Top

Journal of Diabetes & Metabolic Disorders

Published in:

28-01-2023 | Diabetes | Research article

Effect of Oleanolic acid administration on hepatic AMPK, SIRT-1, IL-6 and NF-κB levels in experimental diabetes

Authors: Hatice Iskender, Eda Dokumacioglu, Kubra Asena Terim Kapakin, Ismail Bolat, Behzat Mokhtare, Armagan Hayirli, Guler Yenice

Published in: Journal of Diabetes & Metabolic Disorders | Issue 1/2023

Abstract

Objectives

Diabetes mellitus (DM) is an important public health problem all over the world, considering its complications and increasing prevalence. Oleanolic acid (OA) has anti-diabetic property via modulating glucose metabolism and acting as 5′–adenosine monophosphate (AMP)–activated protein kinase (AMPK) / Sirtuin–1 (SIRT–1) activator and Interleukin 6 (IL–6) / Nuclear factor kappa B (NF–κB) inhibitor. This research questioned if the OA treatment amliorates the hepatic inflammatory profile in the diabetic rats.

Methods

Twenty–eight male Sprague Dawley rats were first subjected to either no diabetes induction (healthy) or diabetes induction by i.p. injection of 50 mg/kg streptozotocin. Then rats in both groups were treated with either tap water or OA (5 mg/kg) within 1 ml tap water by oral gavage for 21 days.

Results

The diabetic rats had higher hepatic MDA (2.88x) and serum AST (2.01x), ALP (2.22x), and ALT (4.27x) levels and 50% lower hepatic SOD level than the healthy rats. The OA treatment significantly reversed these antioxidant parameters in the diabetic rats. The diabetic rats had lower AMPK (85%) and hepatic SIRT–1 (47%) levels and higher hepatic NF–κB (53%) and IL–6 (34%) levels than the healthy rats. Comparing with the health rats, the OA treatment increased hepatic SIRT–1 level, but tended to increase hepatic AMPK level and decrease hepatic NF–κB and IL–6 levels in the diabetic rats. It was also partially effective to ameliorate degenerative changes and necrosis in the diabetic rats.

Conclusion

The OA treatment can be considered to alleviate oxidative stress and reduce severity of inflammation in hepatocytes in the diabetic subjects.

Glovaci D, Fan W, Wong ND. Epidemiology of diabetes mellitus and cardiovascular disease. Curr Cardiol Rep. 2019;21(4):21. https://doi.org/10.1007/s11886-019-1107-y.CrossRefPubMed

Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. https://doi.org/10.1016/j.diabres.2019.107843.

Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol. 2020;16(7):377–90. https://doi.org/10.1038/s41581-020-0278-5.CrossRefPubMedPubMedCentral

Loria P, Lonardo A, Anania F. Liver and diabetes. A vicious circle. Hepatol Res. 2013;43(1):51–64. https://doi.org/10.1111/j.1872-034X.2012.01031.x.CrossRefPubMedPubMedCentral

Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251. https://doi.org/10.1038/nrm3311.CrossRefPubMedPubMedCentral

Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016;48(4):e224. https://doi.org/10.1038/emm.2016.16.CrossRefPubMedPubMedCentral

Kişmiroğlu C, Cengiz S, Yaman M. Biochemistry of AMPK: mechanisms of action and importance in the treatment of diabetes. Eur J Sci Techn. 2020;18:162–70. https://doi.org/10.31590/ejosat.676335.CrossRef

Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434(7029):113–8. https://doi.org/10.1038/nature03354.CrossRefPubMed

Frescas D, Valenti L, Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem. 2005;280(21):20589–95. https://doi.org/10.1074/jbc.M412357200.CrossRefPubMed

10.

Kitada M, Koya D. SIRT1 in type 2 diabetes: mechanisms and therapeutic potential. Diabetes Metab J. 2013;37(5):315–25. https://doi.org/10.4093/dmj.2013.37.5.315.CrossRefPubMedPubMedCentral

11.

Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010;298(4):E751-60. https://doi.org/10.1152/ajpendo.00745.2009.CrossRefPubMedPubMedCentral

12.

