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Inhibition of Type II Diabetes in ob/ob Mice and Enhancement of Mitochodrial Biogenesis in C2C12 Myotubes by Korean Mistletoe Extract

한국산 겨우살이 추출물(KME)의 2형 당뇨 억제 및 근육세포 미토콘드리아 생성 증가 효과

  • Jung, Hoe-Yune (Department of Life Science, Handong Global University) ;
  • Yoo, Yung Choon (Department of Microbiology, College of Medicine, Konyang University) ;
  • Kim, Inbo (Department of Life Science, Handong Global University) ;
  • Sung, Nak Yun (Department of Microbiology, College of Medicine, Konyang University) ;
  • Choi, Ok-Byung (Department of Bioindustry, Hoseo University) ;
  • Choi, Bo-Hwa (Pohang Center for Evaluation of Biomaterials) ;
  • Kim, Jong-Bae (Department of Life Science, Handong Global University)
  • 정회윤 (한동대학교 생명과학과) ;
  • 유영춘 (건양대학교 의과대학 미생물학교실) ;
  • 김인보 (한동대학교 생명과학과) ;
  • 성낙윤 (건양대학교 의과대학 미생물학교실) ;
  • 최옥병 (호서대학교 바이오산업학부) ;
  • 최보화 (포항테크노파크 바이오소재평가센터) ;
  • 김종배 (한동대학교 생명과학과)
  • Received : 2014.11.12
  • Accepted : 2015.01.31
  • Published : 2015.03.31

Abstract

In this study, the anti-diabetic activity of a cold water extract of Korean mistletoe (KME) was investigated in C57BL/6J Lep ob (ob/ob) mice. Oral administration of KME (50 or 100 mg/kg/d) significantly inhibited the level of blood glucose of ob/ob mice after 5 days from the beginning of KME treatment. And the anti-diabetic effect of KME was stabilized 10 days after oral administration, showing a substantial reduction of blood glucose levels by more than 20% as compared with control mice. The results of oral glucose tolerance test (OGTT) revealed that oral administration of KME gave rise to a remarkable improvement in overall glucose response. Oral administration of KME in ob/ob diabetic mice also significantly reduced blood total cholesterol (TCHO) and triglyceride (TG) levels compared with the diabetic control mice. Moreover, in an in vitro experiment using C2C12 myotubes, treatment of KME prominently increased glucose uptake. Interestingly, KME significantly increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-${\alpha}$ ($PGC-1{\alpha}$), a head regulator of mitochondrial biogenesis and oxidative metabolism, and $PGC-1{\alpha}$-associated genes such as glucose transporter type 4 (GLUT4), estrogen-related receptor-${\alpha}$ ($ERR-{\alpha}$), nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TmfA) in C2C12 cells. These results suggest that KME has potential as a novel therapeutic agent for diabetes, and its anti-diabetic activity may be related to the regulation of mitochondrial biogenesis.

본 연구에서는 C57BL/6J ob/ob 마우스를 이용하여 한국산 겨우살이 냉수 추출물(KME)의 항당뇨 활성을 조사하였다. 50 혹은 100 mg/kg의 KME를 1일 1회씩 경구투여 한 결과 KME 투여 개시 5일 후부터 ob/ob 마우스의 혈당이 유의하게 억제되었으며, 10일 후부터 안정된 억제 효과를 나타내고 대조군에 비해 20% 이상의 혈당강하 효과를 나타내었다. 경구 당부하 실험(OGTT)에서는 KME 경구투여 마우스에서 유효한 당부하 억제 활성이 관찰되었다. 또한 KME 경구 투여는 ob/ob 당뇨 마우스의 혈액 내 총 콜레스테롤과 중성 지질의 농도를 억제하는 것으로 나타났다. 한편 C2C12 근육세포를 이용한 in vitro 실험에서 KME를 처리함으로써 glucose uptake가 현저히 증가하였다. 한편 매우 흥미롭게도 KME를 처리한 C2C12 근육세포에 있어서 미토콘드리아 생성과 산화대사 조절물질인 peroxisome proliferator-activated receptor gamma coactivator 1-${\alpha}(PGC-1{\alpha})$를 비롯하여 glucose transporter type 4(GLUT4), estrogen-related receptor-${\alpha}(ERR-{\alpha})$, nuclear respiratory factor-1(NRF-1) 그리고 mitochondrial transcription factor A(TmfA)와 같은 $PGC-1{\alpha}$ 관련 유전자들의 발현이 증가하는 것으로 확인되었다. 이 결과는 KME가 2형 당뇨에 대한 치료물질로서의 작용을 지니며 이러한 KME의 항당뇨 활성은 미토콘드리아 생성의 조절과 관련 있는 것으로 추정된다.

Keywords

References

  1. Grover JK, Yadav S, Vats V. 2002. Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol 82: 81-100.
  2. Zhang HN, He JH, Yuan N, Lin ZB. 2003. In vitro and in vivo protective effect of Ganoderma lucidum polysaccharides on alloxan-induced pancreatic islets damage. Life Sci 73: 2307-2319. https://doi.org/10.1016/S0024-3205(03)00594-0
  3. Xie JT, Mehendale SR, Li X, Quigg R, Wang X, Wang CZ, Wu JA, Aung HH, A Rue P, Bell GI, Yuan CS. 2005. Antidiabetic effect of ginsenoside Re in ob/ob mice. Biochim Biophys Acta 1740: 319-325. https://doi.org/10.1016/j.bbadis.2004.10.010
  4. Kuttan G, Vasudevan DM, Kuttan R. 1992. Tumor reducing activity of an isolated active ingredient from mistletoe extract and its possible mechanism of action. J Exp Clin Cancer Res 11: 7-12.
  5. Kuttan G, Vasudevan DM, Kuttan R. 1988. Isolation and identification of a tumor reducing component from mistletoe extract (Iscador). Cancer Lett 41: 307-314. https://doi.org/10.1016/0304-3835(88)90292-3
  6. Mueller EA, Anderer FA. 1990. Chemical specificity of effector cell/tumor cell bridging by a Viscum album rhamnogalacturonan enhancing cytotoxicity of human NK cell. Immunopharmacol 19: 69-77. https://doi.org/10.1016/0162-3109(90)90028-D
  7. Ribereau-Gayon G, Dumont S, Muller C, Jung ML, Poindron P, Anton R. 1996. Mistletoe lectins I, II and III induce the production of cytokines by cultured human monocytes. Cancer Lett 109: 33-38. https://doi.org/10.1016/S0304-3835(96)04401-1
  8. Hajto T, Hostanska K, Gabius HJ. 1989. Modulatory potency of the beta-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo in rabbits and patients. Cancer Res 49: 4803-4808.
  9. Kovacs E, Hajto T, Hostanska K. 1991. Improvement of DNA repair in lymphocytes of breast cancer patients treated with Viscum album extract (Iscador). Eup J Cancer 27: 1672-1676. https://doi.org/10.1016/0277-5379(91)90443-H
  10. Bloksma N, Schmiermann P, de Reuver M, van Dijk H, Willers J. 1982. Stimulation of humoral and cellular immunity by Viscum preparations. Planta Med 46: 221-227. https://doi.org/10.1055/s-2007-971219
  11. Muller EA, Hamprecht K, Anderer FA. 1989. Biological characterization of a component in extract of Viscum album enhancing human NK cytotoxicity. Immunopharmacol 17: 11-18. https://doi.org/10.1016/0162-3109(89)90003-9
  12. Schink M. 1997. Mistletoe therapy for human cancer: the role of the natural killer cells. Anti-cancer Drugs 8: S47-S51. https://doi.org/10.1097/00001813-199704001-00011
  13. Heiny BM, Beuth J. 1994. Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces beta-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res 14: 1339-1342.
  14. Stettin A, Schultze JL, Stechemesser E, Berg PA. 1990. Antimistletoe lectin antibodies are produced in patients during therapy with an aqueous mistletoe extract derived from Viscum album L. and neutralize lectin-induced cytotoxicity in vitro. Klin Wochenschr 68: 896-900. https://doi.org/10.1007/BF01649034
  15. Beuth J, Ko HL, Gabius HJ, Burrichter H, Oette K, Pulverer G. 1992. Behavior of lymphocyte subsets and expression of activation markers in response to immunotherapy with galactoside-specific lectin from mistletoe in breast cancer patients. Clin Investig 70: 658-661.
  16. Hajto T, Hostanska K, Fischer J, Saller R. 1997. Immunomodulatory effects of Viscum album agglutinin-I on natural immunity. Anticancer Drugs 8: S43-S46. https://doi.org/10.1097/00001813-199704001-00010
  17. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. 2003. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300: 1140-1142. https://doi.org/10.1126/science.1082889
  18. Lowell BB, Shulman GI. 2005. Mitochondrial dysfunction and type 2 diabetes. Science 307: 384-387. https://doi.org/10.1126/science.1104343
  19. Jung HY, Lee AN, Song TJ, An HS, Kim YH, Kim KD, Kim IB, Kim KS, Han BS, Kim CH, Kim KS, Kim JB. 2012. Korean mistletoe (Viscum album coloratum) extract improves endurance capacity in mice by stimulating mitochondrial activity. J Med Food 15: 621-628. https://doi.org/10.1089/jmf.2010.1469
  20. Jung HY, Kim YH, Kim IB, Jeong JS, Lee JH, Do MS, Jung SP, Kim KS, Kim JB. 2013. The Korean mistletoe (Viscum album coloratum) extract has an anti-obesity effect and protects against hepatic steatosis in mice with high-fat diet-induced obesity. Evid Based Complement Alternat Med 2013: 168207.
  21. Yoon TJ, Yoo YC, Kang TB, Shimazaki K, Song SK, Lee KH, Kim SH, Park CH, Azuma I, Kim JB. 1999. Lectins isolated from Korean mistletoe (Viscum album coloratum) induce apoptosis tumor cell. Cancer Lett 136: 33-40. https://doi.org/10.1016/S0304-3835(98)00300-0
  22. Adisakwattana S, Roengsamran S, Hsu WH, Yibchok-anun S. 2005. Mechanisms of antihyperglycemic effect of p-methoxycinnamic acid in normal and streptozotocin-induced diabetic rats. Life Sci 78: 406-412. https://doi.org/10.1016/j.lfs.2005.04.073
  23. Ben-Abraham R, Gazit V, Vofsi O, Ben-Shlomo I, Reznick AZ, Katz Y. 2003. ${\beta}$-Phenylpyruvate and glucose uptake in isolated mouse soleus muscle and cultured C2C12 muscle cells. J Cell Biochem 90: 957-963. https://doi.org/10.1002/jcb.10690
  24. Lindstrom P. 2007. The physiology of obese-hyperglycemic mice (ob/ob mice). Sci World J 7: 666-685. https://doi.org/10.1100/tsw.2007.117
  25. DeFronzo RA. 2004. Pathogenesis of type 2 diabetes mellitus. Med Clin N Am 88: 787-835. https://doi.org/10.1016/j.mcna.2004.04.013
  26. Hanefeld M, Koehler C, Henkel E, Fuecker K, Schaper F, Temelkova-Kurktschiev T. 2000. Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD study. Diabet Med 17: 835-840. https://doi.org/10.1046/j.1464-5491.2000.00408.x
  27. Ryu MJ, Kim SJ, Kim YK, Choi MJ, Tadi S, Lee MH, Lee SE, Chung HK, Jung SB, Kim HJ, Jo YS, Kim KS, Lee SH, Kim JM, Kweon GR, Park KC, Lee JU, Kong YY, Lee CH, Chung J, Shong M. 2013. Crf1 deficiency reduces adipose OXPHOS capacity and triggers inflammation and insulin resistance in mice. PLoS Genet 9: e1003356. https://doi.org/10.1371/journal.pgen.1003356
  28. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. 2003. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34: 267-273. https://doi.org/10.1038/ng1180

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