Generic placeholder image

Cardiovascular & Hematological Disorders-Drug Targets

Editor-in-Chief

ISSN (Print): 1871-529X
ISSN (Online): 2212-4063

Research Article

Protective Effect of Hydroalcoholic Extract of Punica granatum Leaves on High Fructose Induced Insulin Resistance in Experimental Animals

Author(s): Deepti Bandawane*, Ashwini Kotkar and Pooja Ingole

Volume 23, Issue 4, 2023

Published on: 30 November, 2023

Page: [263 - 276] Pages: 14

DOI: 10.2174/011871529X273808231129035950

Price: $65

Abstract

Background: Insulin resistance (IR) is a condition characterized by reduced sensitivity of body tissues to insulin, leading to impaired regulation of downstream metabolic pathways and elevated blood glucose levels. Diets rich in fructose have been proven to cause insulin resistance in test rats, resulting in decreased insulin sensitivity, particularly in the liver, and compromised disposal of glucose from the body. In the search for effective treatments, Plant-derived formulations have gained popularity because to their ability for treating a variety of ailments. One such plant is Punica granatum Linn. from the Punicaceae family, which has long been used in the treatment of diabetes and its consequences. This study investigates the insulin-resistant activity of an extract from Punica granatum leaves. The study goal is to assess the possible protective role of Punica granatum against insulin resistance through various analyses, including serum glucose and insulin levels, lipid profile assessment, measurement of liver enzymes (ALP, SGOT, SGPT), and histopathological examination of liver sections.

Methods: The study involves several key methods to evaluate the insulin-resistant activity of Punica granatum extract in high fructose diet induced insulin resistance animal model. The extract was administered orally to the experimental animals. These methods include the measurement of serum glucose and serum insulin levels, analysis of the lipid profile, quantification of liver enzymes such as ALP, SGOT, and SGPT, and a detailed histopathological examination of liver tissue sections. These analyses collectively provide insights into the impact of Punica granatum extract on insulin resistance and related metabolic parameters.

Results: Findings of this study provide insight on the possible benefits of Punica granatum extract on insulin resistance. Through the assessment of serum glucose and insulin levels, lipid profile analysis, and measurement of liver enzymes, the study elucidates the impact of the extract on key metabolic indicators. Additionally, the histopathological examination of liver sections provides visual insights into the structural changes that may occur as a result of the treatment.

Conclusion: In conclusion, this study highlights the ability of Punica granatum extract as a candidate for addressing insulin resistance. The findings suggest that the extract may have a protective role against insulin resistance, as evidenced by improvements in serum glucose and insulin levels, lipid profile, liver enzyme levels, and histopathological characteristics. Further research and investigations are warranted to fully understand the mechanisms underlying these observed effects and to validate the potential of Punica granatum extract as a therapeutic option for managing insulin resistance and its associated complications.

Keywords: Insulin resistance, high fructose, oral glucose tolerance, metabolic syndrome, Punica granatum, oxidative stress.

