Streptozotosin kaynaklı diyabetik sıçanların karaciğerindeki oksidatif stres belirteçleri: metformin ve sitagliptinin etkileri

Amaç: Bu çalışmanın amacı, streptozotosin (STZ) kaynaklı diyabetik sıçanların karaciğer dokusunda metformin (MET) ve/veya sitagliptinin (STG) antidiyabetik ilaçların olası oksidatif stres etkisini araştırmaktır. Gereç ve Yöntem: Bu çalışmada erişkin dişi Wistar albino sıçanları kullanılmış ve rastgele kontrol normal grubu, kontrol diyabetik grubu ve diyabetik gruba ayrılmıştır. Antidiyabetik ilaç grubuna sahip diyabetik sıçanlar aşağıdaki tedavi edilen alt gruplara ayrıldı: Sitagliptin (10 mg/ kg/ gün), Metformin (200mg/ kg/ gün) ve Kombine metformin sitagliptin ile 4 hafta boyunca tedavi edilen alt gruplar. Sıçan karaciğer dokusunda oksidatif stres belirteçleri (Malondialdehid (MDA), total antioksidan durum (TAS), total oksidan durum (TOS) ve oksidatif stres indeksi (OSI) seviyeleri) ölçüldü. Ek olarak, apoptotik hücre ölümü geçiren hücreler histopatolojik değerlendirme ile TUNEL tekniği kullanılarak belirlendi. Bulgular: STZ + MET + STG uygulanan grubun MDA, TAS ve OSI'si STZ'ye göre azaldı. STZ + MET + STG uygulanan grubun TOS'u STZ'ye göre azaldı. Sonuç: Sıçanlarda deneysel T2D modelinde, sitagliptin metformin ile birlikte kullanıldığında karaciğer dokusunda STZ'nin neden olduğu oksidatif hasara karşı koruyucu etki göstermektedir.

Oxidative stress markers in liver in streptozocin-induced diabetic rats: effects of metformin and sitagliptin

Purpose: This study aims at investigating the oxidative stress effect of antidiabetic drugs of Metformin (MET) and sitagliptin (STG) in the liver tissue of diabetic rats from streptozotocin (STZ). Materials and Methods: Thirty-five female Wistar rats (3-4 months old, weighing 200±25 g) were divided into five groups (with seven rats each) and treated as follows: control (Cont), streptozotocin alone (STZ), streptozotocin + metformin (STZ+MET), streptozotocin + sitagliptin (STZ+STG), streptozotocin + metformin + sitagliptin (STZ+MET+STG). Sitagliptin, Metformin, and combined metformin sitagliptin treated subgroups for four weeks. Malondialdehyde (MDA), total antioxidant status (TAS), total oxidant status (TOS) levels, and oxidative stress index (OSI) ratio were measured in rat liver tissue. Besides, cells undergoing apoptotic cell death were determined using the TUNEL technique through histopathological evaluation. Results: MDA, TAS, and OSI of STZ+MET+STG administered group decreased compared to STZ. TOS of STZ+MET+STG administered group decreased compared to STZ. Conclusion: In the experimental T2D model in rats, it shows protective effect when sitagliptin is used with metformin against oxidative damage in liver tissue caused by STZ.

Keywords:

metformin, sitagliptin oxidative stress, diabet,

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1. Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of diabetes-induced liver damage: the role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16:132-41.
2. Shawky LM, Morsi AA, El Bana E, Hanafy SM. The biological impacts of sitagliptin on the pancreas of a rat model of type 2 diabetes mellitus: drug interactions with metformin. Biology (Basel). 2019;9:6.
3. Alam MM, Ahmad I, Naseem I. Inhibitory effect of quercetin in the formation of advance glycation end products of human serum albumin: An in vitro and molecular interaction study. Int J Biol Macromol. 2015;79:336-43.
4. Eitah HE, Maklad YA, Abdelkader NF, Gamal El Din AA, Badawi MA, Kenawy SA. Modulating impacts of quercetin/sitagliptin combination on streptozotocin- induced diabetes mellitus in rats. Toxicol Appl Pharmacol. 2019;365:30-40.
5. Baig NA, Herrine SK, Rubin R. Liver disease and diabetes mellitus. Clin Lab Med. 2001;21:193-207.
6. Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress: A concise review. Saudi Pharm J. 2016;24:547-53.
7. Bansal AK, Bilaspuri GS. Impacts of oxidative stress and antioxidants on semen functions. Vet Med Int. 2010;2010:686137.
8. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012;5:9-19.
9. Hostalek U, Gwilt M, Hildemann S. therapeutic use of metformin in prediabetes and diabetes prevention. Drugs. 2015;75:1071-94.
10. Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila). 2012;5:536- 43.
11. Carvalho C, Correia S, Santos M, Seiça R, Oliveira C, Moreira P. Metformin promotes isolated rat liver mitochondria impairment. Mol Cel Biochem. 2008;308:75-83.
12. Kelly B, Tannahill GM, Murphy MP, O'Neill LA. Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in lipopolysaccharide (LPS)- activated macrophages. J Biol Chem. 2015;290:20348- 59.
13. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:607-14.
14. Chen YT, Tsai TH, Yang CC, Sun CK, Chang LT, Chen HH et al. Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med. 2013;11:270.
15. Kumar A, Pathak R, Palfrey HA, Stone KP, Gettys TW, Murthy SN. High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats. Nutr Metab. 2020;17:2.
16. Trocha M, Krzystek-Korpacka M, Merwid-Ląd A, Nowak B, Pieśniewska B, Dzięgiel P et al. Sitagliptin- dependent differences in the intensity of oxidative stress in rat livers subjected to ischemia and reperfusion. Oxid Med Cell Longev. 2019;2019:2738605.
17. Vaghasiya J, Sheth N, Bhalodia Y, Manek R. Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes. Regul Peptides. 2011;166:48-54.
18. National Research Council Committee for the Update of the Guide for the C, Use of Laboratory A. The National Academies Collection: Reports funded by National Institutes of Health. Guide for the Care and Use of Laboratory Animals. Washington (DC), National Academy of Sciences, 2011.
19. Wu KK, Huan Y. Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol. 2008;5:47.
20. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38:1103-11.
21. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004;37:277-85.
22. Harma M, Harma M, Erel O. Increased oxidative stress in patients with hydatidiform mole. Swiss Med Wkly. 2003;133:563-66.
23. Kosecik M, Erel O, Sevinc E, Selek Ş. Increased oxidative stress in children exposed to passive smoking. Int J Cardiol. 2005;100:61-4.
24. Yumru M, Savas HA, Kalenderoglu A, Bulut M, Celik H, Erel O. Oxidative imbalance in bipolar disorder subtypes: a comparative study. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1070-4.
25. Li CJ, Yang ZH, Shi XL, Liu DL. Effects of aspirin and enoxaparin in a rat model of liver fibrosis. World J Gastroenterol. 2017;23:6412-9.
26. Soini Y, Pääkkö P, Lehto VP. Histopathological evaluation of apoptosis in cancer. Am J Pathol. 1998;153:1041-53.
27. Al-kuraishy H. Oxidative stress injury and glucolipotoxicity in type 2 diabetes mellitus: the potential role of metformin and sitagliptin. Biomed Res Int. 2020;4:166-72.
