Potential Role of Flavonoids as Anti-diabetic Agents-A Comprehensive Review
Abstract:
Diabetes mellitus is a widespread and debilitating metabolic disorder marked by sustained elevated blood glucose levels, which can culminate in a range of severe complications if unmanaged. Flavonoids, polyphenolic chemicals originating from plants, have attracted a great deal of attention in the field of diabetes research because of their antidiabetic properties. These naturally occurring substances, which are 15 carbons in structure, are widely distributed in fruits, vegetables, and other plant-based diets, have been shown to offer a number of positive benefits, including the capacity to regulate many facets of insulin and glucose homeostasis. These compounds are classified into six major subclasses based on their structural differences. Numerous in vivo and in vitro studies have looked at the antidiabetic potential of flavonoids. Flavonoids have been found to modulate enzymes such as ά-glucosidase and ά-amylase, which are the key enzymes for the reduction of blood glucose levels. Emerging evidence suggests that flavonoids may exert their antidiabetic effects through their ability to modulate various cell signaling pathways involved in glucose metabolism, insulin sensitivity, and inflammation. It has been demonstrated that flavonoids contain anti-inflammatory and antioxidant qualities. These qualities are vital for reducing inflammation and oxidative stress, which are crucial factors to the onset of diabetes. This review aims providing comprehensive elucidation of the cellular and molecular mechanisms underlying the antidiabetic effects of flavonoids, considering their potential impact on various metabolic pathways involved in diabetes.References:
[1] Choudhury, H., Pandey, M., Hua, C. K., Mun, C. S., Jing, J. K., Kong, L., Ern, L. Y., Ashraf, N. A., Kit, S. W., Yee, T. S., Pichika, M. R., Gorain, B., & Kesharwani, P., 2018, An update on natural compounds in the remedy of diabetes mellitus: A systematic review. Journal of Traditional and Complementary Medicine, 8(3): 361–376. https://doi.org/10.1016/j.jtcme.2017.08.012
[2] Kharroubi, A. T., 2015, Diabetes mellitus: The epidemic of the century. World Journal of Diabetes, 6(6): 850. https://doi.org/10.4239/wjd.v6.i6.850
[3] International Diabetes Federation, 2021, IDF Diabetes Atlas, 10th edition. https://idf.org/about-diabetes/diabetes-facts-figures/
[4] Missoun, F., 2018, Antidiabetic bioactive compounds from plants. Medical Technologies Journal, 2(2): 199–214. https://doi.org/10.26415/2572-004x-vol2iss2p199-214
[5] Caro-Ordieres, T., Marín-Royo, G., Opazo-Ríos, L., Jiménez-Castilla, L., Moreno, J. A., Gómez-Guerrero, C., & Egido, J., 2020, The coming age of flavonoids in the treatment of diabetic complications. Journal of Clinical Medicine, 9(2): 346. https://doi.org/10.3390/jcm9020346
[6] AL-Ishaq, Abotaleb, Kubatka, Kajo, & Büsselberg, 2019, Flavonoids and their anti-diabetic effects: Cellular mechanisms and effects to improve blood sugar levels. Biomolecules, 9(9): 430. https://doi.org/10.3390/biom9090430
[7] Venugopala, K. N., Chaudhary, J., Sharma, V., Jain, A., Kumar, M., Sharma, D., & et al., 2022, Exploring the potential of flavonoids as efflorescing antidiabetic: An updated SAR and mechanistic based approach. Pharmacognosy Magazine, 18(80): 791-807. http://www.phcog.com/text.asp?2022/18/80/791/357236
[8] Bai, L., Li, X., He, L., Zheng, Y., Lu, H., Li, J., Zhong, L., Tong, R., Jiang, Z., Shi, J., & Li, J., 2019, Antidiabetic potential of flavonoids from traditional Chinese medicine: A review. The American Journal of Chinese Medicine, 47(05): 933–957. https://doi.org/10.1142/s0192415x19500496
[9] Sohretoglu, D., & Sari, S., 2019, Flavonoids as alpha-glucosidase inhibitors: Mechanistic approaches merged with enzyme kinetics and molecular modelling. Phytochemistry Reviews, 19(5): 1081–1092. https://doi.org/10.1007/s11101-019-09610-6
[10] Ke, R. Q., Wang, Y., Hong, S. H., & Xiao, L. X., 2023, Anti-diabetic effect of quercetin in type 2 diabetes mellitus by regulating the microRNA-92b-3p/EGR1 axis. Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society, 74(2). https://doi.org/10.26402/jpp.2023.2.03
[11] Ansari, P., Choudhury, S. T., Seidel, V., Rahman, A. B., Aziz, Md. A., Richi, A. E., Rahman, A., Jafrin, U. H., Hannan, J. M. A., & Abdel-Wahab, Y. H. A., 2022, Therapeutic potential of quercetin in the management of type-2 diabetes mellitus. Life, 12(8): 1146. https://doi.org/10.3390/life12081146
[12] Yang, Y., Chen, Z., Zhao, X., Xie, H., Du, L., Gao, H., & Xie, C., 2022, Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review. Frontiers in Endocrinology, 13. https://doi.org/10.3389/fendo.2022.990299
[13] Kumari, G., Nigam, V. K., & Pandey, D. M., 2022, The molecular docking and molecular dynamics study of flavonol synthase and flavonoid 3’-monooxygenase enzymes involved for the enrichment of kaempferol. Journal of Biomolecular Structure and Dynamics, 41(6): 2478–2491. https://doi.org/10.1080/07391102.2022.2033324
[14] Qaddoori, M. H., & Al-Shmgani, H. S., 2023, Galangin-Loaded gold nanoparticles: Molecular mechanisms of antiangiogenesis properties in breast cancer. International Journal of Breast Cancer, 2023: 1–14. https://doi.org/10.1155/2023/3251211
[15] Al Duhaidahawi, D., Hasan, S. A., & Al Zubaidy, H. F. S., 2021, Flavonoids in the treatment of diabetes: Clinical outcomes and mechanism to ameliorate blood glucose levels. Current Diabetes Reviews, 17(6). https://doi.org/10.2174/1573399817666201207200346
[16] Mathew, M. G., Jeevanandan, G., Vishwanathaiah, S., Hamzi, K. A., Depsh, M. A. N., & Maganur, P. C., 2022, Parental and Child Outlook on the Impact of ECC on Oral Health-related Quality of Life: A Prospective Interventional Study. The Journal of Contemporary Dental Practice, 23(9), 877–882. https://doi.org/10.5005/jp-journals-10024-3397
[17] Jayaraman, S., Natarajan, S. R., Veeraraghavan, V. P., & Jasmine, S., 2023, Unveiling the anti-cancer mechanisms of calotropin: Insights into cell growth inhibition, cell cycle arrest, and metabolic regulation in human oral squamous carcinoma cells (HSC-3). Journal of oral biology and craniofacial research, 13(6), 704–713. https://doi.org/10.1016/j.jobcr.2023.09.002
[18] Liao, Y., Hu, X., Pan, J., & Zhang, G., 2022, Inhibitory mechanism of baicalein on acetylcholinesterase: Inhibitory interaction, conformational change, and computational simulation. Foods, 11(2): 168. https://doi.org/10.3390/foods11020168
[19] Chan, S.-H., Hung, C.-H., Shih, J.-Y., Chu, P.-M., Cheng, Y.-H., Tsai, Y.-J., Lin, H.-C., & Tsai, K.-L., 2016, Baicalein is an available anti-atherosclerotic compound through modulation of nitric oxide-related mechanism under oxLDL exposure. Oncotarget, 7(28): 42881–42891. https://doi.org/10.18632/oncotarget.10263
[20] Cazarolli, L., Zanatta, L., Alberton, E., Bonorino Figueiredo, M. S., Folador, P., Damazio, R., Pizzolatti, M., & Barreto Silva, F. R., 2008, Flavonoids: Prospective drug candidates. Mini-Reviews in Medicinal Chemistry, 8(13): 1429–1440. https://doi.org/10.2174/138955708786369564
[21] Vishwanathaiah, S., Maganur, P. C., Manoharan, V., Jeevanandan, G., Hakami, Z., Jafer, M. A., Khanagar, S., & Patil, S., 2022, Does Social Media have any Influence during the COVID-19 Pandemic? An Update. The Journal of Contemporary Dental Practice, 23(3), 327–330
[22] Hanchang, W., Wongmanee, N., Yoopum, S., & Rojanaverawong, W., 2022, Protective role of hesperidin against diabetes induced spleen damage: Mechanism associated with oxidative stress and inflammation. Journal of Food Biochemistry, 46(12). https://doi.org/10.1111/jfbc.14444
[23] He, W., Wang, Y., Yang, R., Ma, H., Qin, X., Yan, M., Rong, Y., Xie, Y., Li, L., Si, J., Li, X., & Ma, K., 2022, Molecular mechanism of naringenin against high-glucose-induced vascular smooth muscle cells proliferation and migration based on network pharmacology and transcriptomic analyses. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.862709
[24] Prasad, B.S., & Srinivasan, K.K., 2023, α-Glucosidase Inhibition and Upregulation of PPARγ by Flavonoid Naringenin from Tinospora sinensis Stem, a Possible Mechanism of Antidiabetic Activity. In: Arunachalam, K., Yang, X., Puthanpura Sasidharan, S. (eds) Natural Product Experiments in Drug Discovery. Springer Protocols Handbooks. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2683-2_18
[25] Martín, M. Á., & Ramos, S., 2021, Impact of dietary flavanols on microbiota, immunity and inflammation in metabolic diseases. Nutrients, 13(3): 850. https://doi.org/10.3390/nu13030850
[26] Ahangarpour, A., Sayahi, M., & Sayahi, M., 2019, The antidiabetic and antioxidant properties of some phenolic phytochemicals: A review study. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 13(1): 854-857. https://doi.org/10.1016/j.dsx.2018.11.051
[27] Xu, Z., Ma, G., Zhang, Q., Chen, C., He, Y., Xu, L., Zhou, G., Li, Z., Yang, H., & Zhou, P., 2017, Inhibitory mechanism of epigallocatechin gallate on fibrillation and aggregation of amidated human islet amyloid polypeptide. ChemPhysChem, 18(12): 1611-1619. https://doi.org/10.1002/cphc.201700057
[28] Wang, W., Zhang, Y., Jin, W., Xing, Y., & Yang, A., 2018, Catechin weakens diabetic retinopathy by inhibiting the expression of NF-κB signaling pathway-mediated inflammatory factors. Annals of Clinical and Laboratory Science, 48(5): 594-600.
[29] Wen, L., Wu, D., Tan, X., Zhong, M., Xing, J., Li, W., Li, D., & Cao, F., 2022, The Role of Catechins in regulating diabetes: An update review. Nutrients, 14(21): 4681. https://doi.org/10.3390/nu14214681
[30] Jayaraman, S., Raj Natarajan, S., Ponnusamy, B., Veeraraghavan, V. P., & Jasmine, S., 2023, Unlocking the potential of beta sitosterol: Augmenting the suppression of oral cancer cells through extrinsic and intrinsic signalling mechanisms. The Saudi Dental Journal, 35(8), 1007–1013. https://doi.org/10.1016/j.sdentj.2023.08.003
[31] Kuryłowicz, A., 2020, The role of isoflavones in type 2 diabetes prevention and treatment—a narrative review. International Journal of Molecular Sciences, 22(1): 218. https://doi.org/10.3390/ijms22010218
[32] Hussain, H., & Green, I. R., 2017, A patent review of the therapeutic potential of isoflavones (2012-2016). Expert Opinion on Therapeutic Patents, 27(10): 1135-1146. https://doi.org/10.1080/13543776.2017.1339791
[33] S, D. P. A., Solete, P., Jeevanandan, G., Syed, A. A., Almahdi, S., Alzhrani, M., Maganur, P. C., & Vishwanathaiah, S., 2023, Effect of Various Irrigant Activation Methods and Its Penetration in the Apical Third of Root Canal-In Vitro Study. European Journal of dentistry, 17(1), 57–61. https://doi.org/10.1055/s-0041-1742122.
[34] Abbasi, E., & Khodadadi, I., 2023, Antidiabetic effects of genistein: Mechanism of action. Endocrine, Metabolic & Immune Disorders - Drug Targets, 23(13): 1599-1610. https://doi.org/10.2174/1871530323666230516103420
[35] Zhang, N., Zhang, W., Guo, X., Liu, J., Li, S., Zhang, H., & Fan, B., 2022, Genistein protects against hyperglycemia and fatty liver disease in diet-induced prediabetes mice via activating hepatic insulin signaling pathway. Frontiers in Nutrition, 9. https://doi.org/10.3389/fnut.2022.1072044
[36] Liu, Y., Wang, Q., Wu, K., Sun, Z., Tang, Z., Li, X., & Zhang, B., 2022, Anthocyanins’ effects on diabetes mellitus and islet transplantation. Critical Reviews in Food Science and Nutrition, 63(33): 12102-12125. https://doi.org/10.1080/10408398.2022.2098464
[37] Pazhani, J., Jayaraman, S., Veeraraghavan, V. P., & Jasmine, S., 2024, Endothelin-1 axis as a therapeutic target in oral squamous cell carcinoma: Molecular insights. Journal of stomatology, oral and maxillofacial surgery, 125(6), 101792. Advance online publication. https://doi.org/10.1016/j.jormas.2024.101792
[38] Yang, L., Qiu, Y., Ling, W., Liu, Z., Yang, L., Wang, C., Peng, X., Wang, L., & Chen, J., 2020, Anthocyanins regulate serum adipsin and visfatin in patients with prediabetes or newly diagnosed diabetes: A randomized controlled trial. European Journal of Nutrition, 60(4): 1935-1944. https://doi.org/10.1007/s00394-020-02379-x
[39] Lai, D., Huang, M., Zhao, L., Tian, Y., Li, Y., Liu, D., Wu, Y., & Deng, F., 2019, Delphinidin-induced autophagy protects pancreatic β cells against apoptosis resulting from high-glucose stress via AMPK signaling pathway. Acta Biochimica et Biophysica Sinica, 51(12): 1242-1249. https://doi.org/10.1093/abbs/gmz126
[40] Ahmed, Q. U., Ali, A. H. M., Mukhtar, S., Alsharif, M. A., Parveen, H., Sabere, A. S. M., Nawi, M. S. Mohd., Khatib, A., Siddiqui, M. J., Umar, A., & Alhassan, A. M., 2020, Medicinal potential of isoflavonoids: Polyphenols that may cure diabetes. Molecules, 25(23): 5491. https://doi.org/10.3390/molecules25235491
