Ameliorative Effect of Red Grape Leaf Extract on Insulin Resistance: In Vivo And In Silico Studies
Naglaa M. Hamdy 1, 2*, Hanan M. El-Tantawy 1
Journal of Angiotherapy 8(5) 1-13 https://doi.org/10.25163/angiotherapy.859673
Submitted: 31 March 2024 Revised: 06 May 2024 Published: 10 May 2024
Abstract
Background: The prevalence of insulin resistance and non-alcoholic fatty liver disease (NAFLD) necessitates exploring natural remedies. Grape leaf extract (GLE), containing resveratrol and other polyphenols, shows potential in managing these conditions. The study aimed to investigate the secondary metabolites present in grape leaf extract (GLE), especially resveratrol. Method: Red grape leaves were collected from South Sinai, Egypt, and subjected to ultra-sonication for polyphenol extraction. High-performance liquid chromatography (HPLC) identified six polyphenols, with resveratrol being predominant. Thirty male Sprague Dawley rats were fed a high-fat diet to induce NAFLD. Rats were divided into groups, including GLE-treated and control groups. Biochemical parameters were measured to assess GLE's impact. Molecular docking was performed to understand resveratrol's mechanism of action on insulin resistance and liver dysfunction. Results: HPLC revealed significant levels of resveratrol in GLE. GLE (50%) exhibited control over blood glucose (mg/dl) (94.69 ± 3.16), insulin levels (μIU/ml) (16.80 ± 2.5), and improved insulin resistance HOMA-IR (3.9 ± 1.19). It also lowered liver enzymes such as ALT (45.20 ± 3.31), AST (59.60 ± 2.40), and ALP (335.10 ± 11.01 U/L) and improved lipid profiles (mg/dl), including cholesterol (90±10.2), triglycerides (66.21±4.0), HDL (40.10±3.5), and LDL (50.15±8.0). Molecular docking showed resveratrol's affinity for SIRT-1 and phosphodiesterases, indicating its role in regulating insulin resistance and liver function. Conclusion: GLE, particularly resveratrol, demonstrated synergistic effects in improving insulin resistance and hyperlipidemic liver in rats. It also exhibited hepatoprotective properties. Molecular docking highlighted resveratrol's potential mechanisms, making it a promising therapeutic candidate for managing insulin resistance and NAFLD.
Keywords: Red Grape Leaf Extract, Insulin Resistance, Non-Alcoholic Fatty Liver Disease, Situiin-1 Molecular Docking.
References
Abdelmalek, D. A., Abd-Elhamid, B. N., Abd Ellah, N. H., & Ismail, S. (2023). Resveratrol lipid based nanoparticles show a promising outcome on induced non alcoholic fatty liver disease. Bulletin of Pharmaceutical Sciences Assiut University, 46(2), 715-727.
Abo El-Fadl, S., Osman, A., Al-Zohairy, A., Dahab, A. A., & Abo El Kheir, Z. A. (2020). Assessment of total phenolic, flavonoid content, antioxidant potential and hplc profile of three moringa species leaf extracts. Scientific Journal of Flowers and Ornamental Plants, 7(1), 53-70.
Akhlaghipour, I., Shad, A. N., Askari, V. R., Maharati, A., & Rahimi, V. B. (2023). How caffeic acid and its derivatives combat diabetes and its complications: A systematic review. Journal of Functional Foods, 110, 105862.
Alkhalidy, H., Moore, W., Wang, A., Luo, J., McMillan, R. P., Wang, Y., . . . Liu, D. (2018). Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice. The Journal of nutritional biochemistry, 58, 90-101.
Biswas, N., Balac, P., Narlakanti, S., Haque, M. E., & Hassan, M. M. (2013). Identification of phenolic compounds in processed cranberries by HPLC method. J. Nutr. Food Sci, 3(1).
Blonde, L., Dipp, S., & Cadena, D. (2018). Combination glucose-lowering therapy plans in T2DM: case-based considerations. Advances in Therapy, 35, 939-965.
Bujanda, L., Hijona, E., Larzabal, M., Beraza, M., Aldazabal, P., García-Urkia, N., . . . González, A. (2008). Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC gastroenterology, 8, 1-8.
Chung, J. (2012). Metabolic benefits of inhibiting cAMP-PDEs with resveratrol. Adipocyte 1: 256–258. In.
Ciulca, S., Roma, G., Alexa, E., Radulov, I., Cocan, I., Madosa, E., & Ciulca, A. (2021). variation of polyphenol content and antioxidant activity in some bilberry (Vaccinium myrtillus L.) populations from Romania. Agronomy, 11(12), 2557.
Corcoran, C., & Jacobs, T. F. (2018). Metformin.
El Agamy, D. F., & Ahmed, F. E. D. (2020). Resveratrol and/or Metformin Activates Serum Sirtuin-1 and Decreases Insulin Resistance in High Fructose-Fed Rats. Benha Medical Journal, 37(3), 561-577.
Frum, A., Dobrea, C., Rus, L., Virchea, L., Morgovan, C., Chis, A., . . . Vicas, L. (2022). Valorization of grape pomace and berries as a new and sustainable dietary supplement: development, characterization, and antioxidant activity testing. Nutrients. 2022; 14: 3065. In: s Note: MDPI stays neutral with regard to jurisdictional claims in published ….
Ghafoor, K., & Choi, Y. H. (2009). Optimization of ultrasound assisted extraction of phenolic compounds and antioxidants from grape peel through response surface methodology. Journal of the Korean Society for Applied Biological Chemistry, 52, 295-300.
Gong, L., Guo, S., & Zou, Z. (2020). Resveratrol ameliorates metabolic disorders and insulin resistance in high-fat diet-fed mice. Life sciences, 242, 117212.
Harini Venkata Subbiah, Polani Ramesh Babu, Usha Subbiah, Daniel Rajendran T, Vinod Kumar P, (2021), Immune Dysfunction Linking Periodontitis And Diabetes, Journal of Angiotherapy, 5(2), 2153
Hoenig, M. R., & Sellke, F. W. (2010). Insulin resistance is associated with increased cholesterol synthesis, decreased cholesterol absorption and enhanced lipid response to statin therapy. Atherosclerosis, 211(1), 260-265.
Huang, D.-W., Chang, W.-C., Yang, H.-J., Wu, J. S.-B., & Shen, S.-C. (2018). Gallic acid alleviates hypertriglyceridemia and fat accumulation via modulating glycolysis and lipolysis pathways in perirenal adipose tissues of rats fed a high-fructose diet. International journal of molecular sciences, 19(1), 254.
Kilanowska, A., & Ziólkowska, A. (2020). Role of Phosphodiesterase in the Biology and Pathology of Diabetes. International journal of molecular sciences, 21(21), 8244.
Li, A.-N., Li, S., Zhang, Y.-J., Xu, X.-R., Chen, Y.-M., & Li, H.-B. (2014). Resources and biological activities of natural polyphenols. Nutrients, 6(12), 6020-6047.
Livraghi, V., Mazza, L., Chiappori, F., Cardano, M., Cazzalini, O., Puglisi, R., . . . Zannini, L. (2024). A proteasome-dependent inhibition of SIRT-1 by the resveratrol analogue 4, 4′-dihydroxy-trans-stilbene. Journal of Traditional and Complementary Medicine.
Mohd. Javed Naim, (2024). A review of Dipeptidyl Peptidase-4 (DPP-4) and its potential synthetic derivatives in the management of Diabetes Mellitus, Journal of Angiotherapy, 8(1), 1-12, 9417
Muhammad, M. H., Elwai, S., & Abd El Rahman, S. M. (2019). Anti-adiposity impact of phosphodiesterase-5 inhibitor, Sildenafil is possibly through browning of white adipose tissue and FGF21 in obese rats. Bulletin of Egyptian Society for Physiological Sciences, 39(2), 143-157.
Park, J.-E., & Han, J.-S. (2024). Improving the Effect of Ferulic Acid on Inflammation and Insulin Resistance by Regulating the JNK/ERK and NF-κB Pathways in TNF-α-Treated 3T3-L1 Adipocytes. Nutrients, 16(2), 294.
Petruccelli, J. D., Nandram, B., & Chen, M. (1999). Doing it with SAS: A Supplement to Applied Statistics for Engineers and Scientists: Prentice Hall.
Reda, D., Elshopakey, G. E., Mahgoub, H. A., Risha, E. F., Khan, A. A., Rajab, B. S., . . . Abdelhamid, F. M. (2022). Effects of resveratrol against induced metabolic syndrome in rats: Role of oxidative stress, inflammation, and insulin resistance. Evidence-Based Complementary and Alternative Medicine, 2022.
Russo, B., Picconi, F., Malandrucco, I., & Frontoni, S. (2019). Flavonoids and insulin-resistance: from molecular evidences to clinical trials. International journal of molecular sciences, 20(9), 2061.
Saleh Abd-Qader Abed, Ammar Ahmed Sultan. (2024). Genetic Variants of CYP2C8 Gene Predisposition to Type 2 Diabetes Risk, Journal of Angiotherapy, 8(2), 1-9, 9493.
Samuel, V. T., & Shulman, G. I. (2016). The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. The Journal of clinical investigation, 126(1), 12-22.
Samyuktha P, Pugazharasan, Kuberan, (2021), Assessing The Existing Knowledge on Diabetes to Create Awareness on Its Root Cause: A Preventive Study, Journal of Aniotherapy, 5(2), 2166
Sayed, A. M., Hassanein, E. H., Salem, S. H., Hussein, O. E., & Mahmoud, A. M. (2020). Flavonoids-mediated SIRT1 signaling activation in hepatic disorders. Life sciences, 259, 118173.
Singh, J., Rasane, P., Kaur, R., Kaur, H., Garg, R., Kaur, S., . . . Mlcek, J. (2023). Valorization of grape (Vitis vinifera) leaves for bioactive compounds: novel green extraction technologies and food-pharma applications. Frontiers in Chemistry, 11.
Sodum, N., Rao, V., Cheruku, S. P., Kumar, G., Sankhe, R., Kishore, A., . . . Rao, C. M. (2022). Amelioration of high-fat diet (HFD)+ CCl4 induced NASH/NAFLD in CF-1 mice by activation of SIRT-1 using cinnamoyl sulfonamide hydroxamate derivatives: in-silico molecular modelling and in-vivo prediction. 3 Biotech, 12(7), 147.
Tian, G., Sågetorp, J., Xu, Y., Shuai, H., Degerman, E., & Tengholm, A. (2012). Role of phosphodiesterases in the shaping of sub-plasma-membrane cAMP oscillations and pulsatile insulin secretion. Journal of cell science, 125(21), 5084-5095.
Tiwari, B. K. (2015). Ultrasound: A clean, green extraction technology. TrAC Trends in Analytical Chemistry, 71, 100-109.
Undank, S., Kaiser, J., Sikimic, J., Düfer, M., Krippeit-Drews, P., & Drews, G. (2017). Atrial natriuretic peptide affects stimulus-secretion coupling of pancreatic β-cells. Diabetes, 66(11), 2840-2848.
Wong, R. H., & Howe, P. R. (2018). Resveratrol counteracts insulin resistance—potential role of the circulation. Nutrients, 10(9), 1160.
Xin, P., Han, H., Gao, D., Cui, W., Yang, X., Ying, C., . . . Hao, L. (2013). Alleviative effects of resveratrol on nonalcoholic fatty liver disease are associated with up regulation of hepatic low density lipoprotein receptor and scavenger receptor class B type I gene expressions in rats. Food and chemical toxicology, 52, 12-18.
Yanti, S., Chien, W.-J., & Agrawal, D. C. (2022). Profiling of insulin and resveratrol interaction using multi-spectroscopy and molecular docking study. Beni-Suef University Journal of Basic and Applied Sciences, 11(1), 90.
Zhang, Q.-W., Lin, L.-G., & Ye, W.-C. (2018). Techniques for extraction and isolation of natural products: A comprehensive review. Chinese medicine, 13, 1-26.
Zhang, Y., Chen, M. l., Zhou, Y., Yi, L., Gao, Y. x., Ran, L., . . . Zou, D. (2015). Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Molecular nutrition & food research, 59(8), 1443-1457.
View Dimensions
View Altmetric
Save
Citation
View
Share