28. Derosa G, D'Angelo A, Maffioli P. Sitagliptin in type 2 diabetes mellitus: Efficacy after five years of therapy. Pharmacol Res. 2015;100:127-34.
29. Yabe D, Kuwata H, Kaneko M, Ito C, Nishikino R, Murorani K et al. Use of the Japanese health insurance claims database to assess the risk of acute pancreatitis in patients with diabetes: comparison of DPP-4 inhibitors with other oral antidiabetic drugs. Diabetes Obes Metab. 2015;17:430-34.
30. Arora R, Vig A, Arora S. Lipid peroxidation: a possible marker for diabetes. J Diabetes Metab. 2013;SII:007.
31. Elsawy M, Emara E. The impact of ghrelin on oxidative stress and inflammatory markers on the liver of diabetic rats. Tanta Medical Journal. 2016;44:163-9.
32. Emara E, Elsawy M, Elmashad W, Eldamarawi M. Effect of vitamins (C and E) on endothelial inflammation biomarkers and oxidative stress in diabetic rats. J Appl Sci. 2014;14:3563-70.
33. Gezginci-Oktayoglu S, Basaraner H, Yanardag R. The effects of combined treatment of antioxidants on the liver injury in STZ diabetic rats. Dig Dis Sci. 2008;54:538-46.
34. Koyuturk M, Sacan O, Karabulut S, Turk N, Bolkent S, Yanardag R et al. The role of ghrelin on apoptosis, cell proliferation and oxidant-antioxidant system in the liver of neonatal diabetic rats. Cell Biol Int.. 2015;39:834-41.
35. Parveen K, Khan MR, Mujeeb M, Siddiqui WA. Protective effects of Pycnogenol on hyperglycemia- induced oxidative damage in the liver of type 2 diabetic rats. Chem Biol Interact. 2010;186:219-27.
36. Dogan I, Çandar T, Yuksel E, Kalay S, Oğuz AK, Demirtas S. Potential effects of metformin in DNA BER system based on oxidative status in type 2 diabetes. Biochimie. 2018;154:62-8.
37. Pujadas G, De Nigris V, Prattichizzo F, La Sala L, Testa R, Ceriello A. The dipeptidyl peptidase-4 (DPP- 4) inhibitor teneligliptin functions as antioxidant on human endothelial cells exposed to chronic hyperglycemia and metabolic high-glucose memory. Endocrine. 2017;56:509-20.
38. Mistry GC, Bergman AJ, Zheng W,Hreniuk D, Zinny MA, Gottesdiener KM et al. Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects. Br J Clin Pharmacol. 2008;66:36-42.
39. 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). Mediators Inflamm. 2010;2010:592760.
40. Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2010;20:224-35.
41. Hamden K, Carreau S, Boujbiha MA, Lajmi S, Aloulou D, Kchaou D et al. Hyperglycaemia, stress oxidant, liver dysfunction and histological changes in diabetic male rat pancreas and liver: protective effect of 17 beta-estradiol. Steroids. 2008;73:495-501.
42. Seven A, Guzel S, Seymen O, Civelek S, Bolayirli M, Uncu M et al. Effects of vitamin E supplementation on oxidative stress in streptozotocin induced diabetic rats: investigation of liver and plasma. Yonsei Med J. 2004;45:703-10.
43. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury. J Gastroenterol Hepatol. 2000;15:718-24.
44. Zhang C, Lu X, Tan Y, Li B, Miao X, Jin L et al. Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model. PloS One. 2012;7:e49257.
45. Noor A, Gunasekaran S, Amirtham S, Vijayalakshmi MA. Antidiabetic activity of Aloe vera and histology of organs in streptozotocin-induced diabetic rats. Curr Sci. 2008;94:1070-76.
46. Kume E, Fujimura H, Matsuki N, Ito M, Aruga C, Toriumi W et al. Hepatic changes in the acute phase of streptozotocin (SZ)-induced diabetes in mice. Exp Toxicol Pathol. 2004;55:467-80.
47. Brůha R, Dvořák K, Petrtýl J. Liver disorders in diabetic patients. Vnitrni lekarstvi. 2013;59:546-50.
48. Aksoy N, Vural H, Sabuncu T, Aksoy S. Effects of melatonin on oxidative antioxidative status of tissues in streptozotocin-induced diabetic rats. Cell Biochem Funct. 2003;21:121-5.
49. Baydas G, Reiter R, Yasar A, Tuzcu M, Akdemir I, Nedzvetsky V. Melatonin reduces glial reactivity in the hippocampus, cortex, and cerebellum of streptozotocin-induced diabetic rats. Free Radic Biol Med. 2003;35:797-804.
50. Winiarska K, Fraczyk T, Malinska D, Drozak J, Bryla J. Melatonin attenuates diabetes-induced oxidative stress in rabbits. J Pineal Res. 2006;40:168-76.