Graphical Abstract
[1]
Chen, L.; Chen, R.; Wang, H.; Liang, F. Mechanisms linking inflammation to insulin resistance. Int J of Endocrino, 2015, 1-9.
[2]
Thresher, J.S.; Podolin, D.A.; Wei, Y.; Mazzeo, R.S.; Pagliassotti, M.J. Comparison of the effects of sucrose and fructose on insulin action and glucose tolerance. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2000, 279(4), R1334-R1340.
[http://dx.doi.org/10.1152/ajpregu.2000.279.4.R1334] [PMID: 11004002]
[3]
Fan, C.Y.; Wang, M.X.; Ge, C.X.; Wang, X.; Li, J.M.; Kong, L.D. Betaine supplementation protects against high-fructose-induced renal injury in rats. J. Nutr. Biochem., 2014, 25(3), 353-362.
[4]
Park, J.H.; Kho, M.C.; Kim, H.Y.; Ahn, Y.M.; Lee, Y.J.; Kang, D.G.; Lee, H.S. Blackcurrant suppresses metabolic syndrome induced by high-fructose diet in rats. Evid. Based Complement. Alternat. Med., 2015, 2015, 1-11.
[http://dx.doi.org/10.1155/2015/385976] [PMID: 26504474]
[5]
Hengist, A.; Koumanov, F.; Gonzalez, J.T. Fructose and metabolic health: governed by hepatic glycogen status? J. Physiol., 2019, 597(14), 3573-3585.
[http://dx.doi.org/10.1113/JP277767] [PMID: 30950506]
[6]
Geidl-Flueck, B.; Philipp, A.G. Insights into the hexose liver metabolism-glucose versus fructose. Nutrients, 2017, 9(9), 1026.
[http://dx.doi.org/10.3390/nu9091026]
[7]
Zhang, D.M.; Jiao, R.Q.; Kong, L.D. High dietary fructose: Direct or indirect dangerous factors disturbing tissue and organ functions. Nutrients, 2017, 9(4), 335.
[http://dx.doi.org/10.3390/nu9040335] [PMID: 28353649]
[8]
Suwannaphet, W.; Meeprom, A.; Yibchok-Anun, S.; Adisakwattana, S. Preventive effect of grape seed extract against high-fructose diet-induced insulin resistance and oxidative stress in rats. Food Chem. Toxicol., 2010, 48(7), 1853-1857.
[http://dx.doi.org/10.1016/j.fct.2010.04.021] [PMID: 20412828]
[9]
Putakala, M.; Gujjala, S.; Nukala, S.; Desireddy, S. Beneficial effects of phyllanthus amarus against high fructose diet induced insulin resistance and hepatic oxidative stress in male wistar rats. Appl. Biochem. Biotechnol., 2017, 183(3), 744-764.
[http://dx.doi.org/10.1007/s12010-017-2461-0] [PMID: 28353042]
[10]
Chaudhury, A.; Duvoor, C.; Reddy Dendi, V.S.; Kraleti, S.; Chada, A.; Ravilla, R.; Marco, A.; Shekhawat, N.S.; Montales, M.T.; Kuriakose, K.; Sasapu, A.; Beebe, A.; Patil, N.; Musham, C.K.; Lohani, G.P.; Mirza, W. Clinical review of antidiabetic drugs: Implications for type 2 diabetes mellitus management. Front. Endocrinol., 2017, 8, 6.
[11]
Zhang, L.; Gao, Y.; Zhang, Y.; Liu, J.; Yu, J. Changes in bioactive compounds and antioxidant activities in pomegranate leaves. Sci. Hortic., 2010, 123(4), 543-546.
[http://dx.doi.org/10.1016/j.scienta.2009.11.008]
[12]
Amri, Z.; Ben Khedher, M.R.; Zaibi, M.S. Anti-diabetic effects of pomegranate extracts in long-term high fructose-fat fed rats. Clin Phytosci, 2020, 6, 55.
[http://dx.doi.org/10.1186/s40816-020-00202-y]
[13]
Yin, J.; Zhang, H.; Ye, J. Traditional chinese medicine in treatment of metabolic syndrome. Endocr. Metab. Immune Disord. Drug Targets, 2008, 8(2), 99-111.
[http://dx.doi.org/10.2174/187153008784534330] [PMID: 18537696]
[14]