Jiang X, Chen J, Zhang C, Zhang Z, Tan Y, Feng W, et al. The protective effect of FGF21 on diabetes-induced male germ cell apoptosis is associated with up-regulated testicular AKT and AMPK/Sirt1/PGC-1α signaling. Endocrinology. 2015;156(3):1156–70. https://doi.org/10.1210/en.2014-1619.CrossRefPubMedPubMedCentral

13.

Akbari M, Hassan-Zadeh V. IL-6 signalling pathways and the development of type 2 diabetes. Inflammopharmacology. 2018;26(3):685–98. https://doi.org/10.1007/s10787-018-0458-0.CrossRefPubMed

14.

Iskender H, Yenice G, Dokumacioglu E, Hayirli A, Sevim C, Dokumacioglu A, et al. Astaxanthin alleviates renal damage of rats on high fructose diet through modulating NFκB/SIRT1 pathway and mitigating oxidative stress. Arch Physiol Biochem. 2020;126(1):89–93. https://doi.org/10.1080/13813455.2018.1493609.CrossRefPubMed

15.

Mitchell JP, Carmody RJ. NF-κB and the Transcriptional control of inflammation. Int Rev Cell Mol Biol. 2018;335:41–84. https://doi.org/10.1016/bs.ircmb.2017.07.007.CrossRefPubMed

16.

Kunnumakkara AB, Shabnam B, Girisa S, Harsha C, Banik K, Devi TB, et al. Inflammation, NF-kappaB, and chronic diseases: how are they linked? Crit Rev Immunol. 2020;40(1):1–39. https://doi.org/10.1615/CritRevImmunol.2020033210.CrossRefPubMed

17.

Huang G, Mei X, Hu J. The antioxidant activities of natural polysaccharides. Curr Drug Targets. 2017;18(11):1296–300. https://doi.org/10.2174/1389450118666170123145357.CrossRefPubMed

18.

Yu Z, Sun W, Peng W, Yu R, Li E, Jiang T, et al. Pharmacokinetics in vitro and in vivo of two novel prodrugs of oleanolic acid in rats and its hepatoprotective effects against liver injury induced by CCl4. Mol Pharmacol. 2016;13(5):1699–710. https://doi.org/10.1021/acs.molpharmaceut.6b00129.CrossRef

19.

Ayeleso TB, Matumba MG, Mukwevho E. Oleanolic acid and its derivatives: Biological activities and therapeutic potential in chronic diseases. Molecules. 2017;22(11):1915. https://doi.org/10.3390/molecules22111915.

20.

Sen A. Prophylactic and therapeutic roles of oleanolic acid and its derivatives in several diseases. World J Clin Cases. 2020;8(10):1767–92. https://doi.org/10.12998/wjcc.v8.i10.1767.CrossRefPubMedPubMedCentral

21.

Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes. 2015;6(3):456–80. https://doi.org/10.4239/wjd.v6.i3.456.CrossRefPubMedPubMedCentral

22.

Mohamed J, Nafizah AHN, Zariyantey AH, Budin SB. Mechanisms of diabetes-induced liver damage: the role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16(2):e132-41. https://doi.org/10.18295/squmj.2016.16.02.002.CrossRefPubMed

23.

Dokumacioglu E, Iskender H, Sen TM, Ince I, Dokumacioglu A, Kanbay Y, et al. The effects of hesperidin and quercetin on serum tumor necrosis factor–alpha and interleukin–6 levels in streptozotocin–induced diabetes model. Pharmacogn Mag. 2018;14:167–173. https://doi.org/10.18295/squmj.2016.16.02.002.

24.

Iskender H, Dokumacioglu E, Terim-Kapakin KA, Yenice G, Mohtare B, Bolat I, et al. Effects of oleanolic acid on inflammation and metabolism in diabetic rats. Biotech Histochem. 2021;15:1–8. https://doi.org/10.1080/10520295.2021.1954691.CrossRef

25.

