Potent Hypoglycemic Phytochemicals from Citrus: Citrus for Diabetes

Tayyiba Afzal; Yamin  Bibi; Zia ur Rehman  Mashwani; Syeda Sobia  Gilani; Neelum  Naheed; Aqsa  Jabeen; Raafia Noor  Afzal

doi:10.54393/df.v4i03.78

Authors

Tayyiba Afzal Department of Botany, PMAS Arid Agriculture University, Rawalpindi, Pakistan
Yamin Bibi Department of Botany, PMAS Arid Agriculture University, Rawalpindi, Pakistan
Zia ur Rehman Mashwani Department of Botany, PMAS Arid Agriculture University, Rawalpindi, Pakistan
Syeda Sobia Gilani Department of Botany, PMAS Arid Agriculture University, Rawalpindi, Pakistan
Neelum Naheed Department of Botany, PMAS Arid Agriculture University, Rawalpindi, Pakistan
Aqsa Jabeen Department of Botany, University of Agriculture, Faisalabad, Pakistan
Raafia Noor Afzal School of Chemistry, University of the Punjab, Lahore, Pakistan

DOI:

https://doi.org/10.54393/df.v4i03.78

Keywords:

Citrus, Diabetes, Naringenin, Metabolism, Hesperiden, Fruits

Abstract

In particular, when it comes to the cure and management of chronic diseases, consuming a diet that contain natural products such as; plants is crucial for health promotion. Citrus fruit has been widely consumed and possess nutritional components that supports the management and cure of various disease conditions and the underlying metabolic changes that leads to development of long term serious diseases. Multiple citrus fruit species are analyzed for their curative effect particularly for the diseases that are associated with metabolic alterations such as diabetes, heart burn and dyspepsia. Diabetes is found to be effectively cured and allied health problems are managed by the use of citrus fruits and the specific secondary metabolites found in citrus fruits such has; hesperidin, naringenin and nobiletin. Citrus fruits primarily contain flavonoids, which have a number of advantageous properties for health promotion, especially anti-diabetic effects. Present review enlightened the specific curative potential of citrus fruits and phytochemicals on the living organisms, the potential anti-diabetic efficacy and the metabolic pathway of citrus bioactive compounds hesperidin and naringenin is explained. Mechanistic regulation of metabolic disturbances owing to various disease conditions that are root caused by diabetes are effectively done by the bioactive compounds of citrus fruits. Citrus fruits have matchless benefits when it comes the issues of hyperglycemia, while their antidiabetic effects and have ameliorative effect on diabetes related health problems remain to be verified in detail at molecular and clinical level in forthcoming studies.

References

Naceiri Mrabti H, Bouyahya A, Naceiri Mrabti N, Jaradat N, Doudach L, Faouzi ME. Ethnobotanical survey of medicinal plants used by traditional healers to treat diabetes in the Taza region of Morocco. Evidence-Based Complementary and Alternative Medicine. 2021 Apr; 2021: 5515634. doi: 10.1155/2021/5515634. DOI: https://doi.org/10.1155/2021/5515634

Hussain SB, Shi CY, Guo LX, Kamran HM, Sadka A, Liu YZ. Recent advances in the regulation of citric acid metabolism in citrus fruit. Critical Reviews in Plant Sciences. 2017 Jul; 36(4): 241-56. doi: 10.1080/07352689.2017.1402850. DOI: https://doi.org/10.1080/07352689.2017.1402850

Yun YR, Kim HC, Seo HY. Antiobesity effects of kimchi added with Jeju citrus concentrate on high-fat diet-induced obese mice. Nutrition Research. 2021 Feb; 86: 50-9. doi: 10.1016/j.nutres.2020.11.007. DOI: https://doi.org/10.1016/j.nutres.2020.11.007

Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: a randomized clinical trial. JAMA Internal Medicine. 2017 Jul; 177(7): 930-8. doi: 10.1001/jamainternmed.2017.0936. DOI: https://doi.org/10.1001/jamainternmed.2017.0936

Liu N, Li X, Zhao P, Zhang X, Qiao O, Huang L, et al. A review of chemical constituents and health-promoting effects of citrus peels. Food Chemistry. 2021 Dec; 365: 130585. doi: 10.1016/j.foodchem.2021.130585. DOI: https://doi.org/10.1016/j.foodchem.2021.130585

Behl T, Kumar K, Brisc C, Rus M, Nistor-Cseppento DC, Bustea C, et al. Exploring the multifocal role of phytochemicals as immunomodulators. Biomedicine & Pharmacotherapy. 2021 Jan; 133: 110959. doi: 10.1016/j.biopha.2020.110959. DOI: https://doi.org/10.1016/j.biopha.2020.110959

Lo HY, Li TC, Yang TY, Li CC, Chiang JH, Hsiang CY, et al. Hypoglycemic effects of Trichosanthes kirilowii and its protein constituent in diabetic mice: the involvement of insulin receptor pathway. BMC Complementary and Alternative Medicine. 2017 Dec; 17: 1-9. doi: 10.1186/s12906-017-1578-6. DOI: https://doi.org/10.1186/s12906-017-1578-6

Dwivedi PS, Khanal P, Gaonkar VP, Rasal VP, Patil BM. Identification of PTP1B regulators from Cymbopogon citratus and its enrichment analysis for diabetes mellitus. In Silico Pharmacology. 2021 Apr; 9(1): 30. doi: 10.1007/s40203-021-00088-9. DOI: https://doi.org/10.1007/s40203-021-00088-9

Al-Dosari DI, Ahmed MM, Al-Rejaie SS, Alhomida AS, Ola MS. Flavonoid naringenin attenuates oxidative stress, apoptosis and improves neurotrophic effects in the diabetic rat retina. Nutrients. 2017 Oct; 9(10): 1161. doi: 10.3390/nu9101161. DOI: https://doi.org/10.3390/nu9101161

Li C, Miao X, Li F, Wang S, Liu Q, Wang Y, et al. Oxidative stress-related mechanisms and antioxidant therapy in diabetic retinopathy. Oxidative Medicine and Cellular Longevity. 2017 Jan; 2017: 9702820. doi: 10.1155/2017/9702820. DOI: https://doi.org/10.1155/2017/9702820

Piero MN, Nzaro GM, Njagi JM. Diabetes mellitus-a devastating metabolic disorder. Asian Journal of Biomedical and Pharmaceutical Sciences. 2015 Jan; 5(40): 1. doi: 10.15272/ajbps.v4i40.645. DOI: https://doi.org/10.15272/ajbps.v4i40.645

Ramadan BK, Schaalan MF, Tolba AM. Hypoglycemic and pancreatic protective effects of Portulaca oleracea extract in alloxan induced diabetic rats. BMC Complementary and Alternative Medicine. 2017 Dec; 17: 1-10. doi: 10.1186/s12906-016-1530-1. DOI: https://doi.org/10.1186/s12906-016-1530-1

Achi NK, Ohaeri OC, Ijeh II, Eleazu C. Modulation of the lipid profile and insulin levels of streptozotocin induced diabetic rats by ethanol extract of Cnidoscolus aconitifolius leaves and some fractions: Effect on the oral glucose tolerance of normoglycemic rats. Biomedicine & Pharmacotherapy. 2017 Feb; 86: 562-9. doi: 10.1016/j.biopha.2016.11.133. DOI: https://doi.org/10.1016/j.biopha.2016.11.133

Agulló V, García-Viguera C, Domínguez-Perles R. Beverages based on second quality citrus fruits and maqui berry, a source of bioactive (poly) phenols: Sorting out urine metabolites upon a longitudinal study. Nutrients. 2021 Jan; 13(2): 312. doi: 10.3390/nu13020312. DOI: https://doi.org/10.3390/nu13020312

Kamchansuppasin A, Sirichakwal PP, Bunprakong L, Yamborisut U, Kongkachuichai R, Kriengsinyos W, et al. Glycaemic index and glycaemic load of commonly consumed Thai fruits. International Food Research Journal. 2021 Aug; 28(4): 788-94. doi: 10.47836/ifrj.28.4.15. DOI: https://doi.org/10.47836/ifrj.28.4.15

Reshmi SK, Sudha ML, Shashirekha MN. Starch digestibility and glycemic index of Paranthas supplemented with Citrus maxima (Burm.) Merr. fruit segments. Journal of Food Science and Technology. 2017 Dec; 54: 4370-7. doi: 10.1007/s13197-017-2909-9. DOI: https://doi.org/10.1007/s13197-017-2909-9

Wedamulla NE, Fan M, Choi YJ, Kim EK. Citrus peel as a renewable bioresource: Transforming waste to food additives. Journal of Functional Foods. 2022 Aug; 95: 105163. doi: 10.1016/j.jff.2022.105163. DOI: https://doi.org/10.1016/j.jff.2022.105163

Zayed A, Badawy MT, Farag MA. Valorization and extraction optimization of Citrus seeds for food and functional food applications. Food Chemistry. 2021 Sep; 355: 129609. doi: 10.1016/j.foodchem.2021.129609. DOI: https://doi.org/10.1016/j.foodchem.2021.129609

Gandhi GR, Vasconcelos AB, Wu DT, Li HB, Antony PJ, Li H, et al. Citrus flavonoids as promising phytochemicals targeting diabetes and related complications: A systematic review of in vitro and in vivo studies. Nutrients. 2020 Sep; 12(10): 2907. doi: 10.3390/nu12102907. DOI: https://doi.org/10.3390/nu12102907

Mahmoud AM, Hernandez Bautista RJ, Sandhu MA, Hussein OE. Beneficial effects of citrus flavonoids on cardiovascular and metabolic health. Oxidative Medicine and Cellular Longevity. 2019 Oct; 2019: 5484138. doi: 10.1155/2019/5484138. DOI: https://doi.org/10.1155/2019/5484138

Zhou X, Chen R, Zhong C, Wu J, Li X, Li Q, et al. Fresh fruit intake in pregnancy and association with gestational diabetes mellitus: a prospective cohort study. Nutrition. 2019 Apr; 60: 129-35. doi: 10.1016/j.nut.2018.09.022. DOI: https://doi.org/10.1016/j.nut.2018.09.022

Swathi B, Deepthi A, Sravani B, Namratha S, Sandhya R. A prospective comparative study to evaluate the effect of Myo-inositol plus diet vs diet alone in patients with gestational diabetes mellitus. GSC Biological and Pharmaceutical Sciences. 2021 Mar; 14(3): 197-201. doi: 10.30574/gscbps.2021.14.3.0076. DOI: https://doi.org/10.30574/gscbps.2021.14.3.0076

Benayad O, Bouhrim M, Tiji S, Kharchoufa L, Addi M, Drouet S, et al. Phytochemical profile, α-glucosidase, and α-amylase inhibition potential and toxicity evaluation of extracts from Citrus aurantium (L) peel, a valuable by-product from Northeastern Morocco. Biomolecules. 2021 Oct; 11(11): 1555. doi: 10.3390/biom11111555. DOI: https://doi.org/10.3390/biom11111555

Magalhães ML, de Sousa RV, Miranda JR, Konig IF, Wouters F, Souza FR, et al. Effects of Moro orange juice (Citrus sinensis (L.) Osbeck) on some metabolic and morphological parameters in obese and diabetic rats. Journal of the Science of Food and Agriculture. 2021 Feb; 101(3): 1053-64. doi: 10.1002/jsfa.10714. DOI: https://doi.org/10.1002/jsfa.10714

Oyetayo FL, Akomolafe SF, Oladapo IF. A comparative study on the estimated glycemic index (eGI), phenolic constituents, antioxidative and potential antihyperglycemic effects of different parts of ripe Citrus paradisi fruit. Oriental Pharmacy and Experimental Medicine. 2019 Mar; 19: 81-9. doi: 10.1007/s13596-018-0355-5. DOI: https://doi.org/10.1007/s13596-018-0355-5

Lin YK, Chung YM, Yang HT, Lin YH, Lin YH, Hu WC, et al. The potential of immature poken (Citrus reticulata) extract in the weight management, lipid and glucose metabolism. Journal of Complementary and Integrative Medicine. 2021 May; 19(2): 279-85. doi: 10.1515/jcim-2020-0478. DOI: https://doi.org/10.1515/jcim-2020-0478

Shikishima Y, Tsutsumi R, Kawakami A, Miura H, Nii Y, Sakaue H. Sudachi peel extract powder including the polymethoxylated flavone sudachitin improves visceral fat content in individuals at risk for developing diabetes. Food Science & Nutrition. 2021 Aug; 9(8): 4076-84. doi: 10.1002/fsn3.2339. DOI: https://doi.org/10.1002/fsn3.2339

Al Chalabi SM and Al-Azzawi KS. Positive effect of Allium sativum and Citrus aurantifolium plants on glucose level in diabetic rats using Alloxan. Annals of the Romanian Society for Cell Biology. 2021 Apr; 25(4): 6787-95.

Al-Sayed HM, Abdelaleem MA, Shawky HA. Physiochemical and nutritional evaluation of whole kumquat fruits powder and its protective effect on thyroid hormones and blood sugar levels in diabetic rats. Brazilian Journal of Biology. 2021 Aug; 83: e247071. doi: 10.1590/1519-6984.247071. DOI: https://doi.org/10.1590/1519-6984.247071

Islam A, Tasnin M, Bari MW, Hossain MI, Islam MA. In Vitro Antioxidant and In Vivo Antidiabetic Properties of Citrus Maxima Leaf Extracts in Alloxan-Induced Swiss Albino Diabetic Mice. Asian Food Science Journal. 2021 Mar; 20(2): 66-79. doi: 10.9734/afsj/2021/v20i230270. DOI: https://doi.org/10.9734/afsj/2021/v20i230270

Kasia Benedicta E. Hypoglycaemic Effects of Decoction of Camelia sinensis (Lipton Tea) and Citrus aurantifolia (Lime) on Plasma Glucose Concentration and Weight of Normal Albino Rats. Scholars International Journal of Biochemistry. 2021 Apr; 4(3): 20-5. doi: 10.36348/sijb.2021.v04i03.001. DOI: https://doi.org/10.36348/sijb.2021.v04i03.001

Somanathan Karthiga R, Sukhdeo SV, Madhugiri Lakshminarayan S, Mysuru Nanjarajurs S. Efficacy of Citrus maxima fruit segment supplemented paranthas in STZ induced diabetic rats. Journal of Food Science. 2021 May; 86(5): 2091-102. doi: 10.1111/1750-3841.15707. DOI: https://doi.org/10.1111/1750-3841.15707

Testai L, De Leo M, Flori L, Polini B, Braca A, Nieri P, et al. Contribution of irisin pathway in protective effects of mandarin juice (Citrus reticulata Blanco) on metabolic syndrome in rats fed with high fat diet. Phytotherapy Research. 2021 Aug; 35(8): 4324-33. doi: 10.1002/ptr.7128. DOI: https://doi.org/10.1002/ptr.7128

Dhuique-Mayer C, Gence L, Portet K, Tousch D, Poucheret P. Preventive action of retinoids in metabolic syndrome/type 2 diabetic rats fed with citrus functional food enriched in β-cryptoxanthin. Food & Function. 2020 Oct; 11(10): 9263-71. doi: 10.1039/D0FO02430A. DOI: https://doi.org/10.1039/D0FO02430A

Ramya S, Narayanan V, Ponnerulan B, Saminathan E, Veeranan U. Potential of peel extracts of Punica granatum and Citrus aurantifolia on alloxan-induced diabetic rats. Beni-Suef University Journal of Basic and Applied Sciences. 2020 Dec; 9(1): 1-10. doi: 10.1186/s43088-020-00049-9. DOI: https://doi.org/10.1186/s43088-020-00049-9