Tangvarasittichai, S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J. Diabetes, 2015, 6(3), 456-480.
[http://dx.doi.org/10.4239/wjd.v6.i3.456] [PMID: 25897356]
[15]
Ekor, M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front. Pharmacol., 2014, 4, 177.
[http://dx.doi.org/10.3389/fphar.2013.00177] [PMID: 24454289]
[16]
Trease, G.E.; Evans, W.C. Pharmacognosy, 15th ed.; Sounders Publishers: London, 2002, pp. 42-44.
[17]
Sreedevi, P.; Vijayalakshmi, K.; Venkateswari, R. phytochemical evaluation of punica granatum l. Leaf extract. Int. J. Curr. Pharm. Res., 2017, 9(4), 14.
[http://dx.doi.org/10.22159/ijcpr.2017v9i4.1159]
[18]
Elnawasany, Sally Clinical applications of pomegranate. In: Breeding and Health Benefits of Fruit and Nut Crops; IntechOpen,, 2018.
[http://dx.doi.org/10.5772/intechopen.75962]
[19]
Subha, G. Medicinal utility of pomegranate fruit in regular human diet: A brief review. IJFH, 2017, 3(1), 17-18.
[20]
Patel, AN; Bandawane, DD; Mhetre, NK Pomegranate (Punica granatum Linn.) leaves attenuate disturbed glucose homeostasis and hyperglycemia mediated hyperlipidemia and oxidative stress in streptozotocin induced diabetic rats. Eur. J. Integr. Med., 2014, 6(3), 307-321.
[21]
Bhoi, R; Bandawane, DD; Patel, A Phytochemical and pharmacological activities of pomegranate-a riview. Invent. Rapid : Ethnopharmacol., 2012.
[22]
Shih, CC; Lin, CH; Lin, WL; Wu, JB Momordica charantia extract on insulin resistance and the skeletal muscle GLUT4 protein in fructose-fed rats. J. Ethnopharmacol., 2009, 123(1), 82-90.
[23]
Yin, J; Xing, H; Ye, J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism, 2008, 57(5), 712-717.
[http://dx.doi.org/10.1016/j.metabol.2008.01.013]
[24]
Ghezzi, A.C.; Lucieli, T.C.; José, D.R.; Carla, R.; Rodrigo, A.D.; de Mello, M.A.R. Metabolic syndrome markers in wistar rats of different ages. Diabetol Metab Syndr, 2012, 4(1), 16.
[http://dx.doi.org/10.1186/1758-5996-4-16]
[25]
Incir, S.; Bolayirli, I.M.; Inan, O.; Aydın, M.S.; Bilgin, I.A.; Sayan, I.; Esrefoglu, M.; Seven, A. The effects of genistein supplementation on fructose induced insulin resistance, oxidative stress and inflammation. Life Sci., 2016, 158, 57-62.
[http://dx.doi.org/10.1016/j.lfs.2016.06.014] [PMID: 27350161]
[26]
Matuszkiewicz-Rowińska, J.; Szamotulska, K.; Giers, K.; Jasik, M.; Bartoszewicz, Z.; Romejko-Ciepielewska, K.; Paklerska, E.; Gomółka, M.; Matuszkiewicz-Rowińska, J. Homeostatic model assessment indices in evaluation of insulin resistance and secretion in hemodialysis patients. Med. Sci. Monit., 2013, 19, 592-598.
[http://dx.doi.org/10.12659/MSM.883978] [PMID: 23867834]
[27]
Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis model assessment: insulin resistance and? -cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1985, 28(7), 412-419.
[http://dx.doi.org/10.1007/BF00280883] [PMID: 3899825]
[28]
Katz, A.; Nambi, S.S.; Mather, K.; Baron, A.D.; Follmann, D.A.; Sullivan, G.; Quon, M.J. Quantitative insulin sensitivity check index: A simple, accurate method for assessing insulin sensitivity in humans. J. Clin. Endocrinol. Metab., 2000, 85(7), 2402-2410.
[http://dx.doi.org/10.1210/jcem.85.7.6661] [PMID: 10902785]
[29]
Noha, M.S.; George, S.G.S.; Mona, A.R.; Ghada, M.S.; Nariman, G. Levocetirizine ameliorates high fructose diet-induced insulin resistance, vascular dysfunction and hepatic steatosis in rats. Eur. J. Pharmacol., 2014, 740, 353-363.
[30]
Bandawane, D.D.; Juvekar, A.R. Study of antihyperglycemic, antihyperlipidemic and antioxidant activities of withania coagulans fruits in streptozotocin induced non-insulin dependent diabetes mellitus in rats. Indian Drugs, 2021, 58(12), 63-71.
[31]
Jaydeokar, A.V.; Bandawane, D.D.; Bibave, K.H.; Patil, T.V. Hepatoprotective potential of Cassia auriculata roots on ethanol and antitubercular drug-induced hepatotoxicity in experimental models. Pharm. Biol., 2013, 52(3), 344-355.
[32]
Pugazhenthi, S; Angel, JF; Khandelwal, RL Effects of vanadate administration on the high sucrose diet-induced aberrations in normal rats. Mol. Cell. Biochem., 1993, 122(1), 69-75.
[http://dx.doi.org/10.1007/BF00925739]
[33]
Samuel, V.T.; Shulman, G.I. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. J. Clin. Invest., 2016, 126(1), 12-22.
[http://dx.doi.org/10.1172/JCI77812] [PMID: 26727229]
[34]
Rizkalla, S.W. Health implications of fructose consumption: A review of recent data. Nutr. Metab., 2010, 7(1), 82.
[http://dx.doi.org/10.1186/1743-7075-7-82] [PMID: 21050460]
[35]
Stanhope, K.L. Consuming fructose-sweetened, not glucose-sweetened, beverages increase visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Investig., 2009, 119(5), 1322-1334.
[36]
DeBosch, B.J.; Chen, Z.; Finck, B.N.; Chi, M.; Moley, K.H. Glucose transporter-8 (GLUT8) mediates glucose intolerance and dyslipidemia in high-fructose diet-fed male mice. Mol. Endocrinol., 2013, 27(11), 1887-1896.
[http://dx.doi.org/10.1210/me.2013-1137] [PMID: 24030250]
[37]
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), 1832-1842.
[http://dx.doi.org/10.19082/1832] [PMID: 26955456]
[38]
Salleh, N.H.; Zulkipli, I.N.; Mohd, Y.H.; Ja'afar, F.; Ahmad, N.; Wan Ahmad, W.A.N.; Ahmad, S.R. Systematic review of medicinal plants used for treatment of diabetes in human clinical trials: An ASEAN perspective. eCAM., 2021, 2021, 5570939.
[39]
Graf, B.L.; Raskin, I.; Cefalu, W.T.; Ribnicky, D.M. Plant-derived therapeutics for the treatment of metabolic syndrome. Curr. Opin. Investig. Drugs, 2010, 11(10), 1107-1115.
[PMID: 20872313]
[40]
Gharib, E.; Montasser Kouhsari, S. Study of the antidiabetic activity of punica granatum l. fruits aqueous extract on the alloxan-diabetic wistar rats. Iran. J. Pharm. Res., 2019, 18(1), 358-368.
[PMID: 31089370]
[41]
Laurindo, L.F.; Barbalho, S.M.; Marquess, A.R.; Grecco, A.I.S.; Goulart, R.A.; Tofano, R.J.; Bishayee, A. Pomegranate (Punica granatum L.) and metabolic syndrome risk factors and outcomes: A systematic review of clinical studies. Nutrients, 2022, 14(8), 1665.
[http://dx.doi.org/10.3390/nu14081665] [PMID: 35458227]
[42]
Liu, IM; Tzeng, TF; Liou, SS; Lan, TW Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats. Life Sci, 2007, 81(21-22), 1479-1488.
[http://dx.doi.org/10.1016/j.lfs.2007.08.045]
[43]
Maurya, S.K.; Srivastava, A.K. High fructose diet-induced glucose intolerance and dyslipidemia in adult Syrian golden hamsters. Indian J. Sci. Technol., 2008, 1(6), 1-5.