Zhao H, Liu J, Song L, Liu Z, Han G, Yuan D, et al. Oleanolic acid rejuvenates testicular function through attenuating germ cell DNA damage and apoptosis via deactivation of NF–κB, p53 and p38 signaling pathways. J Pharm Pharmacol. 2017;69(3):295–304. https://doi.org/10.1111/jphp.12668.CrossRefPubMed

26.

Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hidroxynonenal. Methods Enzymol. 1990;186:407–21. https://doi.org/10.1016/0076-6879(90)86134-h.CrossRefPubMed

27.

Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988;34:497–500. https://doi.org/10.1093/clinchem/34.3.497.CrossRefPubMed

28.

Terim–Kapakin KA, Gumus R, Imik H, Kapakin S, Saglam YS. Effects of ascorbic and α–lipoic acid on secretion of HSP–70 and apoptosis in liver and kidneys of broilers exposed to heat stress. Ankara Univ Vet J. 2012;59:279–87. https://doi.org/10.1501/Vetfak_0000002539.CrossRef

29.

Apaydin-Yildirim B, Kordali S, Terim-Kapakin KA, Yildirim F, Aktas-Senocak E, Altın S. Effect of Helichrysum plicatum DC. Subsp, plicatum ethanol extract on gentamicin-induced nephrotoxicity in rats. J Zhejiang Univ Sci B. 2017;18(6):501–11. https://doi.org/10.1631/jzus.B1500291.CrossRefPubMedPubMedCentral

30.

Jugran AK, Rawat S, Devkota PH, Bhatt ID, Rawal RS. Diabetes and plant-derived natural products: from ethnopharmacological approaches to their potential for modern drug discovery and development. Phytother Res. 2021;35(1):223–45. https://doi.org/10.1002/ptr.6821.CrossRefPubMed

31.

Hedayat KM, Lapraz JC, Schuff B. Medicinal plants in clinical practice. The theory of endobiogeny 5th edition 2020;57–60

32.

Kooti W, Farokhipour M, Asadzadeh Z, Ashtary-Larky D, Asadi-Samani M. The role of medicinal plants in the treatment of diabetes: a systematic review. Electron Physician. 2016;8(1):1832–42. https://doi.org/10.19082/1832.CrossRefPubMedPubMedCentral

33.

Salleh NH, Zulkipli IN, Mohd YH, Ja’afar F, Ahmad N, Wan WA, et al. Systematic review of medicinal plants used for treatment of diabetes in human clinical trials: An ASEAN perspective. Evid Based Complement Alternat Med. 2021;2021:5570939. https://doi.org/10.1155/2021/5570939.

34.

Palsamy P, Sivakumar S, Subramanian S. Resveratrol attenuates hyperglycemia-mediated oxidative stress, proinflammatory cytokines and protects hepatocytes ultrastructure in streptozotocin-nicotinamide-induced experimental diabetic rats. Chem Biol Interact. 2010;186(2):200–10. https://doi.org/10.1016/j.cbi.2010.03.028.

35.

Ayala A, Munoz MF, Arguelles S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438. https://doi.org/10.1155/2014/360438.

36.

Tiwari BK, Pandey KB, Abidi AB, Rizvi SI. Markers of oxidative stress during diabetes mellitus. J Biomark. 2013;2013:378790. https://doi.org/10.1155/2013/378790.

37.

Masola B, Oguntibeju OO, Oyenihi AB. Centella asiatica ameliorates diabetes-induced stress in rat tissues via influences on antioxidants and inflammatory cytokines. Biomed Pharmacother. 2018;101:447–57. https://doi.org/10.1016/j.biopha.2018.02.115.CrossRefPubMed

38.

Saha MR, Dey P, Sarkar IDe Sarker D, et al. Acacia nilotica leaf improves insulin resistance and hyperglycemia associated acute hepatic injury and nephrotoxicity by improving systemic antioxidant status in diabetic mice. J Ethnopharmacol. 2018;210:275–86. https://doi.org/10.1016/j.jep.2017.08.036.CrossRefPubMed

39.

