Effects of Cheonghyul-san on Blood Glucose, Hyperlipidemia, Polyol Pathway and Reactive Oxygen Species in ob/ob Mice

청혈산(淸血散)이 ob/ob mouse의 혈당, 고지혈증, Polyol Pathway 및 Reactive Oxygen Species에 미치는 영향

  • Park, Sang-Tae (Department of Internal Medicine, College of Korean Medicine, Dongguk University) ;
  • Jeong, Ji-Cheon (Department of Internal Medicine, College of Korean Medicine, Dongguk University)
  • 한상태 (동국대학교 한의과대학 내과학교실) ;
  • 정지천 (동국대학교 한의과대학 내과학교실)
  • Published : 2008.04.25

Abstract

Etiological studies of diabetes and its complications showed that oxidative stress might play a major role. Therefore, many efforts have been tried to regulate free oxygen radicals for treating diabetes and its complications. Cheonghyul-san has been known to be effective for the antidiabetic, antihyperlipidemic and antiobesitic prescription, and composed of four crude herbs. In male ob/ob mouse with severe obesity, hyperinsulinemia, hypergiycemia, hyperlipidemia, the acting mechanisms of Cheonghyul-san were examined. Mice were grouped and treated for 5 weeks as follows. Both the lean (C57/BL6J black mice) and diabetic (ob/ob mice) control groups received standard chow. The experimental groups were fed with a diet of chow supplemented with 7.5, 15 and 30 mg Cheonghyul-san per 1 kg of body weight for 14 days. The effects of Cheonghyul-san extract on the ob/ob mice were observed by measuring the serum levels of glucose, insulin, lipid components, and the kidney levels of reactive oxygen species (ROS), MDA+HAE, GSH and also the enzyme activities involved in polyol pathway. Cheonghyul-san lowered the levels of serum glucose and insulin in a dose dependent manner. Total cholesterol, triglyceride and free fatty acid levels were decreased, while the HDL-cholesterol level was increased, in Cheonghyul-san treated groups. Renal aldose reductase and sorbitol dehydrogenase activities were increased in the ob/ob mice, whereas those were inhibited in the Cheonghyul-san-administered groups. Cheonghyul-san inhibited the generation of ROS in the kidney. Finally, MDA+HAE level was increased and the GSH level was decreased in the ob/ob mice, whereas those were improved in the Cheonghyul-san-administered groups. The results suggested that Cheonghyul-san exerted the antidiabetic and antihyperlipidemic activities by regulating the activities of polyol pathway enzymes, scavenging ROS, regulating the MDA+HAE and GSH levels in the ob/ob mice.

Keywords

References

  1. Kahn, C.R. The molecular mechanism of insulin action. Ann Rev Med. 34: 145-160, 1985
  2. 김응진 외. 당뇨병학. 서울, 고려의학, pp 15-43, 32-33, 149-169, 391-468, 475-487, 609-616, 1998.
  3. 민헌기. 임상내분비학. 서울, 고려의학, pp 394-414, 1999
  4. Carmine, M., Giuseppe, L., Bruno, T. Insulin resistance and cardiovascular risk ; New insight from molecular and cellular biology. Trends cardiovasc Med. 16: 183-188, 2006 https://doi.org/10.1016/j.tcm.2006.03.008
  5. Clay, F.S. Insulin resistance and atherosclerosis. J Clin Invest. 116: 1813-1822, 2006 https://doi.org/10.1172/JCI29024
  6. Defronzo, R.A. Pathogenesis of type 2 diabetes. Metabolic and molecular implications for identifying diabetes genes. Diabetes Rev. 5: 177-269, 1997
  7. Reaven, G.M. Pathophysiology of insulin resistance in human disease. Physiol Rev. 75: 473-486, 1995 https://doi.org/10.1152/physrev.1995.75.3.473
  8. Polonsky, K.S. et al. Non-insulin dependent diabetes mellitus. A genetically programmed failure of the ${\beta}$ cell to compensate for insulin resistance. New Engl J Med. 334: 777-783, 1998 https://doi.org/10.1056/NEJM199603213341207
  9. Cai, H., Harrison, D.G. Endothelial dysfunction in cardiovascular diseases ; the role of oxidant stress. Circ Res. 87: 840-844, 2000 https://doi.org/10.1161/01.RES.87.10.840
  10. Matsubara, T., Ziff, M. Increased syperoxide anion release from human endothelial cells in response to cytokines. J Immunol. 137: 3295-3298. 1986
  11. Hammers, H.D., Martin, S., Fedesrlin, K., Geisen, K. and Brownlee, M. Aminoguanidine treatment inhibit the development of experimental diabetic retinopathy. Proc Natl Acad Sci USA. 88: 11555-11558, 1991
  12. Pugliese, G., Tilton, G.T. and Williamson, J.R. Glucose- induced metabolic imbalance in the pathogenesis of diabetic vascular disease. Diabetes Metab Rev. 7: 35-59, 1991 https://doi.org/10.1002/dmr.5610070106
  13. Stevens, M.J., Dananberg, J., Feldman, E.L., Lattimer, S.A., Kamijo, M., Thomas, T.P., Shindo, H., Sima, A.A. and Greene, D.A. The linked roles of nitric oxide, aldose reductase and Na-K-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest. 94: 853-859, 1994 https://doi.org/10.1172/JCI117406
  14. 方藥中. 實用中醫內科學. 上海, 上海科學技術出版社, p 477, 1986
  15. 余永譜. 中醫治療內分泌代謝疾病. 浙江, 浙江科學技術出版社, p 239, 243, 1992
  16. 강석봉. 消渴의 傳變證과 당뇨병의 만성합병증에 대한 비교 고찰. 대한한의학회지 19(2):137-152, 1998
  17. 한기선. ob/ob mice에서 順氣散의 항당뇨 활성 및 기전 연구. 경희대학교 대학원 석사학위논문, 2002
  18. 장경선, 정기상, 최찬헌, 오영준. 竹瀝과 누에가루 배합약물이 db/db mouse의 혈당 강하에 미치는 영향. 동의생리병리학회지 17(3):759-764, 2003
  19. 김형준, 윤철호, 정지천. 珍糖元의 고혈당 조절 작용 및 기전에 관한 연구. 대한한방내과학회지 25(2):277-287, 2004
  20. 이철웅, 정지천, 신현철. 고혈당 흰쥐에서 蠐螬의 혈당 조절과 항산화작용에 관한 연구. 대한한의학회지 27(1):91-103, 2006
  21. Thomson, R.H. Colorimetric glucose oxidase method for blood glucose. Clin Chem Acta. 13: 133-135, 1966 https://doi.org/10.1016/0009-8981(66)90281-6
  22. Levinson, S.S. Use of an enzymatic method for cholesterol, designed for continuous flow instrumention, with discrete bichromatic and centrifugation analysis. Clin Chem. 23: 2335-2337, 1977
  23. Flether, M.J. A colorimetric method for estimation serum triglyceride. Clin Chem. 22: 393, 1968 https://doi.org/10.1016/0009-8981(68)90041-7
  24. 金井泉 외. 臨床檢査法槪要. 동경, 금원, p 467, 1983
  25. Yamaoka, T., Nishimura, C., Yamashita, K., Itakura, M., Yamada, T., Fujimoto, J. and 3Kokai, Y. Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA. Diabetologia. 38: 255-261, 1995 https://doi.org/10.1007/BF00400627
  26. Hollmann, S. In Hoppe-Seyler Thiefelder : Handbuch der physiol. und path.-chem. Vol. VIa. Berlin-Heidelberg-New York: Analyse, Springer. p 704, 1964
  27. Cathcart, R., Schwiers, E., Ames, B.N. Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein fluorescent assay. Anal Biochem. 134: 111-116, 1983 https://doi.org/10.1016/0003-2697(83)90270-1
  28. Esterbauer, H., Schaur, R.J. and Zollner, H. Chemistry and Biochemistry of 4-Hydroxynonenal, Malondialdehyde and Related Aldehydes. Free Rad Biol Med. 11: 81-128, 1991 https://doi.org/10.1016/0891-5849(91)90192-6
  29. Ellman, G.L. Tissue sulfhydryl group arch. Biochem Biophys. 82: 70-77, 1959 https://doi.org/10.1016/0003-9861(59)90090-6
  30. Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J. Protein measurement with folin phenol reagent. J Biol Chem. 193: 265-275, 1951
  31. Mordes, J.P. and Rossini, A.A. Animal models of diabetes mellitus. Am J Med. 70(2):353-360, 1981 https://doi.org/10.1016/0002-9343(81)90772-5
  32. Eleazar, S. Animal models of non-insulin-dependent diabetes. Diabetes metabolism reviews. 8(3):179-208, 1992 https://doi.org/10.1002/dmr.5610080302
  33. 孫星衍 輯. 神農本草經. 北京, 科學技術文獻出版社, p 39, 1999
  34. 江蘇新醫學院 編. 中藥大辭典. 上海, 上海科學技術出版社, pp 166-168, 2438-2439, 1979
  35. Han, K.J., Lee, K.S., Kong, K.H., Cho, S.H. Separation and purification of substance having matrix metalloproteinase-9 inhibition effect in Ulmus davidiana Planch. var. japonica Nakai. Anal Schi technol. 16: 179-184, 2003
  36. 정창주. 楡根皮추출물이 흰쥐의 항산화계 및 지질대사에 미치는 영향. 조선대학교 대학원 박사학위논문, 2006
  37. 이환용. 楡根皮의 소염 및 면역 증진 효과. 경희대학교 대학원 박사학위 논문, 2005
  38. 李尙仁. 本草學. 서울, 醫藥社, pp 113-114, 271-272, 492-493, 1981
  39. 송효정. 六味地黃湯加山藥이 Alloxan 당뇨 백서의 혈당 및 혈청 변화에 미치는 영향. 경희의학, 8(4):388-398, 1992