig. 5a) showed glomerular structure with normal capsular space without glomerulosclerosis and renal tubules lesions with distinct epithelium and normal lumen with no degenerative lesion. The results of studying cross sectional area in the diabetic group (Fig. 5b) showed structural damage as glomerulosclerosis with nodular sclerosis (1), mesenchymal expansion along with severe glomerular atrophy (2), increased capsular space (3). The tubulointerstitial structure shows extensive hyalinization in the accumulated renal tubules (4), degeneration of epithelial cells (5) along with tubular cell vacuolization (6) and interstitial fibrosis/tuberculosis atrophy (IFTA). In addition, vascular lesions are visible as hyalinization and structural degeneration of the vascular pole area (8); all of the above changes signify the occurrence of DN. The results of treatment with vildagliptin (Fig. 5c) showed glomerular structure with normal capsular space without glomerulosclerosis with partial mesenchymal expansion and renal tubules with normal epithelium, sometimes with limited vacuolization and local IFTA; a significant reduction in lesions is visible in comparison to the diabetic group.
Fig. 5.
Micrograph of tissue section stained by H & E method for studied groups. Control (a), diabetic (b) and diabetic + vildagliptin (c), (n = 06, 40×). (1) glomerulosclerosis with nodular sclerosis, (2) mesenchymal expansion and glomerular atrophy, (3) increased capsular space, (4) renal tubal hyalinization, (5) degeneration of epithelial cells, (6) tubular cell vacuolization, (7) interstitial fibrosis atrophy (IFTA), (8) structural degeneration of the vascular pole region
Discussion
Here, we showed that the treatment of diabetic rats with vildagliptin reduced hyperglycemia and increased insulin levels. The serum Cr levels were reduced in the diabetic rats treated with vildagliptin. Furthermore, vildagliptin increased activity of CAT, GPx and SOD enzymes as well as reduced lipid peroxidation. Moreover, the treatment of diabetic rats with vildagliptin resulted in decreased glomerular atherosclerosis, improved epithelial cell destruction, and reduced vacuolation of tubular cells, as well as decreased IFTA and vascular lesions.
Several studies have investigated the oxidative stress and its key role that suggest the pathogenic nature and long-term complications of diabetes [18]. The continuous high blood sugar in T2DM causes an imbalance in the antioxidant capacity of the cell, resulting in the imbalance in the production of free radicals and the ROS accumulation in tissue cells. Increasing ROS causes the activation of mechanisms that lead to tissue damage and insulin resistance in the cell [19]. Increasing the ROS level in diabetes can be due to their increased production following lipid peroxidation or their degradation by antioxidant enzymes. Changing the level of these antioxidant enzymes in diabetes can make the tissues susceptible to oxidative stress [2]. Based on the results of former research, the increase in blood glucose induced by diabetes due to the activation of destructive factors, in particular the increase in the production of ROS in the pancreatic tissue, results in injuries insulted to the beta cells of Langerhans islets [20]. It should also be noted that the not specific TBARS method was used to estimate the levels of MDA and lipid peroxidation in the present study. Although, this method is the oldest and one of the most widely used assays for measuring lipid peroxidation end product MDA, more specific methods are also recommended for future studies.
It should be noted that incretin-dependent factors can inhibit the oxidative stress [21]. EL-sayed et al. (2012) reported that the treatment with DPP-4 inhibitors protects kidney from ischemia-reperfusion damage through decreases the lipid peroxidation level, increases the GPx level and improves kidney function in the type 1 diabetic rats [22]. A study has examined the effects of vildagliptin on the glycemic changes and the oxidative stress in the patients with T2DM and found that the vildagliptin reduced the glycemic changes in the diabetic patients, although there were no oxidative stress markers [23]. Shigematsu et al. (2017) evaluated the efficacy of the three DPP-4 inhibitors (vildagliptin, alogliptin, and sitagliptin) in the type 2 diabetics and observed the different effects of these three drugs in lowering the blood glucose levels, with strong effects of vildagliptin and sitagliptin more than alogliptin [24]. Ferreira and colleagues reported that the sitagliptin reduced renal function degradation in type 2 diabetic rats. Through increasing the level of incretin levels in the blood, this DPP-4 inhibitor regulates the insulin release into the blood and indirectly leads to an increase in blood insulin and therefore reduces blood sugar, especially postprandial state. Another benefit of this drug can be help to reduce the production of simple sugars by the liver [25]. The findings have shown that the vildagliptin significantly reduced the ratio of urine albumin to creatinine, glomerulosclerosis and proteinuria in the type 1 diabetic rats, and reduced DNA damage and apoptosis of renal cells, possibly by regulating the expression of GLP-1 receptors in the renal proximal tubule and glomerulus [21]. The DPP-4 inhibitors, through anti-inflammatory activity, have renoprotective effects in the early stages of renal dysfunction[26]. The vildagliptin has renoprotective effects during IRI in non-diabetic rats, and attributed this effect to the possible containment of oxidative stress by the drug [27].
The DPP-4 inhibitors as novel T2DM therapies not only can control blood sugar but also have renoprotective role against complications of chronic diabetes due to various potentials, including anti-apoptotic and anti-oxidant effects [28–31]. Therefore, the present study experimented the effect of vildagliptin on the oxidative stress indices and tissue changes in kidney dysfunction induced by T2DM in rats. The findings of this study are consistent with the anti-oxidative stress effects and tissue improvement of the vildagliptin in previous studies under the conditions of T2DM pathogenicity.
Conclusions
Chronic T2DM was associated with reduced renal function, and increased renal tissue injury and oxidative stresses in rats. Prereatment of diabetic rats with vildagliptin enhanced antioxidant defense mechanisms, improved renal function, and prevented lipid peroxidation and tissue damages during diabetes. The impact of vildagliptin on glomerular filtration rate and tubular-glomerular function, as well as the possible role and function of renal survival mechanisms such as signaling pathways involved in diabetic nephropathy need to be explored in the future research.
Acknowledgements
This work was financially supported by Drug Applied Research Center, Tabriz University of Medical Sciences, in Tabriz, Iran.
Abbreviations
- CAT
Catalase
- FBS
Fasting blood glucose
- GLP-1
Glucagon-like peptide 1
- GPx
Glutathione Peroxidase
- HFD
High-fat diet
- MDA
Malondealdehyde
- OGTT
Oral glucose tolerance test
- ROS
Reactive Oxygen Species
- STZ
Streptozotocin
- TBARS
Thiobarbituric Acid-Reactive Substances
- T2DM
Type 2 diabetes mellitus
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest to disclose.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Srinivasan K, Ramarao P. Animal model in type 2 diabetes research: An overview. Indian J Med Res. 2007;125(3):451. [PubMed] [Google Scholar]
- 2.Tiwari BK, Pandey KB, Abidi A, Rizvi SI. Markers of oxidative stress during diabetes mellitus. J Biomarkers. 2013;2013. [DOI] [PMC free article] [PubMed]
- 3.Susztak K, Raff AC, Schiffer M, Böttinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006;55(1):225–33. doi: 10.2337/diabetes.55.01.06.db05-0894. [DOI] [PubMed] [Google Scholar]
- 4.Burkey BF, Li X, Bolognese L, Balkan B, Mone M, Russell M, et al. Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats. J Pharmacol Exp Ther. 2005;315(2):688–95. doi: 10.1124/jpet.105.087064. [DOI] [PubMed] [Google Scholar]
- 5.Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes. 2008;57(6):1446–54. doi: 10.2337/db08-0057. [DOI] [PubMed] [Google Scholar]
- 6.Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care. 2013;36(4):908–13. doi: 10.2337/dc12-0931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Drucker DJ. The biology of incretin hormones. Cell Metabol. 2006;3(3):153–65. doi: 10.1016/j.cmet.2006.01.004. [DOI] [PubMed] [Google Scholar]
- 8.Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology. 2002;143(11):4397–408. doi: 10.1210/en.2002-220405. [DOI] [PubMed] [Google Scholar]
- 9.Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–705. doi: 10.1016/S0140-6736(06)69705-5. [DOI] [PubMed] [Google Scholar]
- 10.Flock G, Baggio LL, Longuet C, Drucker DJ. Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes. 2007;56(12):3006–13. doi: 10.2337/db07-0697. [DOI] [PubMed] [Google Scholar]
- 11.Rosenstock J, Zinman B. Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2007;14(2):98–107. doi: 10.1097/MED.0b013e3280a02f65. [DOI] [PubMed] [Google Scholar]
- 12.Srinivasan K, Viswanad B, Asrat L, Kaul C, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005;52(4):313–20. doi: 10.1016/j.phrs.2005.05.004. [DOI] [PubMed] [Google Scholar]
- 13.Morino S, Kondo T, Sasaki K, Adachi H, Suico MA, Sekimoto E, et al. Mild electrical stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. PloS One. 2008;3(12):e4068. doi: 10.1371/journal.pone.0004068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bayrami G, Karimi P, Agha-Hosseini F, Feyzizadeh S, Badalzadeh R. Effect of ischemic postconditioning on myocardial function and infarct size following reperfusion injury in diabetic rats pretreated with vildagliptin. J Cardiovasc Pharmacol Therap. 2018;23(2):174–83. doi: 10.1177/1074248417729881. [DOI] [PubMed] [Google Scholar]
- 15.Uchiyama M, Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978;86(1):271–8. doi: 10.1016/0003-2697(78)90342-1. [DOI] [PubMed] [Google Scholar]
- 16.Delmas-Beauvieux M, Peuchant E, Dumon M, Receveur M, Le Bras M, Clerc M. Relationship between red blood cell antioxidant enzymatic system status and lipoperoxidation during the acute phase of malaria. Clin Biochem. 1995;28(2):163–9. doi: 10.1016/0009-9120(94)00071-3. [DOI] [PubMed] [Google Scholar]
- 17.Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70(1):158–69. [PubMed] [Google Scholar]
- 18.Ceriello A. Oxidative stress and glycemic regulation. Metabolism. 2000;49(2):27–9. doi: 10.1016/S0026-0495(00)80082-7. [DOI] [PubMed] [Google Scholar]
- 19.Yang H, Jin X, Lam CWK, Yan S-K. Oxidative stress and diabetes mellitus. Clin Chem Lab Med. 2011;49(11):1773–82. doi: 10.1515/cclm.2011.250. [DOI] [PubMed] [Google Scholar]
- 20.Biswas SK, de Faria JBL. Hypertension induces oxidative stress but not macrophage infiltration in the kidney in the early stage of experimental diabetes mellitus. Am J Nephrol. 2006;26(5):415–22. doi: 10.1159/000095707. [DOI] [PubMed] [Google Scholar]
- 21.Joo KW, Kim S, Ahn S-y, Chin HJ, Chae D-W, Lee J, et al. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney. BMC Nephrol. 2013;14(1):98. doi: 10.1186/1471-2369-14-98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.EL-SAYED L, EL-ATTAR S. Dipeptidyl Peptidase-4 Inhibitor protects against renal damage in renal ischemia reperfusion injury in streptozotocin induced diabetic rats. Med J Cairo Univ. 2012;80(2).
- 23.Kim NH, Kim D-L, Kim KJ, Kim NH, Choi KM, Baik SH, et al. Effects of vildagliptin or pioglitazone on glycemic variability and oxidative stress in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a 16-week, randomised, open label, pilot study. Endocrinol Metab. 2017;32(2):241–7. doi: 10.3803/EnM.2017.32.2.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Shigematsu E, Yamakawa T, Oba MS, Suzuki J, Nagakura J, Kadonosono K, et al. A randomized controlled trial of vildagliptin versus alogliptin: effective switch from sitagliptin in patients with type 2 diabetes. J Clin Med Res. 2017;9(7):567. doi: 10.14740/jocmr3012w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Ferreira L, Teixeira-de-Lemos E, Pinto F, Parada B, Mega C, Vala H, et al. Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediat Inflamm. 2010;2010. [DOI] [PMC free article] [PubMed]
- 26.Kodera R, Shikata K, Takatsuka T, Oda K, Miyamoto S, Kajitani N, et al. Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes. Biochem Biophys Res Commun. 2014;443(3):828–33. doi: 10.1016/j.bbrc.2013.12.049. [DOI] [PubMed] [Google Scholar]
- 27.Glorie LL, Verhulst A, Matheeussen V, Baerts L, Magielse J, Hermans N, et al. DPP4 inhibition improves functional outcome after renal ischemia-reperfusion injury. Am J Physiol Ren Physiol. 2012;303(5):F681–8. [DOI] [PubMed]
- 28.Jin HY, Liu WJ, Park JH, Baek HS, Park TS. Effect of dipeptidyl peptidase-IV (DPP-IV) inhibitor (Vildagliptin) on peripheral nerves in streptozotocin-induced diabetic rats. Archives of medical research. 2009 Oct 1;40(7):536 – 44. [DOI] [PubMed]
- 29.Wu YJ, Guo X, Li CJ, Li DQ, Zhang J, Yang Y, Kong Y, Guo H, Liu DM, Chen LM. Dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits pancreatic beta cell apoptosis in association with its effects suppressing endoplasmic reticulum stress in db/db mice. Metabolism. 2015;64(2):226–35. doi: 10.1016/j.metabol.2014.08.006. [DOI] [PubMed] [Google Scholar]
- 30.Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjörnsdottir S, Camisasca RP, Couturier A, Baron MA. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab. 2008;10(11):1047–56. doi: 10.1111/j.1463-1326.2008.00859.x. [DOI] [PubMed] [Google Scholar]
- 31.de Lima Ávila D, de Araújo GR, Silva M, de Amorim Miranda PH, Diniz MF, Pedrosa ML, Silva ME, de Lima WG, Costa DC. Vildagliptin ameliorates oxidative stress and pancreatic beta cell destruction in type 1 diabetic rats. Arch Med Res. 2013;44(3):194–202. doi: 10.1016/j.arcmed.2013.03.004. [DOI] [PubMed] [Google Scholar]