Anwer T, Alkarbi ZA, Hassan NA, Alshahrani S, Khan G, et al. Modulatory effect of zingerone against STZ-nicotinamide induced type-2 diabetes mellitus in rats. Arch Physiol Biochem. 2021;127(4):304–10. https://doi.org/10.1080/13813455.2019.1637436.CrossRefPubMed

40.

Ren BC, Zhang YF, Liu SS, Cheng XJ, Yang X, Cui XG, et al. Curcumin alleviates oxidative stress and inhibits apoptosis in diabetic cardiomyopathy via Sirt1-Foxo1 and PI3K-Akt signalling pathways. J Cell Mol Med. 2020;24(21):12355–67. https://doi.org/10.1111/jcmm.15725.CrossRefPubMedPubMedCentral

41.

Wang N, Zhang J, Qin M, Yi W, Yu S, Chen Y, et al. Amelioration of streptozotocin induced pancreatic β cell damage by morin: involvement of the AMPK FOXO3 catalase signaling pathway. Int J Mol Med. 2018;41(3):1409–18. https://doi.org/10.3892/ijmm.2017.3357.CrossRefPubMed

42.

Wang X, Li YL, Wu H, Liu JZ, Hu JX, Liao N, et al. Antidiabetic effect of oleanolic acid: a promising use of a traditional pharmacological agent. Phytother Res. 2011;25(7):1031–40. https://doi.org/10.1002/ptr.3385.CrossRefPubMed

43.

Hasanvand A, Amini-Khoei H, Hadian MR, Abdollahi A, Tavangar SM, Dehpour AR, et al. Anti-inflammatory effect of AMPK signaling pathway in rat model of diabetic neuropathy. Inflammopharmacology. 2016;24(5):207–19. https://doi.org/10.1007/s10787-016-0275-2.CrossRefPubMed

44.

Ban Q, Cheng J, Sun X, Jiang Y, Guo M. Effect of feeding type 2 diabetes mellitus rats with synbiotic yogurt sweetened with monk fruit extract on serum lipid levels and hepatic AMPK (5′ adenosine monophosphate-activated protein kinase) signaling pathway. Food Funct. 2020;11(9):7696–706. https://doi.org/10.1039/d0fo01860k.CrossRefPubMed

45.

Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):e245-5. https://doi.org/10.1038/emm.2016.81.CrossRefPubMedPubMedCentral

46.

Tanyıldız S, Yıldırım H, Uğur H, Yaman M. AMPK’s natural activators and relationships with diseases. Eur J Sci Technol. 2021;21:389–401. https://doi.org/10.31590/ejosat.762959.CrossRef

47.

Yang Z, Kahn BB, Shi H, Xue BZ. Macrophage α1 AMP-activated protein kinase (α1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J Biol Chem. 2010;285(25):19051–9. https://doi.org/10.1074/jbc.M110.123620.CrossRefPubMedPubMedCentral

48.

Abedimanesh N, Asghari S, Mohammadnejad K, Daneshvar Z, Rahmani S, Shokoohi S, et al. The antidiabetic effects of betanin in streptozotocininduced diabetic rats through modulating AMPK/SIRT1/NFκB signaling pathway. Nutr Metab (Lond). 2021;18(1):92. https://doi.org/10.1186/s12986-021-00621-9.CrossRefPubMed

49.

Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Sign. 2013;25(10):1939–48. https://doi.org/10.1016/j.cellsig.2013.06.007.CrossRef

50.

Gregorio E, Colell A, Morales A, Marí M. Relevance of SIRT1-NF-kappaB Axis as therapeutic target to ameliorate inflammation in liver disease. Int J Mol Sci. 2020;21(11):3858. https://doi.org/10.3390/ijms21113858.CrossRefPubMedPubMedCentral

51.

Yang H, Zhang W, Pan H, Feldser HG, Lainez E, Miller C, et al. SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-κB activity. PLoS ONE. 2012;7(9):e46364. https://doi.org/10.1371/journal.pone.0046364.CrossRefPubMedPubMedCentral

52.

Zatterale F, Longo M, Naderi J, Raciti GA, Desiderio A, Miele C, et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol. 2020;10:1607. https://doi.org/10.3389/fphys.2019.01607.CrossRefPubMedPubMedCentral

53.