[http://dx.doi.org/10.17485/ijst/2008/v1i6.5]
[44]
Rader, D.J. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am. J. Med., 2007, 120(3), S12-S18.
[http://dx.doi.org/10.1016/j.amjmed.2007.01.003] [PMID: 17320517]
[45]
Jung, U.; Cho, Y.Y.; Choi, M.S. Apigenin ameliorates dyslipidemia, hepatic steatosis and insulin resistance by modulating metabolic and transcriptional profiles in the liver of high-fat diet-induced obese mice. Nutrients, 2016, 8(5), 305.
[http://dx.doi.org/10.3390/nu8050305] [PMID: 27213439]
[46]
Modak, M.; Dixit, P.; Londhe, J.; Ghaskadbi, S.; Devasagayam, T.P.A. Indian herbs and herbal drugs used for the treatment of diabetes. J. Clin. Biochem. Nutr., 2007, 40(3), 163-173.
[http://dx.doi.org/10.3164/jcbn.40.163] [PMID: 18398493]
[47]
Barman, S.; Das, S. Antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of Punica granatum in alloxan-induced non-insulin-dependent diabetes mellitus albino rats. Indian J. Pharmacol., 2012, 44(2), 219-224.
[http://dx.doi.org/10.4103/0253-7613.93853] [PMID: 22529479]
[48]
Park, J.Y.; Mi, G.J.; Jung, M.O. Sasa quelpaertensis leaf extract ameliorates dyslipidemia, insulin resistance, and hepatic lipid accumulation in high-fructose-diet-fed rats., 2020, 12(12), 3762.
[http://dx.doi.org/10.3390/nu12123762]
[49]
Stanhope, K.L.; Havel, P.J. Fructose consumption: Potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance. Curr. Opin. Lipidol., 2008, 19(1), 16-24.
[http://dx.doi.org/10.1097/MOL.0b013e3282f2b24a] [PMID: 18196982]
[50]
Khalid, M.; Alkaabi, J.; Khan, M.A.B.; Adem, A. Insulin signal transduction perturbations in insulin resistance. Int. J. Mol. Sci., 2021, 22(16), 8590.
[http://dx.doi.org/10.3390/ijms22168590] [PMID: 34445300]
[51]
Visinoni, S.; Khalid, N.F.I.; Joannides, C.N.; Shulkes, A.; Yim, M.; Whitehead, J.; Tiganis, T.; Lamont, B.J.; Favaloro, J.M.; Proietto, J.; Andrikopoulos, S.; Fam, B.C. The role of liver fructose-1,6-bisphosphatase in regulating appetite and adiposity. Diabetes, 2012, 61(5), 1122-1132.
[http://dx.doi.org/10.2337/db11-1511] [PMID: 22517657]
[52]
Pereira, R.; Botezelli, J.; da Cruz Rodrigues, K.; Mekary, R.; Cintra, D.; Pauli, J.; da Silva, A.; Ropelle, E.; de Moura, L. Fructose consumption in the development of obesity and the effects of different protocols of physical exercise on the hepatic metabolism. Nutrients, 2017, 9(4), 405.
[http://dx.doi.org/10.3390/nu9040405] [PMID: 28425939]
[53]
Kovacs, P; Harper, I; Hanson, RL; Infante, AM; Bogardus, C; Tataranni, PA; Baier, LJ A novel missense substitution (Val1483Ile) in the fatty acid synthase gene (FAS) is associated with percentage of body fat and substrate oxidation rates in nondiabetic Pima Indians. Diabetes, 2004, 53, 1915e9.
[54]
Timson, D.J. Fructose 1,6- bis phosphatase: getting the message across. Biosci. Rep., 2019, 39(3), BSR20190124.
[http://dx.doi.org/10.1042/BSR20190124] [PMID: 30804231]
[55]
Claycombe, K.J.; Jones, B.H.; Standridge, M.K.; Guo, Y.; Chun, J.T.; Taylor, J.W.; Moustaïd-Moussa, N. Insulin increases fatty acid synthase gene transcription in human adipocytes. Am. J. Physiol., 1998, 274(5), R1253-R1259.
