Efficacy of the Hibiscus surattensis L. Leaves Active Fraction in Reducing the Levels of HbA1c, AGEs, and Glucose Uptake in Muscle Cells of Diabetic Type 2 Model Rat
Keywords:
AGEs, HbA1C, Hibiscus surattensis L, glut-4
Abstract
Hibiscus surattensis L. is a traditional medicinal plant often used for diabetes treatment in Indonesia, especially in Central Sulawesi. The leaves contain mainly kaempferol, morine, and trifolin which have various pharmacological effects, including high antioxidant properties and the potential to increase insulin secretion. Therefore, this study aims to investigate the efficacy of the Hibiscus surattensis L. leaves (HSL) active fraction in reducing the levels of HbA1c, AGEs, and GLUT-4 expression in the muscle tissue of rat model with type 2 diabetes mellitus using a high-fat and fructose diet of 1.8 g/kg BW (HFD/HF) for 8 weeks. A total of 20 male rats were randomly assigned into four groups namely (1) normal control diet with standard rat chow; (2) negative control with HFD/HF diet; (3) treatment group with metformin 100 mg/kg BW as standard; (4) treatment group given HSL active fraction (FEA) 50 mg/kg BW. All treatments were given orally for 21 days and the data were analyzed by ANOVA and continued with the LSD post hoc test. HFD/HF induction significantly increased the HbA1c and AGEs levels 3.5 times and 1.88 times higher than the normal control group. Moreover, the treatments significantly reduced (p<0.05) HbA1c and AGEs levels compared to the negative control on day 21. Blood HbA1C levels with FEA treatment decreased by 56.4%, while AGEs reduced by 54.7%. GLUT 4 expression in the muscle tissue was significantly different from the negative control with p<0.05. The results also indicate that the administration of FEA had an antidiabetic effect by reducing the levels of HbA1C and AGEs along with other potentially beneficial effects on the treatment of type 2 DM with the probable mechanism of targeting GLUT4 glucose transporter by increasing its translocation and expression.
References
Abdul-Ghani, M. A., & Defronzo, R. A. 2010. Pathogenesis of insulin resistance in skeletal muscle. Journal of Biomedicine and Biotechnology, 2010. https://doi.org/10.1155/2010/476279.
Al-Goblan, A. S., Al-Alfi, M. A., & Khan, M. Z. 2014. Mechanism linking diabetes mellitus and obesity. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 7, 587-591. https://doi.org/10.2147/DMSO.S67400.
Al Kury, L. T., Abdoh, A., Ikbariah, K., Sadek, B., & Mahgoub, M. 2022. In vitro and in vivo antidiabetic potential of monoterpenoids: An update. Molecules, 27(1), 1-29. https://doi.org/10.3390/molecules27010182.
Anoopa John L, Kannappan N, M. P. 2020. Evaluation of hepatoprotective activity in methanolic extract of Aerial parts of Hibiscus surattensis. Research J. Pharm. and Tech, 13(10), 4635-4640. https://doi.org/10.5958/0974-360X.2020.00816.1.
Astari, L., Cahyono, H., & Widjajanto, E. 2017. Correlation of interleukin-10, superoxide dismutase (SOD), and malondialdehyde (MDA) levels with HbA1c in pediatric type 1 diabetes mellitus. Journal of Tropical Life Science, 7(3), 286-292. https://doi.org/10.11594/jtls.07.03.15.
Cepas, V., Collino, M., Mayo, J. C., & Sainz, R. M. 2020. Redox signaling and advanced glycation endproducts (AGEs) in diet-related diseases. Antioxidants, 9(2), 1-20. https://doi.org/10.3390/antiox9020142.
Chadt, A., & Al-Hasani, H. 2020. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Archiv, 472(9), 1273-1298. https://doi.org/10.1007/s00424-020-02417-x.
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. 2017. Clinical Review of Antidiabetic Drugs: Implications for type 2 diabetes mellitus management. Frontiers in Endocrinology, 8(January). https://doi.org/10.3389/fendo.2017.00006.
Choi, S. H., & Ginsberg, H. N. 2011. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends in Endocrinology and Metabolism, 22(9), 353-363. https://doi.org/10.1016/j.tem.2011.04.007.
Fang, J. Y., Lin, C. H., Huang, T. H., & Chuang, S. Y. 2019. In vivo rodent models of type 2 diabetes and their usefulness for evaluating flavonoid bioactivity. Nutrients, 11(3). https://doi.org/10.3390/nu11030530.
Feitosa, S. G., Viana, K. F., Luna, E. C. M., Costa, F. W. G., Cavalcante, R. B., Chaves, F. N., Chaves, H. V., & Pereira, K. M. A. 2018. Immunohistochemical evaluation of GLUT-3 and GLUT-4 in oral epithelial dysplasia and oral squamous cell carcinoma. Asian Pacific Journal of Cancer Prevention, 19(7), 1779-1783. https://doi.org/10.22034/APJCP.2018.19.7.1779.
Hajiaghaalipour, F., Khalilpourfarshbafi, M., & Arya, A. 2015. Modulation of glucose transporter protein by dietary flavonoids in type 2 diabetes mellitus. International Journal of Biological Sciences, 11(5), 508-524. https://doi.org/10.7150/ijbs.11241.
Haroun, M. A., Elsayed, L. A., Rashed, L. A., & Mohammed, M. A. 2011. The effect of high fat diet and high fructose intake on insulin resistance and GLP-1 in experimental animals. Medical Journal of Cairo University, 79(2), 23-32. www.medicaljournalofcairouniversity.com.
International Diabetes Federation. 2021. IDF Diabetes Atlas 10th edition. www.diabetesatlas.org.
Jafri, A. A., Sharma, S. B., Khurana, N., M, M., Singh, U. R., & Luthra, K. 2019. Herbal anti-hyperglycemic compound increases expression of glucose transporter molecules in diabetic rats. Journal of Diabetes & Metabolism, 10(4), 4-10. https://doi.org/10.35248/2155-6156.19.10.824.
Jiang, Z., Wang, J., Zhao, P., Zhang, L., & Guo, Y. 2019. HbA1c: High in acute cerebral infarction and low in brain trauma. Progress in Molecular Biology and Translational Science (1st ed., Vol. 162). Elsevier Inc. https://doi.org/10.1016/bs.pmbts.2019.01.008.
Kasole, R., Martin, H. D., & Kimiywe, J. 2019. Traditional medicine and its role in the management of diabetes mellitus: “patients’’ and herbalists’ perspectives".” Evidence-Based Complementary and Alternative Medicine, 2019. https://doi.org/10.1155/2019/2835691.
Kucera, O., & Cervinkova, Z. 2014. Experimental models of non-alcoholic fatty liver disease in rats. World Journal of Gastroenterology, 20(26), 8364-8376. https://doi.org/10.3748/wjg.v20.i26.8364.
Kyrou, I., Tsigos, C., Mavrogianni, C., Cardon, G., Van Stappen, V., Latomme, J., Kivelä, J., Wikström, K., Tsochev, K., Nanasi, A., Semanova, C., Mateo-Gallego, R., Lamiquiz-Moneo, I., Dafoulas, G., Timpel, P., Schwarz, P. E. H., Iotova, V., Tankova, T., Makrilakis, K., & Manios, Y. 2020. Sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for type 2 diabetes: A narrative review with emphasis on data from Europe. BMC Endocrine Disorders, 20(Suppl 1), 1-13. https://doi.org/10.1186/s12902-019-0463-3.
Lozano, I., Van Der Werf, R., Bietiger, W., Seyfritz, E., Peronet, C., Pinget, M., Jeandidier, N., Maillard, E., Marchioni, E., Sigrist, S., & Dal, S. 2016. High-fructose and high-fat diet-induced disorders in rats: Impact on diabetes risk, hepatic and vascular complications. Nutrition and Metabolism, 13(1), 1-13. https://doi.org/10.1186/s12986-016-0074-1.
Malafaia, A. B., Nassif, P. A. N., Ribas, C. A. P. M., Ariede, B. L., Sue, K. N., & Cruz, M. A. 2013. Obesity induction with high fat sucrose in rats. Arquivos Brasileiros de Cirurgia Digestiva : ABCD = Brazilian Archives of Digestive Surgery, 26 Suppl 1(Suplemento 1), 17-21.
McArdle, M. A., Finucane, O. M., Connaughton, R. M., McMorrow, A. M., & Roche, H. M. 2013. Mechanisms of obesity-induced inflammation and insulin resistance: Insights into the emerging role of nutritional strategies. Frontiers in Endocrinology, 4(MAY), 1-23. https://doi.org/10.3389/fendo.2013.00052.
Moldogazieva, N. T., Mokhosoev, I. M., Mel’Nikova, T. I., Porozov, Y. B., & Terentiev, A. A. 2019. Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases. Oxidative Medicine and Cellular Longevity, 2019. https://doi.org/10.1155/2019/3085756.
Pereira, R. M., Botezelli, J. D., da Cruz Rodrigues, K. C., Mekary, R. A., Cintra, D. E., Pauli, J. R., da Silva, A. S. R., Ropelle, E. R., & de Moura, L. P. 2017. Fructose consumption in the development of obesity and the effects of different protocols of physical exercise on the hepatic metabolism. Nutrients, 9(4), 1-21. https://doi.org/10.3390/nu9040405.
Pereira, R. M., De Moura, L. P., Muñoz, V. R., Da Silva, A. S. R., Gaspar, R. S., Ropelle, E. R., & Pauli, J. R. 2017. Molecular mechanisms of glucose uptake in skeletal muscle at rest and in response to exercise. Motriz. Revista de Educacao Fisica, 23, 1-8. https://doi.org/10.1590/S1980-6574201700SI0004.
Ramasamy, R., Yan, S. F., & Schmidt, A. M. 2011. Receptor for AGE (RAGE): Signaling mechanisms in the pathogenesis of diabetes and its complications. Annals of the New York Academy of Sciences, 1243(1), 88-102. https://doi.org/10.1111/j.1749-6632.2011.06320.x.
Ratwita, W., Sukandar, E. Y., Adnyana, I. K., & Kurniati, N. F. 2017. Alpha mangostin and xanthone from Mangosteen (Garcinia mangostana L.) role on glucose tolerance and glucose transporter-4 in diabetes mellitus. International Journal of Pharmacognosy and Phytochemical Research, 9(9), 1206-1212. https://doi.org/10.25258/phyto.v9i09.10307.
Rena, G., Hardie, D. G., & Pearson, E. R. 2017. The mechanisms of action of metformin. Diabetologia, 60(9), 1577-1585. https://doi.org/10.1007/s00125-017-4342-z.
Richter, E. A., & Hargreaves, M. 2013. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiological Reviews, 93(3), 993-1017. https://doi.org/10.1152/physrev.00038.2012.
Sadowska-Bartosz, I., & Bartosz, G. 2015. Prevention of protein glycation by natural compounds. Molecules, 20(2), 3309-3334. https://doi.org/10.3390/molecules20023309.
Sanchis, P., Rivera, R., Berga, F., Fortuny, R., Adrover, M., Costa-Bauza, A., Grases, F., & Masmiquel, L. 2018. Phytate decreases formation of advanced glycation end-products in patients with type II diabetes: randomized crossover trial. Scientific Reports, 8(1), 1-13. https://doi.org/10.1038/s41598-018-27853-9.
Sharma, M., Arora, M., Mustafa, I., Kumar, S., Mittal, A., & Soam, S. S. 2017. Correlation of glycated hemoglobin with oxidative stress and erythrocyte fragility in type-2 diabetes mellitus. International Journal of Contemporany Medical Research, 4(9), 1909-1911.
Sherwani, S. I., Khan, H. A., Ekhzaimy, A., Masood, A., & Sakharkar, M. K. 2016. Significance of HbA1c test in diagnosis and prognosis of diabetic patients. Biomarker Insights, 11, 95-104. https://doi.org/10.4137/Bmi.s38440.
Varghese, F., Bukhari, A. B., Malhotra, R., & De, A. 2014. IHC profiler: An open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE, 9(5). https://doi.org/10.1371/journal.pone.0096801.
Yuliet, Sukandar, E. Y., & Adnyana, I. K. 2020. Active subfractions, phytochemical constituents, dipeptidyl peptidase-IV inhibitory activity and antioxidant of leaf extract from Hibiscus surattensis L. The Natural Products Journal: Vol. 10(4) (pp. 400-410). https://doi.org/10.2174/2210315509666190626125330.
Al-Goblan, A. S., Al-Alfi, M. A., & Khan, M. Z. 2014. Mechanism linking diabetes mellitus and obesity. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 7, 587-591. https://doi.org/10.2147/DMSO.S67400.
Al Kury, L. T., Abdoh, A., Ikbariah, K., Sadek, B., & Mahgoub, M. 2022. In vitro and in vivo antidiabetic potential of monoterpenoids: An update. Molecules, 27(1), 1-29. https://doi.org/10.3390/molecules27010182.
Anoopa John L, Kannappan N, M. P. 2020. Evaluation of hepatoprotective activity in methanolic extract of Aerial parts of Hibiscus surattensis. Research J. Pharm. and Tech, 13(10), 4635-4640. https://doi.org/10.5958/0974-360X.2020.00816.1.
Astari, L., Cahyono, H., & Widjajanto, E. 2017. Correlation of interleukin-10, superoxide dismutase (SOD), and malondialdehyde (MDA) levels with HbA1c in pediatric type 1 diabetes mellitus. Journal of Tropical Life Science, 7(3), 286-292. https://doi.org/10.11594/jtls.07.03.15.
Cepas, V., Collino, M., Mayo, J. C., & Sainz, R. M. 2020. Redox signaling and advanced glycation endproducts (AGEs) in diet-related diseases. Antioxidants, 9(2), 1-20. https://doi.org/10.3390/antiox9020142.
Chadt, A., & Al-Hasani, H. 2020. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Archiv, 472(9), 1273-1298. https://doi.org/10.1007/s00424-020-02417-x.
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. 2017. Clinical Review of Antidiabetic Drugs: Implications for type 2 diabetes mellitus management. Frontiers in Endocrinology, 8(January). https://doi.org/10.3389/fendo.2017.00006.
Choi, S. H., & Ginsberg, H. N. 2011. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends in Endocrinology and Metabolism, 22(9), 353-363. https://doi.org/10.1016/j.tem.2011.04.007.
Fang, J. Y., Lin, C. H., Huang, T. H., & Chuang, S. Y. 2019. In vivo rodent models of type 2 diabetes and their usefulness for evaluating flavonoid bioactivity. Nutrients, 11(3). https://doi.org/10.3390/nu11030530.
Feitosa, S. G., Viana, K. F., Luna, E. C. M., Costa, F. W. G., Cavalcante, R. B., Chaves, F. N., Chaves, H. V., & Pereira, K. M. A. 2018. Immunohistochemical evaluation of GLUT-3 and GLUT-4 in oral epithelial dysplasia and oral squamous cell carcinoma. Asian Pacific Journal of Cancer Prevention, 19(7), 1779-1783. https://doi.org/10.22034/APJCP.2018.19.7.1779.
Hajiaghaalipour, F., Khalilpourfarshbafi, M., & Arya, A. 2015. Modulation of glucose transporter protein by dietary flavonoids in type 2 diabetes mellitus. International Journal of Biological Sciences, 11(5), 508-524. https://doi.org/10.7150/ijbs.11241.
Haroun, M. A., Elsayed, L. A., Rashed, L. A., & Mohammed, M. A. 2011. The effect of high fat diet and high fructose intake on insulin resistance and GLP-1 in experimental animals. Medical Journal of Cairo University, 79(2), 23-32. www.medicaljournalofcairouniversity.com.
International Diabetes Federation. 2021. IDF Diabetes Atlas 10th edition. www.diabetesatlas.org.
Jafri, A. A., Sharma, S. B., Khurana, N., M, M., Singh, U. R., & Luthra, K. 2019. Herbal anti-hyperglycemic compound increases expression of glucose transporter molecules in diabetic rats. Journal of Diabetes & Metabolism, 10(4), 4-10. https://doi.org/10.35248/2155-6156.19.10.824.
Jiang, Z., Wang, J., Zhao, P., Zhang, L., & Guo, Y. 2019. HbA1c: High in acute cerebral infarction and low in brain trauma. Progress in Molecular Biology and Translational Science (1st ed., Vol. 162). Elsevier Inc. https://doi.org/10.1016/bs.pmbts.2019.01.008.
Kasole, R., Martin, H. D., & Kimiywe, J. 2019. Traditional medicine and its role in the management of diabetes mellitus: “patients’’ and herbalists’ perspectives".” Evidence-Based Complementary and Alternative Medicine, 2019. https://doi.org/10.1155/2019/2835691.
Kucera, O., & Cervinkova, Z. 2014. Experimental models of non-alcoholic fatty liver disease in rats. World Journal of Gastroenterology, 20(26), 8364-8376. https://doi.org/10.3748/wjg.v20.i26.8364.
Kyrou, I., Tsigos, C., Mavrogianni, C., Cardon, G., Van Stappen, V., Latomme, J., Kivelä, J., Wikström, K., Tsochev, K., Nanasi, A., Semanova, C., Mateo-Gallego, R., Lamiquiz-Moneo, I., Dafoulas, G., Timpel, P., Schwarz, P. E. H., Iotova, V., Tankova, T., Makrilakis, K., & Manios, Y. 2020. Sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for type 2 diabetes: A narrative review with emphasis on data from Europe. BMC Endocrine Disorders, 20(Suppl 1), 1-13. https://doi.org/10.1186/s12902-019-0463-3.
Lozano, I., Van Der Werf, R., Bietiger, W., Seyfritz, E., Peronet, C., Pinget, M., Jeandidier, N., Maillard, E., Marchioni, E., Sigrist, S., & Dal, S. 2016. High-fructose and high-fat diet-induced disorders in rats: Impact on diabetes risk, hepatic and vascular complications. Nutrition and Metabolism, 13(1), 1-13. https://doi.org/10.1186/s12986-016-0074-1.
Malafaia, A. B., Nassif, P. A. N., Ribas, C. A. P. M., Ariede, B. L., Sue, K. N., & Cruz, M. A. 2013. Obesity induction with high fat sucrose in rats. Arquivos Brasileiros de Cirurgia Digestiva : ABCD = Brazilian Archives of Digestive Surgery, 26 Suppl 1(Suplemento 1), 17-21.
McArdle, M. A., Finucane, O. M., Connaughton, R. M., McMorrow, A. M., & Roche, H. M. 2013. Mechanisms of obesity-induced inflammation and insulin resistance: Insights into the emerging role of nutritional strategies. Frontiers in Endocrinology, 4(MAY), 1-23. https://doi.org/10.3389/fendo.2013.00052.
Moldogazieva, N. T., Mokhosoev, I. M., Mel’Nikova, T. I., Porozov, Y. B., & Terentiev, A. A. 2019. Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases. Oxidative Medicine and Cellular Longevity, 2019. https://doi.org/10.1155/2019/3085756.
Pereira, R. M., Botezelli, J. D., da Cruz Rodrigues, K. C., Mekary, R. A., Cintra, D. E., Pauli, J. R., da Silva, A. S. R., Ropelle, E. R., & de Moura, L. P. 2017. Fructose consumption in the development of obesity and the effects of different protocols of physical exercise on the hepatic metabolism. Nutrients, 9(4), 1-21. https://doi.org/10.3390/nu9040405.
Pereira, R. M., De Moura, L. P., Muñoz, V. R., Da Silva, A. S. R., Gaspar, R. S., Ropelle, E. R., & Pauli, J. R. 2017. Molecular mechanisms of glucose uptake in skeletal muscle at rest and in response to exercise. Motriz. Revista de Educacao Fisica, 23, 1-8. https://doi.org/10.1590/S1980-6574201700SI0004.
Ramasamy, R., Yan, S. F., & Schmidt, A. M. 2011. Receptor for AGE (RAGE): Signaling mechanisms in the pathogenesis of diabetes and its complications. Annals of the New York Academy of Sciences, 1243(1), 88-102. https://doi.org/10.1111/j.1749-6632.2011.06320.x.
Ratwita, W., Sukandar, E. Y., Adnyana, I. K., & Kurniati, N. F. 2017. Alpha mangostin and xanthone from Mangosteen (Garcinia mangostana L.) role on glucose tolerance and glucose transporter-4 in diabetes mellitus. International Journal of Pharmacognosy and Phytochemical Research, 9(9), 1206-1212. https://doi.org/10.25258/phyto.v9i09.10307.
Rena, G., Hardie, D. G., & Pearson, E. R. 2017. The mechanisms of action of metformin. Diabetologia, 60(9), 1577-1585. https://doi.org/10.1007/s00125-017-4342-z.
Richter, E. A., & Hargreaves, M. 2013. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiological Reviews, 93(3), 993-1017. https://doi.org/10.1152/physrev.00038.2012.
Sadowska-Bartosz, I., & Bartosz, G. 2015. Prevention of protein glycation by natural compounds. Molecules, 20(2), 3309-3334. https://doi.org/10.3390/molecules20023309.
Sanchis, P., Rivera, R., Berga, F., Fortuny, R., Adrover, M., Costa-Bauza, A., Grases, F., & Masmiquel, L. 2018. Phytate decreases formation of advanced glycation end-products in patients with type II diabetes: randomized crossover trial. Scientific Reports, 8(1), 1-13. https://doi.org/10.1038/s41598-018-27853-9.
Sharma, M., Arora, M., Mustafa, I., Kumar, S., Mittal, A., & Soam, S. S. 2017. Correlation of glycated hemoglobin with oxidative stress and erythrocyte fragility in type-2 diabetes mellitus. International Journal of Contemporany Medical Research, 4(9), 1909-1911.
Sherwani, S. I., Khan, H. A., Ekhzaimy, A., Masood, A., & Sakharkar, M. K. 2016. Significance of HbA1c test in diagnosis and prognosis of diabetic patients. Biomarker Insights, 11, 95-104. https://doi.org/10.4137/Bmi.s38440.
Varghese, F., Bukhari, A. B., Malhotra, R., & De, A. 2014. IHC profiler: An open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE, 9(5). https://doi.org/10.1371/journal.pone.0096801.
Yuliet, Sukandar, E. Y., & Adnyana, I. K. 2020. Active subfractions, phytochemical constituents, dipeptidyl peptidase-IV inhibitory activity and antioxidant of leaf extract from Hibiscus surattensis L. The Natural Products Journal: Vol. 10(4) (pp. 400-410). https://doi.org/10.2174/2210315509666190626125330.
Published
2022-12-20
How to Cite
Susanto, Y., Sukandar, E. Y., I Ketut Adnyana, & Tandi, J. (2022). Efficacy of the Hibiscus surattensis L. Leaves Active Fraction in Reducing the Levels of HbA1c, AGEs, and Glucose Uptake in Muscle Cells of Diabetic Type 2 Model Rat. Indonesian Journal of Pharmacy, 33(4), 630-640. https://doi.org/10.22146/ijp.4291
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Research Article