Manna P, Das J, Ghosh J, Sil PC. Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid. Free Radic Biol Med. 2010;48(11):1465–84. https://doi.org/10.1016/j.freeradbiomed.2010.02.025.CrossRefPubMed

54.

Romagnoli M, Gomez-Cabrera MC, Perrelli MG, Biasi F, Pallardó FV, Sastre J, et al. Xanthine oxidase-induced oxidative stress causes activation of NF-kappaB and inflammation in the liver of type I diabetic rats. Free Radic Biol Med. 2010;49(2):n171-7. https://doi.org/10.1016/j.freeradbiomed.2010.03.024.CrossRef

55.

Svistounov D, Smedsrød B. Hepatic clearance of advanced glycation end products (AGEs): myth or truth? J Hepatol. 2004;41:1038–40. https://doi.org/10.1016/j.jhep.2004.10.004.CrossRefPubMed

56.

Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327–34. https://doi.org/10.1001/jama.286.3.327.CrossRefPubMed

57.

Foss-Freitas MC, Foss NT, Donadi EA, Foss MC. In vitro TNF-alpha and IL-6 production by adherent peripheral blood mononuclear cells obtained from type 1 and type 2 diabetic patients evaluated according to the metabolic control. Ann NY Acad Sci. 2006;1079:177–80. https://doi.org/10.1196/annals.1375.027.CrossRefPubMed

58.

Pollier J, Goossens A, Oleanolic acid. Phytochemistry. 2012;77:10–5. https://doi.org/10.1016/j.phytochem.2011.12.022.CrossRefPubMed

59.

Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med. 2009;75(15):1549–60. https://doi.org/10.1055/s-0029-1186102.CrossRefPubMed

60.

An Q, Hu Q, Wang B, Cui W, Wu F, Ding Y. Oleanolic acid alleviates diabetic rat carotid artery injury through the inhibition of NLRP3 inflammasome signaling pathways. Mol Med Rep. 2017;16(6):8413–9. https://doi.org/10.3892/mmr.2017.7594.CrossRefPubMed

61.

Camer D, Yu Y, Szabo A, Huang XF. The molecular mechanisms underpinning the therapeutic properties of oleanolic acid, its isomer and derivatives for type 2 diabetes and associated complications. Mol Nutr Food Res. 2014;58:1750–9. https://doi.org/10.1002/mnfr.201300861.CrossRefPubMed

62.

Yaman T, Uyar A, Celik I, Alkan EE, Keles OF, Yener Z. Histopathological and immunohistochemical study of antidiabetic effects of heracleum persicum extract in experimentally diabetic rats. IJPER. 2017;51(3):450–7. https://doi.org/10.5530/ijper.51.3s.66.CrossRef

Title: Effect of Oleanolic acid administration on hepatic AMPK, SIRT-1, IL-6 and NF-κB levels in experimental diabetes
Authors: Hatice Iskender
Eda Dokumacioglu
Kubra Asena Terim Kapakin
Ismail Bolat
Behzat Mokhtare
Armagan Hayirli
Guler Yenice
Publication date: 28-01-2023
Publisher: Springer International Publishing
Keyword: Diabetes
Published in: Journal of Diabetes & Metabolic Disorders / Issue 1/2023
Electronic ISSN: 2251-6581
DOI: https://doi.org/10.1007/s40200-022-01178-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2023

Natural activators of AMPK signaling: potential role in the management of type-2 diabetes

Relationship of cardiovascular risk factors, pericardial fat, and carotid thickness with coronary plaque type in patients with diabetes mellitus

Effects of eicosapentaenoic acid supplementation on heat shock protein 27, glycemic status and anthropometric indices in type 2 diabetes patients

The prevalence of uncontrolled diabetes mellitus in patients with type 2 diabetes: a multicenter cross-sectional study

Underlying biochemical effects of intermittent fasting, exercise and honey on streptozotocin-induced liver damage in rats

Future treatment of Diabetes – Tyrosine Kinase inhibitors

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials