DOI QR코드

DOI QR Code

Ginsenosides for the treatment of insulin resistance and diabetes: Therapeutic perspectives and mechanistic insights

  • Tae Hyun Kim (Drug Information Research Institute, Muscle Physiome Research Center, College of Pharmacy, Sookmyung Women's University)
  • Received : 2023.12.15
  • Accepted : 2024.03.04
  • Published : 2024.05.01

Abstract

Diabetes mellitus (DM) is a systemic disorder of energy metabolism characterized by a sustained elevation of blood glucose in conjunction with impaired insulin action in multiple peripheral tissues (i.e., insulin resistance). Although extensive research has been conducted to identify therapeutic targets for the treatment of DM, its global prevalence and associated mortailty rates are still increasing, possibly because of challenges related to long-term adherence, limited efficacy, and undesirable side effects of currently available medications, implying an urgent need to develop effective and safe pharmacotherapies for DM. Phytochemicals have recently drawn attention as novel pharmacotherapies for DM based on their clinical relevance, therapeutic efficacy, and safety. Ginsenosides, pharmacologically active ingredients primarily found in ginseng, have long been used as adjuvants to traditional medications in Asian countries and have been reported to exert promising therapeutic efficacy in various metabolic diseases, including hyperglycemia and diabetes. This review summarizes the current pharmacological effects of ginsenosides and their mechanistic insights for the treatment of insulin resistance and DM, providing comprehensive perspectives for the development of novel strategies to treat DM and related metabolic complications.

Keywords

Acknowledgement

The figure and the graphical abstract of this manuscript was created with Biorender.com.

References

  1. Muoio DM, Newgard CB. Mechanisms of disease:Molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 2008;9:193-205. https://doi.org/10.1038/nrm2327.
  2. Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med 2017;23:804-14. https://doi.org/10.1038/nm.4350.
  3. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 2022;183:109119. https://doi.org/10.1016/j.diabres.2021.109119.
  4. Bommer C, Heesemann E, Sagalova V, Manne-Goehler J, Atun R, Barnighausen T, Vollmer S. The global economic burden of diabetes in adults aged 20-79 years: a cost-of-illness study. Lancet Diabetes Endocrinol 2017;5:423-30. https://doi.org/10.1016/S2213-8587(17)30097-9.
  5. Suto G, Molnar GA, Rokszin G, Fabian I, Kiss Z, Szekanecz Z, Poor G, Jermendy G, Kempler P, Wittmann I. Risk of morbidity and mortality in patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor and/or dipeptidyl peptidase-4 inhibitor: a nationwide study. BMJ Open Diabetes Res Care 2021;9:e001765. https://doi.org/10.1136/bmjdrc-2020-001765.
  6. Kong M, Xie K, Lv M, Li J, Yao J, Yan K, Wu X, Xu Y, Ye D. Anti-inflammatory phytochemicals for the treatment of diabetes and its complications: lessons learned and future promise. Biomed Pharmacother 2021;133:110975. https://doi.org/10.1016/j.biopha.2020.110975.
  7. Alam S, Sarker MMR, Sultana TN, Chowdhury MNR, Rashid MA, Chaity NI, Zhao C, Xiao J, Hafez EE, Khan SA, et al. Antidiabetic phytochemicals from medicinal plants: prospective candidates for new drug discovery and development. Front Endocrinol 2022;13:800714. https://doi.org/10.3389/fendo.2022.800714.
  8. Fan W, Huang Y, Zheng H, Li S, Li Z, Yuan L, Cheng X, He C, Sun J. Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: pharmacology and mechanisms. Biomed Pharmacother 2020;132:110915. https://doi.org/10.1016/j.biopha.2020.110915.
  9. Park SH, Chung S, Chung M, Choi H, Hwang J, Park JH. Effects of Panax ginseng on hyperglycemia, hypertension, and hyperlipidemia: a systematic review and meta-analysis. J Ginseng Res 2022;46:188-205. https://doi.org/10.1016/j.jgr.2021.10.002.
  10. Phung HM, Jang D, Trinh TA, Lee D, Nguyen QN, Kim C, Kang KS. Regulation of appetite-related neuropeptides by Panax ginseng: a novel approach for obesity treatment. J Ginseng Res 2022;46:609-19. https://doi.org/10.1016/j.jgr.2022.03.007.
  11. Kim JH, Yi Y, Kim M, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41:435-43. https://doi.org/10.1016/j.jgr.2016.08.004.
  12. Bai L, Gao J, Wei F, Zhao J, Wang D, Wei J. Therapeutic potential of ginsenosides as an adjuvant treatment for diabetes. Front Pharmacol 2018;9:423. https://doi.org/10.3389/fphar.2018.00423.
  13. Qi L, Wang C, Yuan C. Ginsenosides from American ginseng: chemical and pharmacological diversity. Phytochemistry 2011;72:689-99. https://doi.org/10.1016/j.phytochem.2011.02.012.
  14. Schlag EM, McIntosh MS. Ginsenoside content and variation among and within American ginseng (Panax quinquefolius L.) populations. Phytochemistry 2006;67:1510-9. https://doi.org/10.1016/j.phytochem.2006.05.028.
  15. Yoon SJ, Kim SK, Lee NY, Choi YR, Kim HS, Gupta H, Youn GS, Sung H, Shin MJ, Suk KT. Effect of Korean red ginseng on metabolic syndrome. J Ginseng Res 2021; 45:380-9. https://doi.org/10.1016/j.jgr.2020.11.002.
  16. Ru W, Wang D, Xu Y, He X, Sun Y, Qian L, Zhou X, Qin Y. Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.). Drug Discov Ther 2015;9:23-32. https://doi.org/10.5582/ddt.2015.01004.
  17. Ratan ZA, Haidere MF, Hong YH, Park SH, Lee J, Lee J, Cho JY. Pharmacological potential of ginseng and its major component ginsenosides. J Ginseng Res 2021;45:199-210. https://doi.org/10.1016/j.jgr.2020.02.004.
  18. Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci 2018;14:1483-96. https://doi.org/10.7150/ijbs.27173.
  19. Kraegen EW, James DE, Jenkins AB, Chisholm DJ. Dose-response curves for in vivo insulin sensitivity in individual tissues in rats. Am J Physiol 1985;248:353. https://doi.org/10.1152/ajpendo.1985.248.3.E353.
  20. Krycer JR, Sharpe LJ, Luu W, Brown AJ. The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metabol 2010;21:268-76. https://doi.org/10.1016/j.tem.2010.01.001.
  21. Li M, Chi X, Wang Y, Setrerrahmane S, Xie W, Xu H. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Targeted Ther 2022;7:216. https://doi.org/10.1038/s41392-022-01073-0.
  22. Perry RJ, Camporez JG, Kursawe R, Titchenell PM, Zhang D, Perry CJ, Jurczak MJ, Abudukadier A, Han MS, Zhang X, et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 2015;160:745-58. https://doi.org/10.1016/j.cell.2015.01.012.
  23. Titchenell PM, Quinn WJ, Lu M, Chu Q, Lu W, Li C, Chen H, Monks BR, Chen J, Rabinowitz JD, et al. Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production. Cell Metabol 2016;23:1154-66. https://doi.org/10.1016/j.cmet.2016.04.022.
  24. Whiteman EL, Cho H, Birnbaum MJ. Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metabol 2002;13:444-51. https://doi.org/10.1016/s1043-2760(02)00662-8.
  25. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001;292:1728-31. https://doi.org/10.1126/science.292.5522.1728.
  26. Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest 2004;114:963-8. https://doi.org/10.1172/JCI22098.
  27. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 2013;123:2764-72. https://doi.org/10.1172/JCI67227.
  28. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012;13:251-62. https://doi.org/10.1038/nrm3311.
  29. Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, Hashemi M, Hushmandi K, Ashrafizadeh M, Zarrabi A, et al. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: a pre-clinical and clinical investigation. Biomed Pharmacother 2022;146:112563. https://doi.org/10.1016/j.biopha.2021.112563.
  30. Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metabol 2009;9:407-16. https://doi.org/10.1016/j.cmet.2009.03.012.
  31. Feng Y, Chen Y, Wu X, Chen J, Zhou Q, Liu B, Zhang L, Yi C. Interplay of energy metabolism and autophagy. Autophagy 2024;20:4-14. https://doi.org/10.1080/15548627.2023.2247300.
  32. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 2012;336:918-22. https://doi.org/10.1126/science.1215327.
  33. Jeong KJ, Kim GW, Chung SH. AMP-activated protein kinase: an emerging target for ginseng. J Ginseng Res 2014;38:83-8. https://doi.org/10.1016/j.jgr.2013.11.014.
  34. Pories WJ, Dohm GL. Diabetes: have we got it all wrong? Hyperinsulinism as the culprit: surgery provides the evidence. Diabetes Care 2012;35:2438-42. https://doi.org/10.2337/dc12-0684.
  35. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 2008;31(Suppl 2):262. https://doi.org/10.2337/dc08-s264.
  36. Corkey BE. Diabetes: have we got it all wrong? Insulin hypersecretion and food additives: cause of obesity and diabetes? Diabetes Care 2012;35:2432-7. https://doi.org/10.2337/dc12-0825.
  37. Kim MK, Reaven GM, Chen YI, Kim E, Kim SH. Hyperinsulinemia in individuals with obesity: role of insulin clearance. Obesity 2015;23:2430-4. https://doi.org/10.1002/oby.21256.
  38. Erion DM, Shulman GI. Diacylglycerol-mediated insulin resistance. Nat Med 2010;16:400-2. https://doi.org/10.1038/nm0410-400.
  39. Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, Mauer J, Xu E, Hammerschmidt P, Bronneke HS, et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metabol 2014;20:678-86. https://doi.org/10.1016/j.cmet.2014.08.002.
  40. Raichur S, Wang ST, Chan PW, Li Y, Ching J, Chaurasia B, Dogra S, Ohman MK, Takeda K, Sugii S, et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metabol 2014;20:687-95. https://doi.org/10.1016/j.cmet.2014.09.015.
  41. Zhou P, Xie W, He S, Sun Y, Meng X, Sun G, Sun X. Ginsenoside Rb1 as an antidiabetic agent and its underlying mechanism analysis. Cells 2019;8:204. https://doi.org/10.3390/cells8030204.
  42. Shang W, Yang Y, Zhou L, Jiang B, Jin H, Chen M. Ginsenoside Rb1 stimulates glucose uptake through insulin-like signaling pathway in 3T3-L1 adipocytes. J Endocrinol 2008;198:561-9. https://doi.org/10.1677/JOE-08-0104.
  43. Shen L, Haas M, Wang DQ-, May A, Lo CC, Obici S, Tso P, Woods SC, Liu M. Ginsenoside Rb1 increases insulin sensitivity by activating AMP-activated protein kinase in male rats. Phys Rep 2015;3:e12543. https://doi.org/10.14814/phy2.12543.
  44. Yu X, Ye L, Zhang H, Zhao J, Wang G, Guo C, Shang W. Ginsenoside Rb1 ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice. J Ginseng Res 2015;39:199-205. https://doi.org/10.1016/j.jgr.2014.11.004.
  45. Chen W, Wang J, Luo Y, Wang T, Li X, Li A, Li J, Liu K, Liu B. Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res 2016;40:351-8. https://doi.org/10.1016/j.jgr.2015.11.002.
  46. Ahmad SS, Chun HJ, Ahmad K, Choi I. Therapeutic applications of ginseng for skeletal muscle-related disorder management. J Ginseng Res 2024;48:12-9. https://doi.org/10.1016/j.jgr.2023.06.003.
  47. Zha W, Sun Y, Gong W, Li L, Kim W, Li H. Ginseng and ginsenosides: therapeutic potential for sarcopenia. Biomed Pharmacother 2022;156:113876. https://doi.org/10.1016/j.biopha.2022.113876.
  48. Park K, Ahn CW, Kim Y, Nam JS. The effect of Korean Red Ginseng on sarcopenia biomarkers in type 2 diabetes patients. Arch Gerontol Geriatr 2020;90:104108. https://doi.org/10.1016/j.archger.2020.104108.
  49. Cnop M, Welsh N, Jonas J, Jorns A, Lenzen S, Eizirik DL. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 2005;54(Suppl 2):97. https://doi.org/10.2337/diabetes.54.suppl_2.s97.
  50. Chen F, Chen Y, Kang X, Zhou Z, Zhang Z, Liu D. Anti-apoptotic function and mechanism of ginseng saponins in Rattus pancreatic β-cells. Biol Pharm Bull 2012;35:1568-73. https://doi.org/10.1248/bpb.b12-00461.
  51. Chen Y, Liu Q, An P, Jia M, Luan X, Tang J, Zhang H, Ginsenoside Rd. A promising natural neuroprotective agent. Phytomedicine 2022;95:153883. https://doi.org/10.1016/j.phymed.2021.153883.
  52. Ding L, Yang Q, Zhang E, Wang Y, Sun S, Yang Y, Tian T, Ju Z, Jiang L, Wang X, et al. Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice. Acta Pharm Sin B 2021;11:1541-54. https://doi.org/10.1016/j.apsb.2021.03.038.
  53. Li J, Huang Q, Yao Y, Ji P, Mingyao E, Chen J, Zhang Z, Qi H, Liu J, Chen Z, et al. Biotransformation, pharmacokinetics, and pharmacological activities of ginsenoside Rd against multiple diseases. Front Pharmacol 2022;13:909363. https://doi.org/10.3389/fphar.2022.909363.
  54. Wang W, Guan F, Sagratini G, Yan J, Xie J, Jin Z, Liu M, Liu H, Liu J. Ginsenoside Rd attenuated hyperglycemia via Akt pathway and modulated gut microbiota in streptozotocin-induced diabetic rats. Curr Res Food Sci 2023;6:100491. https://doi.org/10.1016/j.crfs.2023.100491.
  55. Yao L, Han Z, Zhao G, Xiao Y, Zhou X, Dai R, Han M, Wang Z, Xin R, Wang S. Ginsenoside Rd ameliorates high fat diet-induced obesity by enhancing adaptive thermogenesis in a cAMP-dependent manner. Obesity 2020;28:783-92. https://doi.org/10.1002/oby.22761.
  56. Chu JMT, Lee DKM, Wong DPK, Wong RNS, Yung KKL, Cheng CHK, Yue KKM. Ginsenosides attenuate methylglyoxal-induced impairment of insulin signaling and subsequent apoptosis in primary astrocytes. Neuropharmacology 2014;85:215-23. https://doi.org/10.1016/j.neuropharm.2014.05.029.
  57. Kaviani M, Keshtkar S, Azarpira N, Hossein Aghdaei M, Geramizadeh B, Karimi MH, Yaghobi R, Esfandiari E, Shamsaeefar A, Nikeghbalian S, et al. Cytoprotective effects of ginsenoside Rd on apoptosis-associated cell death in the isolated human pancreatic islets. EXCLI J 2019;18:666-76. https://doi.org/10.17179/excli2019-1698.
  58. Tang K, Qin W, Wei R, Jiang Y, Fan L, Wang Z, Tan N. Ginsenoside Rd ameliorates high glucose-induced retinal endothelial injury through AMPK-STRT1 interdependence. Pharmacol Res 2022;179:106123. https://doi.org/10.1016/j.phrs.2022.106123.
  59. Song X, Wang L, Fan D. Insights into recent studies on biotransformation and pharmacological activities of ginsenoside Rd. Biomolecules 2022;12:512. https://doi.org/10.3390/biom12040512.
  60. Mohanan P, Subramaniyam S, Mathiyalagan R, Yang D. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. J Ginseng Res 2018;42:123-32. https://doi.org/10.1016/j.jgr.2017.01.008.
  61. Yan H, Jin H, Fu Y, Yin Z, Yin C. Production of rare ginsenosides Rg3 and Rh2 by endophytic bacteria from Panax ginseng. J Agric Food Chem 2019;67:8493-9. https://doi.org/10.1021/acs.jafc.9b03159.
  62. Kim H, Lee E, Ko S, Choi K, Park J, Im D. Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cells. Arch Pharm Res (Seoul) 2004;27:429-35. https://doi.org/10.1007/BF02980085.
  63. Gao Y, Yan J, Li J, Li X, Yang S, Chen N, Li L, Zhang L. Ginsenoside Rg3 ameliorates acetaminophen-induced hepatotoxicity by suppressing inflammation and oxidative stress. J Pharm Pharmacol 2021;73:322-31. https://doi.org/10.1093/jpp/rgaa069.
  64. Xu W, Lyu W, Duan C, Ma F, Li X, Li D. Preparation and bioactivity of the rare ginsenosides Rg3 and Rh2: an updated review. Fitoterapia 2023;167:105514. https://doi.org/10.1016/j.fitote.2023.105514.
  65. Lee H, Hong Y, Tran Q, Cho H, Kim M, Kim C, Kwon SH, Park S, Park J, Park J. A new role for the ginsenoside RG3 in antiaging via mitochondria function in ultraviolet-irradiated human dermal fibroblasts. J Ginseng Res 2019;43:431-41. https://doi.org/10.1016/j.jgr.2018.07.003.
  66. Shin Y, Jung H, Choi W, Lim C. Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines. Mol Biol Rep 2013;40:269-79. https://doi.org/10.1007/s11033-012-2058-1.
  67. Lee H, Kong G, Tran Q, Kim C, Park J, Park J. Relationship between ginsenoside Rg3 and metabolic syndrome. Front Pharmacol 2020;11:130. https://doi.org/10.3389/fphar.2020.00130.
  68. Lee O, Lee H, Kim J, Lee B. Effect of ginsenosides Rg3 and Re on glucose transport in mature 3T3-L1 adipocytes. Phytother Res 2011;25:768-73. https://doi.org/10.1002/ptr.3322.
  69. Zhang C, Yu H, Ye J, Tong H, Wang M, Sun G. Ginsenoside Rg3 protects against diabetic cardiomyopathy and promotes adiponectin signaling via activation of PPAR-γ. Int J Mol Sci 2023;24:16736. https://doi.org/10.3390/ijms242316736].
  70. Kim MJ, Koo YD, Kim M, Lim S, Park YJ, Chung SS, Jang HC, Park KS. Rg3 improves mitochondrial function and the expression of key genes involved in mitochondrial biogenesis in C2C12 myotubes. Diabetes Metab J 2016;40:406-13. https://doi.org/10.4093/dmj.2016.40.5.406.
  71. Kim YJ, Park SM, Jung HS, Lee EJ, Kim TK, Kim T, Kwon MJ, Lee SH, Rhee BD, Kim M, et al. Ginsenoside Rg3 prevents INS-1 cell death from intermittent high glucose stress. Islets 2016;8:57-64. https://doi.org/10.1080/19382014.2016.1161874.
  72. Kang KS, Yamabe N, Kim HY, Park JH, Yokozawa T. Therapeutic potential of 20 (S)-ginsenoside Rg(3) against streptozotocin-induced diabetic renal damage in rats. Eur J Pharmacol 2008;591:266-72. https://doi.org/10.1016/j.ejphar.2008.06.077.
  73. Kim K, Jung Yang H, Lee I, Kim K, Park J, Jeong H, Kim Y, Seok Ahn K, Na Y, Jang H. The aglycone of ginsenoside Rg3 enables glucagon-like peptide-1 secretion in enteroendocrine cells and alleviates hyperglycemia in type 2 diabetic mice. Sci Rep 2015;5:18325. https://doi.org/10.1038/srep18325.
  74. Gao Y, Li J, Wang J, Li X, Li J, Chu S, Li L, Chen N, Zhang L. Ginsenoside Rg1 prevent and treat inflammatory diseases: a review. Int Immunopharm 2020;87:106805. https://doi.org/10.1016/j.intimp.2020.106805.
  75. Alolga RN, Nuer-Allornuvor GF, Kuugbee ED, Yin X, Ma G. Ginsenoside Rg1 and the control of inflammation implications for the therapy of type 2 diabetes: a review of scientific findings and call for further research. Pharmacol Res 2020;152:104630. https://doi.org/10.1016/j.phrs.2020.104630.
  76. Lee H, Lee O, Kim K, Lee B. Ginsenoside Rg1 promotes glucose uptake through activated AMPK pathway in insulin-resistant muscle cells. Phytother Res 2012;26:1017-22. https://doi.org/10.1002/ptr.3686.
  77. Liu Q, Zhang F, Zhang W, Pan A, Yang Y, Liu J, Li P, Liu B, Qi L. Ginsenoside Rg1 inhibits glucagon-induced hepatic gluconeogenesis through akt-FoxO1 interaction. Theranostics 2017;7:4001-12. https://doi.org/10.7150/thno.18788.
  78. Mo J, Zhou Y, Yang R, Zhang P, He B, Yang J, Li S, Shen Z, Chen P. Ginsenoside Rg1 ameliorates palmitic acid-induced insulin resistance in HepG2 cells in association with modulating Akt and JNK activity. Pharmacol Rep 2019;71:1160-7. https://doi.org/10.1016/j.pharep.2019.07.004.
  79. Fan X, Zhang C, Niu S, Fan B, Gu D, Jiang K, Li R, Li S. Ginsenoside Rg1 attenuates hepatic insulin resistance induced by high-fat and high-sugar by inhibiting inflammation. Eur J Pharmacol 2019;854:247-55. https://doi.org/10.1016/j.ejphar.2019.04.027.
  80. Xie Q, Zhang X, Zhou Q, Xu Y, Sun L, Wen Q, Wang W, Chen Q. Antioxidant and anti-inflammatory properties of ginsenoside Rg1 for hyperglycemia in type 2 diabetes mellitus: systematic reviews and meta-analyses of animal studies. Front Pharmacol 2023;14:1179705. https://doi.org/10.3389/fphar.2023.1179705.
  81. Sun Y, Yang Y, Liu S, Yang S, Chen C, Lin M, Zeng Q, Long J, Yao J, Yi F, et al. New therapeutic approaches to and mechanisms of ginsenoside Rg1 against neurological diseases. Cells 2022;11:2529. https://doi.org/10.3390/cells11162529.
  82. Dong X, Kong L, Huang L, Su Y, Li X, Yang L, Ji P, Li W, Li W. Ginsenoside Rg1 treatment protects against cognitive dysfunction via inhibiting PLC-CN-NFAT1 signaling in T2DM mice. J Ginseng Res 2023;47:458-68. https://doi.org/10.1016/j.jgr.2022.12.006.
  83. Kim D. Gut microbiota-mediated pharmacokinetics of ginseng saponins. J Ginseng Res 2018;42:255-63. https://doi.org/10.1016/j.jgr.2017.04.011.
  84. Tian F, Huang S, Xu W, Chen L, Su J, Ni H, Feng X, Chen J, Wang X, Huang Q. Compound K attenuates hyperglycemia by enhancing glucagon-like peptide-1 secretion through activating TGR5 via the remodeling of gut microbiota and bile acid metabolism. J Ginseng Res 2022;46:780-9. https://doi.org/10.1016/j.jgr.2022.03.006.
  85. Chen L, Zhou L, Huang J, Wang Y, Yang G, Tan Z, Wang Y, Zhou G, Liao J, Ouyang D. Single- and multiple-dose trials to determine the pharmacokinetics, safety, tolerability, and sex effect of oral ginsenoside compound K in healthy Chinese volunteers. Front Pharmacol 2017;8:965. https://doi.org/10.3389/fphar.2017.00965.
  86. Han GC, Ko SK, Sung JH, Chung SH. Compound K enhances insulin secretion with beneficial metabolic effects in db/db mice. J Agric Food Chem 2007;55:10641-8. https://doi.org/10.1021/jf0722598.
  87. Gu J, Li W, Xiao D, Wei S, Cui W, Chen W, Hu Y, Bi X, Kim Y, Li J, et al. Compound K, a final intestinal metabolite of ginsenosides, enhances insulin secretion in MIN6 pancreatic β-cells by upregulation of GLUT2. Fitoterapia 2013;87:84-8. https://doi.org/10.1016/j.fitote.2013.03.020.
  88. Hwang Y, Oh D, Choi MC, Lee SY, Ahn K, Chung H, Lim S, Chung SH, Jeong I. Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats. Korean J Intern Med (Engl Ed) 2018;33:347-55. https://doi.org/10.3904/kjim.2015.208.
  89. Kim DY, Yuan HD, Chung IK, Chung SH. Compound K, intestinal metabolite of ginsenoside, attenuates hepatic lipid accumulation via AMPK activation in human hepatoma cells. J Agric Food Chem 2009;57:1532-7. https://doi.org/10.1021/jf802867b.
  90. Dai S, Hong Y, Xu J, Lin Y, Si Q, Gu X. Ginsenoside Rb2 promotes glucose metabolism and attenuates fat accumulation via AKT-dependent mechanisms. Biomed Pharmacother 2018;100:93-100. https://doi.org/10.1016/j.biopha.2018.01.111.
  91. Lee K, Jung TW, Lee H, Kim S, Shin Y, Whang W. The antidiabetic effect of ginsenoside Rb2 via activation of AMPK. Arch Pharm Res (Seoul) 2011;34:1201-8. https://doi.org/10.1007/s12272-011-0719-6.
  92. Huang Q, Wang T, Yang L, Wang H. Ginsenoside Rb2 alleviates hepatic lipid accumulation by restoring autophagy via induction of Sirt1 and activation of AMPK. Int J Mol Sci 2017;18:1063. https://doi.org/10.3390/ijms18051063.
  93. Meng F, Su X, Li W, Zheng Y. Ginsenoside Rb3 strengthens the hypoglycemic effect through AMPK for inhibition of hepatic gluconeogenesis. Exp Ther Med 2017;13:2551-7. https://doi.org/10.3892/etm.2017.4280.
  94. Wang Y, Fu W, Xue Y, Lu Z, Li Y, Yu P, Yu X, Xu H, Sui D. Ginsenoside Rc ameliorates endothelial insulin resistance via upregulation of angiotensin-converting enzyme 2. Front Pharmacol 2021;12:620524. https://doi.org/10.3389/fphar.2021.620524.
  95. Lee M, Hwang J, Kim S, Yoon S, Kim M, Yang HJ, Kwon DY. Ginsenoside Rc, an active component of Panax ginseng, stimulates glucose uptake in C2C12 myotubes through an AMPK-dependent mechanism. J Ethnopharmacol 2010;127:771-6. https://doi.org/10.1016/j.jep.2009.11.022.
  96. Yuan H, Kim DY, Quan H, Kim SJ, Jung MS, Chung SH. Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3β via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells. Chem Biol Interact 2012;195:35-42. https://doi.org/10.1016/j.cbi.2011.10.006.
  97. Zhu Y, Yang H, Deng J, Fan D. Ginsenoside Rg5 improves insulin resistance and mitochondrial biogenesis of liver via regulation of the sirt1/PGC-1α signaling pathway in db/db mice. J Agric Food Chem 2021;69:8428-39. https://doi.org/10.1021/acs.jafc.1c02476.
  98. Gao Y, Yang M, Su Y, Jiang H, You X, Yang Y, Zhang H. Ginsenoside Re reduces insulin resistance through activation of PPAR-γ pathway and inhibition of TNF-α production. J Ethnopharmacol 2013;147:509-16. https://doi.org/10.1016/j.jep.2013.03.057.
  99. Wang H, Teng Y, Li S, Li Y, Li H, Jiao L, Wu W. UHPLC-MS-Based serum and urine metabolomics reveals the anti-diabetic mechanism of ginsenoside Re in type 2 diabetic rats. Molecules 2021;26:6657. https://doi.org/10.3390/molecules26216657].
  100. Shi Y, Wan X, Shao N, Ye R, Zhang N, Zhang Y. Protective and anti-angiopathy effects of ginsenoside Re against diabetes mellitus via the activation of p38 MAPK, ERK1/2 and JNK signaling. Mol Med Rep 2016;14:4849-56. https://doi.org/10.3892/mmr.2016.5821.
  101. Quan H, Yuan H, Jung MS, Ko SK, Park YG, Chung SH. Ginsenoside Re lowers blood glucose and lipid levels via activation of AMP-activated protein kinase in HepG2 cells and high-fat diet fed mice. Int J Mol Med 2012;29:73-80. https://doi.org/10.3892/ijmm.2011.805.
  102. Liu Y, Deng J, Fan D. Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway. Food Funct 2019;10:2538-51. https://doi.org/10.1039/c9fo00095j.
  103. Bang H, Kwak JH, Ahn HY, Shin DY, Lee JH. Korean red ginseng improves glucose control in subjects with impaired fasting glucose, impaired glucose tolerance, or newly diagnosed type 2 diabetes mellitus. J Med Food 2014;17:128-34. https://doi.org/10.1089/jmf.2013.2889.
  104. Park K, Kim Y, Kim J, Kang S, Park JS, Ahn CW, Nam JS. Supplementation with Korean red ginseng improves current perception threshold in Korean type 2 diabetes patients: a randomized, double-blind, placebo-controlled trial. J Diabetes Res 2020;2020:5295328. https://doi.org/10.1155/2020/5295328.
  105. Jovanovski E, Lea-Duvnjak-Smircic n, Komishon A, Au-Yeung F, Zurbau A, Jenkins AL, Sung M, Josse R, Vuksan V. Vascular effects of combined enriched Korean Red ginseng (Panax Ginseng) and American ginseng (Panax Quinquefolius) administration in individuals with hypertension and type 2 diabetes: a randomized controlled trial. Compl Ther Med 2020;49:102338. https://doi.org/10.1016/j.ctim.2020.102338.
  106. Ni H, Yu N, Yang X. The study of ginsenoside on PPARgamma expression of mononuclear macrophage in type 2 diabetes. Mol Biol Rep 2010;37:2975-9. https://doi.org/10.1007/s11033-009-9864-0.
  107. Reeds DN, Patterson BW, Okunade A, Holloszy JO, Polonsky KS, Klein S. Ginseng and ginsenoside Re do not improve β-cell function or insulin sensitivity in overweight and obese subjects with impaired glucose tolerance or diabetes. Diabetes Care 2011;34:1071-6. https://doi.org/10.2337/dc10-2299.
  108. Chang W, Tsai Y, Huang C, Hsieh CC, Chaunchaiyakul R, Fang Y, Lee S, Kuo C. Null effect of ginsenoside Rb1 on improving glycemic status in men during a resistance training recovery. J Int Soc Sports Nutr 2015;12:34. https://doi.org/10.1186/s12970-015-0095-6.
  109. Deng J, Liu Y, Duan Z, Zhu C, Hui J, Mi Y, Ma P, Ma X, Fan D, Yang H. Protopanaxadiol and protopanaxatriol-type saponins ameliorate glucose and lipid metabolism in type 2 diabetes mellitus in high-fat diet/streptozocin-induced mice. Front Pharmacol 2017;8:506. https://doi.org/10.3389/fphar.2017.00506.