[PMID: 9644037]
[56]
Lin, S.; Thomas, T.C.; Storlien, L.H.; Huang, X.F. Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int. J. Obes., 2000, 24(5), 639-646.
[http://dx.doi.org/10.1038/sj.ijo.0801209] [PMID: 10849588]
[57]
Wilcox, G. Insulin and insulin resistance. Clin. Biochem. Rev., 2005, 26(2), 19-39.
[PMID: 16278749]
[58]
Thorburn, A.W.; Storlien, L.H.; Jenkins, A.B.; Khouri, S.; Kraegen, E.W. Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am. J. Clin. Nutr., 1989, 49(6), 1155-1163.
[http://dx.doi.org/10.1093/ajcn/49.6.1155] [PMID: 2658534]
[59]
Grundy, SM Metabolic syndrome: Connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol., 2006, 47(6), 1093-100.
[60]
Janssen, J.A.M.J.L. Hyperinsulinemia and its pivotal role in aging, obesity, type 2 diabetes, cardiovascular disease and cancer. Int. J. Mol. Sci., 2021, 22(15), 7797.
[http://dx.doi.org/10.3390/ijms22157797] [PMID: 34360563]
[61]
Cheng-Chu, H.; Chen-Chung, L.; Yi-Chun, L.; Lucy, S.H.; Liang-Yi, W.; Shu-Chen, H. Proteomic changes associated with metabolic syndrome in a fructose-fed rat model. Yao Wu Shi Pin Fen Xi, 2016, 24(4), 754-761.
[62]
Huang, D.; Dhawan, T.; Young, S.; Yong, W.H.; Boros, L.G.; Heaney, A.P. Fructose impairs glucose-induced hepatic triglyceride synthesis. Lipids Health Dis., 2011, 10(1), 20.
[http://dx.doi.org/10.1186/1476-511X-10-20] [PMID: 21261970]
[63]
He, K.; Wang, J.; Shi, H.; Yu, Q.; Zhang, X.; Guo, M.; Sun, H.; Lin, X.; Wu, Y.; Wang, L.; Wang, Y.; Xian, X.; Liu, G. An interspecies study of lipid profiles and atherosclerosis in familial hypercholesterolemia animal models with low-density lipoprotein receptor deficiency. Am. J. Transl. Res., 2019, 11(5), 3116-3127.
[PMID: 31217881]
[64]
Moughaizel, M.; Dagher, E.; Jablaoui, A.; Thorin, C.; Rhimi, M.; Desfontis, J.C.; Mallem, Y. Long-term high-fructose high-fat diet feeding elicits insulin resistance, exacerbates dyslipidemia and induces gut microbiota dysbiosis in WHHL rabbits. PLoS One, 2022, 17(2), e0264215.
[http://dx.doi.org/10.1371/journal.pone.0264215] [PMID: 35196347]
[65]
Choi, S.H.; Ginsberg, H.N. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol. Metab., 2011, 22(9), 353-363.
[http://dx.doi.org/10.1016/j.tem.2011.04.007] [PMID: 21616678]
[66]
Tripathi, Y.B.; Pandey, V. Obesity and endoplasmic reticulum (ER) stresses. Front. Immunol., 2012, 3, 240.
[http://dx.doi.org/10.3389/fimmu.2012.00240] [PMID: 22891067]
[67]
Sanders, F.W.B.; Griffin, J.L. De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol. Rev. Camb. Philos. Soc., 2016, 91(2), 452-468.
[http://dx.doi.org/10.1111/brv.12178] [PMID: 25740151]
[68]
Coronati, M; Baratta, F; Pastori, D; Ferro, D; Angelico, F; Del Ben, M. Added fructose in non-alcoholic fatty liver disease and in metabolic syndrome: A narrative review. Nutrients, 2022, 14(6), 1127.
[http://dx.doi.org/10.3390/nu14061127]
[69]
Lee, J.S.; Jun, D.W.; Kim, E.K.; Jeon, H.J.; Nam, H.H.; Saeed, W.K. Histologic and metabolic derangement in high-fat, high-fructose, and combination diet animal models. Scientific World Journal, 2015, 2015, 1-9.
[http://dx.doi.org/10.1155/2015/306326] [PMID: 26090514]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy