Effects of Ononis natrix on glucose and lipid metabolism: An in vivo study

Year 2024, Volume: 28 Issue: 1, 278 - 288, 28.06.2025

Mohammad A. Al-mterin Nour Aboalhaija Malek A. Zihlif Fatma U. Afifi

Abstract

Several medicinal plants have been used historically and are claimed to be effective in either preventing or treating diabetes. This study aimed to evaluate the effect and the mechanism of O. natrix extract (ONE) as an antihyperglycemic and antihyperlipidemic agents in in vivo experiments. Lipid profile was analyzed using fully automated chemistry analyzer. Blood serum samples were used to measure high-density lipoprotein (HDL), triglycerides (TG), total cholesterol (TC) and Low-density lipoprotein (LDL). The expression levels of AMPK alpha-2 and Glut-4 receptors in diabetic rats were investigated using Western blotting. Oral starch tolerance test (OSTT) and oral glucose tolerance test (OGTT) were determined for the plant extracts at three concentrations on Wistar rats. Acarbose or metformin and glipizide were used as positive controls. Blood glucose levels were measured at −30, 0, 45, 90 and 135 min.ONE (250mg/kg and 125 mg/kg), administered before or after induction of diabetes using streptozotocin (STZ), significantly (p<0.05) reduced the blood glucose level by applying preventive and treatment protocols. The expression levels of Glut-4 receptors were significantly increased in rats given ONE (250 mg and 125 mg/kg) compared to the diabetic rats after 8 days of treatment. ONE (250 mg/kg) enhanced significantly (p<0.05) starch tolerance area under the curve (AUC) and glucose tolerance AUC. O. natrix extracts can activate the Glut-4 receptor, and enhance the glucose and starch tolerance in experimental rats. Hence, this widely distributed species in Jordan can be considered as a potential candidate for management of diabetes.

Keywords

O. natrix , diabetes mellitus , OSTT , OGTT , Glut-4

References

• [1] Ginter E, Simko V. Type 2 diabetes mellitus, pandemic in 21st century. Adv Exp Med Biol.2012;771:42-50. https://doi.org/10.1007/978-1-4614-5441-0_6
• [2] Al-Qerem W, Jarab AS, Badinjki M, Hyassat D, Qarqaz R. Exploring variables associated with medication non-adherence in patients with type 2 diabetes mellitus. PLoS One. 2021;16(8):e0256666. https://doi.org/10.1371/journal.pone.0256666
• [3] Powers AC, Niswender KD, Rickels MR. Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J.(Eds). Harrison's Principles of Internal Medicine.McGraw-Hill Education, New York, 2018, pp.2850-2859.
• [4] WHO Health topics-Diabetes. https://www.who.int/health-topics/diabetes♯tab=tab_1(accessed January 14, 2023)
• [5] Badran M, Laher I. Type II Diabetes mellitus in Arabic-speaking countries. Int J Endocrinol. 2012;902873. https://doi.org/ 10.1155/2012/902873
• [6] Zhang H, Tan C, Wang H, Xue S, Wang M. Study on the history of traditional Chinese medicine to treat diabetes. Eur J Integr Med. 2010;2(1): 41-46.
• [7] Afifi-Yazar FU, Kasabri V, Abu-Dahab R. Medicinal plants from Jordan in the treatment of diabetes: Traditional uses vs. in vitro and in vivo evaluations. Planta Med. 2011;77: 1210-1220. https://doi.org/10.1055/s-0031-1279983.
• [8] Unuofin JO, Lebelo SL. Antioxidant effects and mechanisms of medicinal plants and their bioactive compounds for the prevention and treatment of type 2 diabetes: An updated review. Oxid Med Cell Longev. 2020;1356893. https://doi.org/10.1155/2020/1356893
• [9] Al-Aboudi A, Afifi FU. Plants used for the treatment of diabetes in Jordan: A review of scientific evidence. Pharm Biol.2011;49(3):221-239.
• [10] Wazaify M., Afifi FU., El-Khateeb M. Ajlouni K. Complementary and alternative medicine use among Jordanian patients with diabetes. Complement Ther Clin Pract. 2011;17: 71-75. https://doi.org/10.1016/j.ctcp.2011.02.002
• [11] Al-Mterin MA, Aboalhaija NH, Abaza IF, Kailani MH, Zihlif MA, Afifi FU. Chromatographic analysis (LC-MS and GC-MS), antioxidant activity, total phenol and total flavonoid determination of Ononis natrix L. grown in Jordan. Jordan J Chem. 2021;16(1): 31-39.
• [12] Al-Eisawi DMH, Flora of Jordan Checklist, revised ed. 1., The University of Jordan Press, Amman, Jordan 2013.
• [13] Elamrani A, Benaissa M. Chemical composition and antibacterial activity of the essential oil of Ononis natrix from Morocco. J Essent Oil Bear Pl. 2010;13(4): 477-488. https://doi.org/10.1080/0972060x.2010.10643852
• [14] Mhamdi B, Abbassi F, Abdelly C. Chemical composition, antioxidant and antimicrobial activities of the edible medicinal Ononis natrix growing wild in Tunisia. Nat Prod Res. 2015;29(12): 1157-1160. https://doi.org/10.1080/14786419.2014.981188
• [15] Yousaf M, Al-Rehaily AJ, Ahmad MS, Mustafa J, Al-Yahya MA, Al-Said MS, Zhao J, Khan IA. A 5-alkylresorcinol and three 3, 4-dihydroisocoumarins derived from Ononis natrix. Phytochem Letters. 2015;13: 1-5.
• [16] Oz BE, Iscan GS, Akkol EK, Suntar I, Keles H, Acikara OB. Wound healing and anti-inflammatory activity of some Ononis taxons. Biomed Biomed Pharmacother. 2017; 91:1096-1105. https://doi.org/10.1016/j.biopha.2017.05.040.
• [17] Hudaib M, Mohammad M, Bustanji Y, Tayyem R, Yousef M, Abuirjeie M, Aburjai T. Ethnopharmacological survey of medicinal plants in Jordan, Mujib Nature Reserve and surrounding area. J Ethnopharmacol. 2008;120(1):63-71. https://doi.org/10.1016/j.jep.2008.07.031.
• [18] Al-Mubideen BF, Al-Serhan AA, Amarin JZ, Al-Dweikat A, Al-Muhaisen R, Abu Shreik Y, Suradi HH, Al-Ameer HJ, Zihlif MA. Ononis natrix L. lowers the blood glucose concentration in Wistar rats with streptozotocin-induced diabetes mellitus. Endocr Metab Immune Disord Drug Targets. 2021;21(5):854-858. https://doi.org/10.2174/1871530320999200818140359.
• [19] Eriksson A, Attvall S, Bonnier M, Eriksson JW, Rosander B, Karlsson FA. Short-term effects of metformin in type 2 diabetes. Diabetes Obes Metab. 2007;9(3): 330-336. https://doi.org/10.1111/j.1463-1326.2006.00611
• [20] Geerling JJ, Boon MR, van der Zon G, van den Berg SVD, van den Hoek AM, Lombes M, Princen H, Havekes L, Rensen P, Guigas B. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes. 2014; 63(3):880-891. https://doi.org/10.2337/db13-019.
• [21] Modak M, Dixit P, Londhe J, Ghaskadbi S, Devasagayam TPA. Indian herbs and herbal drugs used for the treatment ofdiabetes. J Clin Biochem Nutr. 2007;40(3): 163-173. https://doi.org/10.3164/jcbn.40.163
• [22] Patel DK, Prasad SK, Kumar R, Hemalatha S. An overview on antidiabetic medicinal plants having insulin mimetic property. Asian Pac J Trop Biomed. 2012;2(4): 320-330. https://doi.org/10.1016/S2221-1691(12)60032-X
• [23] Abu-Odeh AM, Talib WH. Middle East medicinal plants in the ttreatment of diabetes: A review. Molecules. 2021;26:742. https://doi.org/10.3390/molecules26030742.
• [24] Hamada Y, Fujii H, Fukagawa M. Role of oxidative stress in diabetic bone disorder. Bone. 2009; 45 Suppl 1:S35-38. https://doi.org/10.1016/j.bone.2009.02.004.
• [25] Mezrag A, Malafronte N, Bouheroum M,Travaglino C, Russo D, Milella D, Severino L, De Tommasi N, Braca A, Dal Piaz F. Phytochemical and antioxidant activity studies on Ononis angustissima L. aerial parts: Isolation of two new flavonoids. Nat Prod Res. 2017; 31(5): 507-514. https://doi.org/10.1080/14786419.2016.1195381.
• [26] Ghorbani A. Mechanisms of antidiabetic effects of flavonoid rutin. Biomed Pharmacother. 2017; 96:305-312. https://doi.org/10.1016/j.biopha.2017.10.001.
• [27] Al-Ishaq RK, Abotaleb M, Kubatka P, Kajo K, Büsselberg D. Flavonoids and their anti-diabetic effects: Cellular mechanisms and effects to improve blood sugar levels. Biomolecules 2019;9:430. https://doi.org/10.3390%2Fbiom9090430.
• [28] Oyedemi SO, Nwaogu G, Chukwuma CI, Adayemi OT, Matsabisa MG, Swain SS, Aiyegoro OA. Quercetin modulates hyperglycemia by improving the pancreatic antioxidant status and enzymes activities linked with glucose metabolism in type 2 diabetes model of rats: In silico studies of molecular interaction of quercetin with hexokinase and catalase. J Food Biochem. 2020; 44(2):e13127. https://doi.org/10.1111/jfbc.13127.
• [29] Zang Y, Igarashi K, Li Y. Anti-diabetic effects of luteolin and luteolin-7-O-glucoside on KK-A(y) mice. Biosci Biotechnol Biochem. 2016;80(8): 1580-1586. https://doi.org/10.1080/09168451.2015.1116928.
• [30] Barky A, Ezz A, Mohammed T. The potential role of apigenin in diabetes mellitus. Int J Clin Case Rep Rev. 2020;3(1): 32. https://doi.org/10.31579/2690-4861/032..
• [31] Vessal M, Hemmati M, Vasei M. Antidiabetic effects of quercetin in streptozocin-induced diabetic rats. Comp Biochem Physiol C Toxicol Pharmacol. 2003;135c(3): 357-364. https://doi.org/10.1016/s1532-0456(03)00140-6.
• [32] Kamalakkannan N, Prince PSM. Rutin improves the antioxidant status in streptozotocin-induced diabetic rat tissues. Mol Cell Biochem. 2006;293(1-2): 211-219. https://doi.org/ 10.1007/s11010-006-9244-1.
• [33] Eddouks M, Lemhadri A, Zeggwagh NA, Michel JB. Potent hypoglycaemic activity of the aqueous extract of Chamaemelum nobile in normal and streptozotocin-induced diabetic rats. Diabetes Res Clin Prac. 2005;67(3): 189-195. https://doi.org/10.1016/j.diabres.2004.07.015.
• [34] El-Amin M, Virk P, Elobeid MA, Almarhoon ZM, Hassan ZK, Omer SA, Merghani NM, Daghestani MH, Al-Olayan EM. Anti-diabetic effect of Murraya koenigii (L) and Olea europaea (L.) leaf extracts on streptozotocin induced diabetic rats. Pak J Pharm Sci.2013;26(2): 359-365.
• [35] Fruehwald-Schultes B, Oltmanns KM, Toschek B, Sopke S, Kern W, Born J, Fehm HL, Peters A. Short-term treatment withmetformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. Metabolism. 2002;51(4): 531-536. https://doi.org/10.1053/meta.2002.31332.
• [36] Pournaghi P, Sadrkhanlou RA, Hasanzadeh S, Foroughi A. An investigation on body weights, blood glucose levels and pituitary-gonadal axis hormones in diabetic and metformin-treated diabetic female rats. Vet Res Forum. 2012;3(2):79-84.
• [37] Rauter AP, Martins A, Borges C, Mota-Filipe H, Pinto R, Sepodes B, Justino J. Antihyperglycaemic and protective effects of flavonoids on streptozotocin-induced diabetic rats. Phytother Res. 2010; 24 Suppl 2:S133-138. https://doi.org/10.1002/ptr.3017
• [38] Lu Q, Hao M, Wu W, Zhang N, Isaac AT, Yin J, Zhu X, Du l, Yin X. Antidiabetic cataract effects of GbE, rutin and quercetin are mediated by the inhibition of oxidative stress and polyol pathway. Acta Biochim Pol. 2018;65(1): 35-41.https://doi.org/10.18388/abp.2016_1387.
• [39] Dhanya R, Arya AD, Nisha P, Jayamurthy P. Quercetin, a lead compound against Type 2 Diabetes ameliorates glucose uptake via AMPK pathway in skeletal muscle cell line. Front Pharmacol. 2017;8: 336. https://doi.org/10.3389/fphar.2017.00336.
• [40] Alam F, Islam MA, Khalil MI, Gan SH. Metabolic control of Type 2 Diabetes by targeting the GLUT4 glucose transporter: intervention approaches. Curr Pharm Des. 2016; 22(20): 3034-3049. https://doi:10.2174/1381612822666160307145801.
• [41] Ding L, Jin D, Chen X. Luteolin enhances insulin sensitivity via activation of PPARγ transcriptional activity in adipocytes. J Nutr Biochem.2010;21(10): 941-947. https://doi.org/10.1016/j.jnutbio.2009.07.009.
• [42] Tundis R, Loizzo MR, Menichini F. Natural products as alpha-amylase and alpha glucosidase inhibitors and their hypoglycaemic potential in the treatment of diabetes: an update. Mini Rev Med Chem. 2010;10(4): 315-331. https://doi.org/10.2174/138955710791331007.
• [43] Kasabri V, Afifi FU, Hamdan I. In vitro and in vivo acute antihyperglycemic effects of five selected indigenous plants from Jordan used in traditional medicine. J Ethnopharmacol. 2011;133(2):888-896. https://doi.org/10.1016/j.jep.2010.11.025.
• [44] Balfour JA, McTavish D., Acarbose. An update of its pharmacology and therapeutic use in dibetes mellitus. Drugs. 1993;46(6): 1025-1054.https://doi.org/10.2165/00003495-199346060-00007.
• [45] Yee HS, Fong NT. A review of the safety and efficacy of acarbose in diabetes mellitus. Pharmacotherapy. 1996;16(5):792-805.
• [46] Yerlikaya S, Zengin G, Mollica A, Baloglu MC, Celik Altunoglu Y, Aktumsek A.. A multidirectional perspective for novel functional products: In vitro pharmacological activities and in silico studies on Ononis natrix subsp. hispanica. Front Pharmacol. 2017;8: 600. https://doi.org/10.3389/fphar.2017.00600.
• [47] Mojica L, Meyer A, Berhow MA, de Mejía EG. Bean cultivars (Phaseolus vulgaris L.) have similar high antioxidant capacity, in vitro inhibition of α-amylase and α-glucosidase while diverse phenolic composition and concentration. Food Res Int. 2015;69: 38-48.
• [48] Al-Eisawi DMH, Field Guide to Wild Flowers of Jordan and Neighboring Countries, first ed., Jordan Press Foundation Al Rai, Amman, Jordan. 1998.
• [49] Feinbrun-Dothan N. Flora Palaestina/4. Alismataceae to Orchidaceae., first ed., Israel Academy of Sciences and Humanities, Jerusalem, Israel. 1986.
• [50] Furman BL. Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol. 2015;70: 5.47.1-5.47.20. https://doi.org/10.1002/0471141755.ph0547s70.
• [51] Ranjan V, Vats M, Gupta N, Sardana S. Antidiabetic potential of whole plant of Adiantum capillus veneris Linn. in streptozotocin induced diabetic rats. Int J Pharm Clin Res. 2014;6(4): 341-347.
• [52] Martin SS, Giugliano RP, Murphy SA, Wassermann SM, Stein EA, Ceska R, Lopez-Miranda J, Georgiev B, Lorenzatti AJ, Tikkanen MJ, Sever PS, Keech AC, Pedersen T, Sabatine MS. Comparison of low-density lipoprotein cholesterol assessment by Martin/Hopkins estimation, Friedewald estimation, and preparative ultracentrifugation: Insights from the FOURIER trial. JAMA Cardiol. 2018;3(8):749-753. https://doi.org/10.1001/jamacardio.2018.1533.