Kazeem MI, Bankole HA, Oladokun TI, Bello AO, Maliki MA. Citrus aurantifolia (Christm.) Swingle (lime) fruit extract inhibits the activities of polyol pathway enzymes. EFood. 2020 Aug; 1(4): 310-5. doi: 10.2991/efood.k.200824.001. DOI: https://doi.org/10.2991/efood.k.200824.001

Ali AM, Gabbar MA, Abdel-Twab SM, Fahmy EM, Ebaid H, Alhazza IM, et al. Antidiabetic potency, antioxidant effects, and mode of actions of Citrus reticulata fruit peel hydroethanolic extract, hesperidin, and quercetin in nicotinamide/streptozotocin-induced Wistar diabetic rats. Oxidative Medicine and Cellular Longevity. 2020 Jun; 2020: 1730492. doi: 10.1155/2020/1730492. DOI: https://doi.org/10.1155/2020/1730492

Ani PN and Ochu KE. Anti-diabetic, anti-hyperlipidemic and hepatoprotective potential of shaddock (Citrus maxima) peel extract. Acta Scientiarum Polonorum Technologia Alimentaria. 2020 Sep; 19(3): 271-8. doi: 10.17306/J.AFS.0811. DOI: https://doi.org/10.17306/J.AFS.0811

Ferro Y, Montalcini T, Mazza E, Foti D, Angotti E, Gliozzi M, et al. Randomized clinical trial: bergamot citrus and wild cardoon reduce liver steatosis and body weight in non-diabetic individuals aged over 50 years. Frontiers in Endocrinology. 2020 Aug; 11: 494. doi: 10.3389/fendo.2020.00494. DOI: https://doi.org/10.3389/fendo.2020.00494

Surboyo MD, Mahdani FY, Ernawati DS, Hadi P, Hendarti HT, Parmadiati AE, et al. Number of macrophages and transforming growth factor β expression in Citrus limon L. Tlekung peel oil-treated traumatic ulcers in diabetic rats. Tropical Journal of Pharmaceutical Research. 2021 May; 18(7): 1427-33. doi: 10.4314/tjpr.v18i7.9. DOI: https://doi.org/10.4314/tjpr.v18i7.9

Han HY, Lee SK, Choi BK, Lee DR, Lee HJ, Kim TW. Preventive effect of Citrus aurantium peel extract on high-fat diet-induced non-alcoholic fatty liver in mice. Biological and Pharmaceutical Bulletin. 2019 Feb; 42(2): 255-60. doi: 10.1248/bpb.b18-00702. DOI: https://doi.org/10.1248/bpb.b18-00702

Fu M, Zou B, An K, Yu Y, Tang D, Wu J, et al. Anti-asthmatic activity of alkaloid compounds from Pericarpium Citri Reticulatae (Citrus reticulata ‘Chachi’). Food & Function. 2019 Jan; 10(2): 903-11. doi: 10.1039/C8FO01753K. DOI: https://doi.org/10.1039/C8FO01753K

Ulla A, Alam MA, Rahman M, Isha Olive Khan DM, Sikder B, Islam M, et al. Supplementation of Citrus maxima fruits peel powder improves glucose intolerance and prevents oxidative stress in liver of alloxan-induced diabetic rats. Mediterranean Journal of Nutrition and Metabolism. 2019 Jan; 12(1): 33-44. doi: 10.3233/MNM-18211. DOI: https://doi.org/10.3233/MNM-18211

Wang L, Lee WW, Yang HW, Ryu BM, Cui YR, Lee SC, et al. Protective effect of water extract of Citrus pomace against AAPH-induced oxidative stress in vitro in Vero cells and in vivo in zebrafish. Preventive Nutrition and Food Science. 2018 Dec; 23(4): 301. doi: 10.3746/pnf.2018.23.4.301. DOI: https://doi.org/10.3746/pnf.2018.23.4.301

Ahmed E, Arshad M, Khan MZ, Amjad MS, Sadaf HM, Riaz I, et al. Secondary metabolites and their multidimensional prospective in plant life. Journal of Pharmacognosy and Phytochemistry. 2017 Feb; 6(2): 205-14.

Kumar R and Tewari AK. Isolation of medicinally important constituents from rare and exotic medicinal plants. In: Synthesis of Medicinal Agents from Plants. 2018 Jan: 229-256. doi: 10.1016/B978-0-08-102071-5.00010-6. DOI: https://doi.org/10.1016/B978-0-08-102071-5.00010-6

Sivakumar PM, Prabhakar PK, Cetinel S, Prabhawathi V. Molecular insights on the therapeutic effect of selected flavonoids on diabetic neuropathy. Mini Reviews in Medicinal Chemistry. 2022 Aug; 22(14): 1828-46. doi: 10.2174/1389557522666220309140855. DOI: https://doi.org/10.2174/1389557522666220309140855

Bule M, Abdurahman A, Nikfar S, Abdollahi M, Amini M. Antidiabetic effect of quercetin: A systematic review and meta-analysis of animal studies. Food and Chemical Toxicology. 2019 Mar; 125: 494-502. doi: 10.1016/j.fct.2019.01.037. DOI: https://doi.org/10.1016/j.fct.2019.01.037

Ahmed OM, Ahmed AA, Fahim HI, Zaky MY. Quercetin and naringenin abate diethylnitrosamine/acetylaminofluorene-induced hepatocarcinogenesis in Wistar rats: The roles of oxidative stress, inflammation and cell apoptosis. Drug and Chemical Toxicology. 2022 Jan; 45(1): 262-73. doi: 10.1080/01480545.2019.1683187. DOI: https://doi.org/10.1080/01480545.2019.1683187

Gupta A, Jacobson GA, Burgess JR, Jelinek HF, Nichols DS, Narkowicz CK, et al. Citrus bioflavonoids dipeptidyl peptidase-4 inhibition compared with gliptin antidiabetic medications. Biochemical and Biophysical Research Communications. 2018 Sep; 503(1): 21-5. doi: 10.1016/j.bbrc.2018.04.156. DOI: https://doi.org/10.1016/j.bbrc.2018.04.156

Shaikh S, Lee EJ, Ahmad K, Ahmad SS, Lim JH, Choi I. A comprehensive review and perspective on natural sources as dipeptidyl peptidase-4 inhibitors for management of diabetes. Pharmaceuticals. 2021 Jun; 14(6): 591. doi: 10.3390/ph14060591. DOI: https://doi.org/10.3390/ph14060591

Prasathkumar M, Anisha S, Dhrisya C, Becky R, Sadhasivam S. Therapeutic and pharmacological efficacy of selective Indian medicinal plants–a review. Phytomedicine Plus. 2021 May; 1(2): 100029. doi: 10.1016/j.phyplu.2021.100029. DOI: https://doi.org/10.1016/j.phyplu.2021.100029

Al-Aubaidy HA, Dayan A, Deseo MA, Itsiopoulos C, Jamil D, Hadi NR, Thomas CJ. Twelve-week mediterranean diet intervention increases citrus bioflavonoid levels and reduces inflammation in people with type 2 diabetes mellitus. Nutrients. 2021 Mar; 13(4): 1133. doi: 10.3390/nu13041133. DOI: https://doi.org/10.3390/nu13041133

Salah M, Ismail KA, Khadrawy SM. Nobiletin protects against diabetes-induced testicular injury via hypophysis–gonadal axis upregulation and amelioration of oxidative stress. Molecular Biology Reports. 2022 Jan; 49: 189-203. doi: 10.1007/s11033-021-06858-0. DOI: https://doi.org/10.1007/s11033-021-06858-0

Singh V, Chahal TS, Grewal SK, Gill PS. Effect of fruit development stages on antioxidant properties and bioactive compounds in peel, pulp and juice of grapefruit varieties. Journal of Food Measurement and Characterization. 2021 Jun; 15: 2531-9. doi: 10.1007/s11694-021-00841-w. DOI: https://doi.org/10.1007/s11694-021-00841-w

El-Shahawy AA, Abdel-Moneim A, Ebeid AS, Eldin ZE, Zanaty MI. A novel layered double hydroxide-hesperidin nanoparticles exert antidiabetic, antioxidant and anti-inflammatory effects in rats with diabetes. Molecular Biology Reports. 2021 Jun; 48: 5217-32. doi: 10.1007/s11033-021-06527-2. DOI: https://doi.org/10.1007/s11033-021-06527-2

Liu S, Dong J, Bian Q. A dual regulatory effect of naringenin on bone homeostasis in two diabetic mice models. Traditional Medicine and Modern Medicine. 2020 Jun; 3(02): 101-8. doi: 10.1142/S2575900020500093. DOI: https://doi.org/10.1142/S2575900020500093

Ding S, Qiu H, Huang J, Chen R, Zhang J, Huang B, et al. Activation of 20-HETE/PPARs involved in reno-therapeutic effect of naringenin on diabetic nephropathy. Chemico-Biological Interactions. 2019 Jul; 307: 116-24. doi: 10.1016/j.cbi.2019.05.004. DOI: https://doi.org/10.1016/j.cbi.2019.05.004

Ali MY, Zaib S, Rahman MM, Jannat S, Iqbal J, Park SK, et al. Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Chemico-Biological Interactions. 2019 May; 305: 180-94. doi: 10.1016/j.cbi.2019.03.018. DOI: https://doi.org/10.1016/j.cbi.2019.03.018

Sundaram R, Nandhakumar E, Haseena Banu H. Hesperidin, a citrus flavonoid ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats. Toxicology Mechanisms and Methods. 2019 Nov; 29(9): 644-53. doi: 10.1080/15376516.2019.1646370. DOI: https://doi.org/10.1080/15376516.2019.1646370

Liu WY, Liou SS, Hong TY, Liu IM. Hesperidin prevents high glucose-induced damage of retinal pigment epithelial cells. Planta Medica. 2018 Sep; 84(14): 1030-7. doi: 10.1055/a-0601-7020. DOI: https://doi.org/10.1055/a-0601-7020

Patil KK, Meshram RJ, Dhole NA, Gacche RN. Role of dietary flavonoids in amelioration of sugar induced cataractogenesis. Archives of Biochemistry and Biophysics. 2016 Mar; 593: 1-11. doi: 10.1016/j.abb.2016.01.015. DOI: https://doi.org/10.1016/j.abb.2016.01.015

Constantin RP, Constantin RP, Bracht A, Yamamoto NS, Ishii-Iwamoto EL, Constantin J. Molecular mechanisms of citrus flavanones on hepatic gluconeogenesis. Fitoterapia. 2014 Jan; 92: 148-62. doi: 10.1016/j.fitote.2013.11.003. DOI: https://doi.org/10.1016/j.fitote.2013.11.003

Puri M, Verma ML, Mahale K. Processing of citrus peel for the extraction of flavonoids for biotechnological applications. In: Handbook on flavonoids: dietary sources, properties and health benefits. 2012: 443-459.

Pradhan SP, Sahoo S, Behera A, Sahoo R, Sahu PK. Memory amelioration by hesperidin conjugated gold nanoparticles in diabetes induced cognitive impaired rats. Journal of Drug Delivery Science and Technology. 2022 Mar; 69: 103145. doi: 10.1016/j.jddst.2022.103145. DOI: https://doi.org/10.1016/j.jddst.2022.103145

Khan MF, Mathur A, Pandey VK, Kakkar P. Endoplasmic reticulum stress-dependent activation of TRB3-FoxO1 signaling pathway exacerbates hyperglycemic nephrotoxicity: Protection accorded by Naringenin. European Journal of Pharmacology. 2022 Feb; 917: 174745. doi: 10.1016/j.ejphar.2022.174745. DOI: https://doi.org/10.1016/j.ejphar.2022.174745