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http://dx.doi.org/10.1016/j.jgr.2019.06.001

Diol-ginsenosides from Korean Red Ginseng delay the development of type 1 diabetes in diabetes-prone biobreeding rats  

Ju, Chung (College of Pharmacy, Seoul National University)
Jeon, Sang-Min (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University)
Jun, Hee-Sook (College of Pharmacy, Gachon University)
Moon, Chang-Kiu (College of Pharmacy, Seoul National University)
Publication Information
Journal of Ginseng Research / v.44, no.4, 2020 , pp. 619-626 More about this Journal
Abstract
Background: The effects of diol-ginsenoside fraction (Diol-GF) and triol-ginsenoside fraction (Triol-GF) from Korean Red Ginseng on the development of type 1 diabetes (T1D) were examined in diabetes-prone biobreeding (DP-BB) rats that spontaneously develop T1D through an autoimmune process. Methods: DP-BB female rats were treated with Diol-GF or Triol-GF daily from the age of 3-4 weeks up to 11-12 weeks (1 mg/g body weight). Results: Diol-GF delayed the onset, and reduced the incidence, of T1D. Islets of Diol-GF-treated DP-BB rats showed significantly lower insulitis and preserved higher plasma and pancreatic insulin levels. Diol-GF failed to change the proportion of lymphocyte subsets such as T cells, natural killer cells, and macrophages in the spleen and blood. Diol-GF had no effect on the ability of DP-BB rat splenocytes to induce diabetes in recipients. Diol-GF and diol-ginsenoside Rb1 significantly decreased tumor necrosis factor α production, whereas diol-ginsenosides Rb1 and Rd decreased interleukin 1β production in RAW264.7 cells. Furthermore, mixed cytokine- and chemical-induced β-cell cytotoxicity was greatly inhibited by Diol-GF and diol-ginsenosides Rc and Rd in RIN5mF cells. However, nitric oxide production in RAW264.7 cells was unaffected by diol-ginsenosides. Conclusion: Diol-GF, but not Triol-GF, significantly delayed the development of insulitis and T1D in DP-BB rats. The antidiabetogenic action of Diol-GF may result from the decrease in cytokine production and increase in β-cell resistance to cytokine/free radical-induced cytotoxicity.
Keywords
${\beta}$-cell cytotoxicity; Cytokines; Diol-ginsenosides; Type 1 diabetes;
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Times Cited By KSCI : 7  (Citation Analysis)
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1 Rabinovitch A, Baquerizo H, Pukel C, Sumoski W. Effects of cytokines on rat pancreatic islet cell monolayer cultures: distinction between functional and cytotoxic effects on islet beta-cells. Reg Immunol 1989;2(2):77-82.
2 Kim YK, Guo Q, Packer L. Free radical scavenging activity of red ginseng aqueous extracts. Toxicology 2002;172(2):149-56.   DOI
3 Ahuja A, Kim JH, Kim JH, Yi YS, Cho JY. Functional role of ginseng-derived compounds in cancer. J Ginseng Res 2018;42(3):248-54.   DOI
4 Mohanan P, Subramaniyam S, Mathiyalagan R, Yang DC. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. J Ginseng Res 2018;42(2):123-32.   DOI
5 Leung KW, Wong AS. Pharmacology of ginsenosides: a literature review. Chin Med 2010;5:20.   DOI
6 Burkart V, Brenner HH, Hartmann B, Kolb H. Metabolic activation of islet cells improves resistance against oxygen radicals or streptozocin, but not nitric oxide. J Clin Endocrinol Metab 1996;81(11):3966-71.   DOI
7 Bleich D, Chen S, Zipser B, Sun D, Funk CD, Nadler JL. Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. J Clin Invest 1999;103(10):1431-6.   DOI
8 Carpenter L, Cordery D, Biden TJ. Inhibition of protein kinase C delta protects rat INS-1 cells against interleukin-1beta and streptozotocin-induced apoptosis. Diabetes 2002;51(2):317-24.   DOI
9 Ismail MF, Gad MZ, Hamdy MA. Study of the hypolipidemic properties of pectin, garlic and ginseng in hypercholesterolemic rabbits. Pharmacol Res 1999;39(2):157-66.   DOI
10 Deng HL, Zhang JT. Anti-lipid peroxilative effect of ginsenoside Rb1 and Rg1. Chin Med J (Engl) 1991;104(5):395-8.
11 Kim CS, Jeong Sl, Lee YG. A rapid separation of an edible panaxadiol and panaxatriol in ginseng saponins by benzene ethylene resin adsorption. J Ginseng Res 1998;22(3):211-5.
12 Clark M, Kroger CJ, Tisch RM. Type 1 diabetes: a chronic anti-selfinflammatory response. Front Immunol 2017;8:1898.   DOI
13 Yoon JW, Jun HS. Cellular and molecular pathogenic mechanisms of insulindependent diabetes mellitus. Ann N Y Acad Sci 2001;928:200-11.   DOI
14 Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulindependent diabetic patients. Diabetes Care 1995;18(10):1373-5.   DOI
15 Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from Panax ginseng. J Ginseng Res 2015;39(4):287-98.   DOI
16 Kim SK, Kwak YS, Kim SW, Hwang SY, Ko YS, Yoo CM. Improved method for the preparation of crude ginseng saponin. J Ginseng Res 1998;22(3):155-60.
17 Kimura I, Nakashima N, Sugihara Y, Fu-jun C, Kimura M. The antihyperglycaemic blend effect of traditional chinese medicine byakko-ka-ninjinto on alloxan and diabetic KK-CA(y) mice. Phytother Res 1999;13(6):484-8.   DOI
18 Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41(4):435-43.   DOI
19 Gui QF, Xu ZR, Xu KY, Yang YM. The efficacy of ginseng-related therapies in type 2 diabetes mellitus: an updated systematic review and meta-analysis. Medicine (Baltimore) 2016;95(6):e2584.   DOI
20 Kim JS, Jang HJ, Kim SS, Oh MY, Kim HJ, Lee SY, Eom DW, Ham JY, Han DJ. Red ginseng administration before islet isolation attenuates apoptosis and improves islet function and transplant outcome in a syngeneic mouse marginal islet mass model. Transplant Proc 2016;48(4):1258-65.   DOI
21 Hong YJ, Kim N, Lee K, Hee Sonn C, Eun Lee J, Tae Kim S, Ho Baeg I, Lee KM. Korean red ginseng (Panax ginseng) ameliorates type 1 diabetes and restores immune cell compartments. J Ethnopharmacol 2012;144(2):225-33.   DOI
22 Rabinovitch A. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation? Diabetes 1994;43(5):613-21.   DOI
23 Kim YH, Park KH, Rho HM. Transcriptional activation of the Cu,Znsuperoxide dismutase gene through the AP2 site by ginsenoside Rb2 extracted from a medicinal plant, Panax ginseng. J Biol Chem 1996;271(40):24539-43.   DOI
24 Chang MS, Lee SG, Rho HM. Transcriptional activation of Cu/Zn superoxide dismutase and catalase genes by panaxadiol ginsenosides extracted from Panax ginseng. Phytother Res 1999;13(8):641-4.   DOI
25 Lee KU, Amano K, Yoon JW. Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes 1988;37(7):989-91.   DOI
26 Like AA, Biron CA, Weringer EJ, Byman K, Sroczynski E, Guberski DL. Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med 1986;164(4):1145-59.   DOI
27 Eizirik DL, Sandler S, Welsh N, Cetkovic-Cvrlje M, Nieman A, Geller DA, Pipeleers DG, Bendtzen K, Hellerstrom C. Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. J Clin Invest 1994;93(5):1968-74.   DOI
28 Nicoletti F, Meroni PL, Landolfo S, Gariglio M, Guzzardi S, Barcellini W, Lunetta M, Mughini L, Zanussi C. Prevention of diabetes in BB/Wor rats treated with monoclonal antibodies to interferon-gamma. Lancet 1990;336(8710):319.
29 Andersen NA, Larsen CM, Mandrup-Poulsen T. TNFalpha and IFNgamma potentiate IL-1beta induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans. Diabetologia 2000;43(11):1389-96.   DOI
30 Eizirik DL, Flodstrom M, Karlsen AE, Welsh N. The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells. Diabetologia 1996;39(8):875-90.   DOI
31 Padgett LE, Broniowska KA, Hansen PA, Corbett JA, Tse HM. The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis. Ann N Y Acad Sci 2013;1281(1):16-35.   DOI
32 Wallberg M, Cooke A. Immune mechanisms in type 1 diabetes. Trends Immunol 2013;34(12):583-91.   DOI
33 Li M, Song LJ, Qin XY. Advances in the cellular immunological pathogenesis of type 1 diabetes. J Cell Mol Med 2014;18(5):749-58.   DOI
34 Thomas HE, Graham KL, Chee J, Thomas R, Kay TW, Krishnamurthy B. Proinflammatory cytokines contribute to development and function of regulatory T cells in type 1 diabetes. Ann N Y Acad Sci 2013;1283(1):81-6.   DOI
35 Suarez-PinzonWL,Mabley JG, Strynadka K, Power RF, Szabo C, Rabinovitch A. An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice. J Autoimmun 2001;16(4):449-55.   DOI
36 Rabinovitch A. Immunoregulation by cytokines in autoimmune diabetes. Adv Exp Med Biol 2003;520:159-93.   DOI
37 Mordes JP, Bortell R, Blankenhorn EP, Rossini AA, Greiner DL. Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J 2004;45(3):278-91.   DOI
38 Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am 2010;39(3):481-97.   DOI
39 Lee K-H, Morris-Natschke S, Qian K, Dong Y, Yang X, Zhou T, Belding E, Wu SF, Wada K, Akiyama T. Recent progress of research on herbal products used in traditional chinese medicine: the herbs belonging to the divine husbandman's herbal foundation canon (Shen Nong Ben Cao Jing). J Trad Complem Med 2012;2(1):6-26.   DOI
40 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58(11):1685-93.   DOI
41 Chung YH, Jun HS, Kang Y, Hirasawa K, Lee BR, Van Rooijen N, Yoon JW. Role of macrophages and macrophage-derived cytokines in the pathogenesis of Kilham rat virus-induced autoimmune diabetes in diabetes-resistant Bio-Breeding rats. J Immunol 1997;159(1):466-71.
42 Hong BN, Ji MG, Kang TH. The efficacy of red ginseng in type 1 and type 2 diabetes in animals. Evid Based Complement Alternat Med 2013;2013:593181.
43 Kim JH, Kang SA, Han SM, Shim I. Comparison of the antiobesity effects of the protopanaxadiol- and protopanaxatriol-type saponins of red ginseng. Phytother Res 2009;23(1):78-85.   DOI
44 Nicoletti F, Di Marco R, Morrone S, Zaccone P, Lembo D, Grasso S, Santoni A, Meroni PL, Bendtzen K. Reduction of spontaneous autoimmune diabetes in diabetes-prone BB rats with the novel immunosuppressant fusidic acid. Effect on T-cell proliferation and production of interferon-gamma. Immunology 1994;81(2):317-21.
45 Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982;126(1):131-8.   DOI
46 Rabinovitch A, Suarez-Pinzon W, El-Sheikh A, Sorensen O, Power RF. Cytokine gene expression in pancreatic islet-infiltrating leukocytes of BB rats: expression of Th1 cytokines correlates with beta-cell destructive insulitis and IDDM. Diabetes 1996;45(6):749-54.   DOI
47 Nicoletti F, Zaccone P, Di Marco R, Lunetta M, Magro G, Grasso S, Meroni P, Garotta G. Prevention of spontaneous autoimmune diabetes in diabetes-prone BB rats by prophylactic treatment with antirat interferon-gamma antibody. Endocrinology 1997;138(1):281-8.   DOI
48 Sobel DO, Goyal D, Ahvazi B, Yoon JW, Chung YH, Bagg A, Harlan DM. Low dose poly I:C prevents diabetes in the diabetes prone BB rat. J Autoimmun 1998;11(4):343-52.   DOI