Glucose Transporters and AMP-Activated Protein Kinase Modulation Effects of Decursin and Decursinol Angelate on Diabetic Rats

당뇨유발 흰쥐에서 당수송 인자와 AMP-Activated Protein Kinase의 조절에 대한 데커신과 데커시놀 안젤레이트의 효과

  • Ok, Seon (Department of Pharmacy, Kyungsung University) ;
  • Lee, Ju-Hee (Department of Pharmacy, Kyungsung University) ;
  • Kim, Ik-Hwan (Department of Biotechnology, Korea University) ;
  • Kang, Jae-Seon (Department of Pharmacy, Kyungsung University)
  • Received : 2011.06.01
  • Accepted : 2011.07.25
  • Published : 2011.08.31

Abstract

Diabetes has been one of major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has been focused as a novel therapeutic target for the treatment of metabolic syndromes, because AMPK increases glucose uptake through independent insulin signal pathway. In this study, we investigated the anti-diabetic effect of Angelica gigas Nakai extract (AGNEX), a mixture of decursin and decursinol angelate (53 : 47), decursin and decursinol angelate on blood glucose, glucose transport (GLUT) and AMPK expression levels in streptozotocin (STZ)-induced diabetic rats. To induce diabetes, 50 mg/kg of STZ was injected via i.v. route and AGNEX 2 mg/kg (STZ+AG), decursin 2 mg/kg (STZ+D), decursinol angelate 2 mg/kg (STZ+DA), and metformin 100 mg/kg (STZ+M) were administered orally for 21 days. STZ+DA group showed a significant decrease in fasting blood glucose levels compared to the other groups. Decursinol angelate significantly upregulated expression of glucose transporter 4 (GLUT4) and phosphorylation of AMPK (p-AMPK) in skeletal muscle of rats. In pancreas of rats, decursinol angelate significantly increased expression of GLUT2 through down-regulation of p-AMPK. In addition to the result of pancreatic islets morphology, AGNEX, decursin, decursinol angelate, and metformin treated group recovered ${\beta}$-cell damage by hyperglycemia. These results indicate that decursinol angelate might be a potential anti-diabetic agent and AGNEX could be useful in the treatment of diabetes mellitus.

Keywords

References

  1. Delarue, J. and Magnan, C. : Free fatty acids and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care. 10, 142 (2007). https://doi.org/10.1097/MCO.0b013e328042ba90
  2. 김응진, 민헌기, 최영길, 이태희, 허갑범, 신순현, 강성구, 김광원 이현철 : 제 3판 당뇨병학. 대한당뇨병학회 310 (2005).
  3. Arner, P. : Insulin resistance in type 2 diabetes: role of fatty acids. Diabetes Metab. Res. Rev. 18, S5 (2002). https://doi.org/10.1002/dmrr.254
  4. Chomczynski, P. and Sacchi, N. : Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156 (1987).
  5. Ziel, F. H., Venkatesan, N. and Davidson, M. B. : Glucose transport is rate limiting for skeletal muscle glucose metabolism in normal and STZ-induced diabetic rats. Diabetes 37, 885 (1988). https://doi.org/10.2337/diabetes.37.7.885
  6. Unger, R. H. : Diabetic hyperglycemia: link to impaired glucose transport in pancreatic beta cells. Science 251, 1200 (1991). https://doi.org/10.1126/science.2006409
  7. Towler, M. C. and Hardie, D. G. : AMP-activated protein kinase in metabolic control and insulin signaling. Circ. Res. 100, 328 (2007). https://doi.org/10.1161/01.RES.0000256090.42690.05
  8. Hardie, D. G. : AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat. Rev. Mol. Cell. Biol. 8, 774 (2007). https://doi.org/10.1038/nrm2249
  9. Zhang, B. B., Zhou, G. and Li, C. : AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell. Metab. 9, 407 (2009). https://doi.org/10.1016/j.cmet.2009.03.012
  10. Kahn, B. B., Alquier, T., Carling, D. and Hardie, D. G. : AMPactivated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell. Metab. 1, 15 (2005). https://doi.org/10.1016/j.cmet.2004.12.003
  11. Bergeron, R., Previs, S. F., Cline, G. W., Perret, P., Russell, R. R. 3rd., Young, L. H. and Shulman, G. I. : Effect of 5- aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50, 1076 (2001). https://doi.org/10.2337/diabetes.50.5.1076
  12. Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M. F., Goodyear, L. J. and Moller, D. E. : Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167 (2001). https://doi.org/10.1172/JCI13505
  13. Lee, S. H., Lee, Y. S., Jung, S. H., Shin, K. H., Kim, B. K. and Kang, S. S. : Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch. Pharm. Res. 26, 727 (2003). https://doi.org/10.1007/BF02976682
  14. Kang, S. Y., Lee, K. Y., Park, M. J., Kim, Y. C., Markelonis, G. J., Oh, T. H. and Kim, Y. C. : Decursin from Angelica gigas mitigates amnesia induced by scopolamine in mice. Neurobiology of Learning and Memory 79, 11 (2003). https://doi.org/10.1016/S1074-7427(02)00007-2
  15. Kim, K. M., Jung, J. Y., Hwang, S., W., Kim, M. J. and Kang, J. S. : Isolation and purification of decursin and decursinol angelate in Angelica gigas Nakai. The Korean Society of Food Science and Nutrition 38, 635 (2009).
  16. Cheng, J. T., Huang, C. C., Liu, I. M., Tzeng, T. F. and Chang, C. J. : Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats. Diabetes 55, 819 (2006). https://doi.org/10.2337/diabetes.55.03.06.db05-0934
  17. Brozinick, J. T., Jr., McCoid, S. C., Reynolds, T. H., Nardone, N. A., Hargrove, D. M., Stevenson, R. W., Cushman, S. W. and Gibbs, E. M. : GLUT4 overexpression in db/db mice dosedependently ameliorates diabetes but is not a lifelong cure. Diabetes 50, 593 (2001). https://doi.org/10.2337/diabetes.50.3.593
  18. Hardie, D. G. : The AMP-activated protein kinase pathwaynew players upstream and downstream. J. Cell. Sci. 117, 5479 (2004). https://doi.org/10.1242/jcs.01540
  19. Im, S. S., Kim, S. Y., Kim, H. I. and Ahn, Y. H. : Transcriptional regulation of glucose sensors in pancreatic beta cells and liver.Curr. Diabetes Rev. 2, 11 (2006). https://doi.org/10.2174/157339906775473581
  20. Olson, A. L. and Pessin, J. E. : Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu. Rev. Nutr. 16, 235 (1996). https://doi.org/10.1146/annurev.nu.16.070196.001315
  21. Thorens, B., Flier, J. S., Lodish, H. F. and Kahn, B. B. : Differential regulation of two glucose transporters in rat liver by fasting and refeeding and by diabetes and insulin treatment. Diabetes 39, 712 (1990). https://doi.org/10.2337/diabetes.39.6.712
  22. Kefas, B. A., Heimberg, H., Vaulont, S., Meisse, D., Hue, L., Pipeleers, D. and Van de Casteele, M. : AICA-riboside induces apoptosis of pancreatic beta cells through stimulation of AMPactivated protein kinase. Diabetologia 46, 250 (2003). https://doi.org/10.1007/s00125-002-1030-3
  23. Kim, W. H., Lee, J. W., Suh, Y. H., Lee, H. J., Lee, S. H., Oh, Y. K., Gao, B. and Jung, M. H. : AICAR potentiates ROS production induced by chronic high glucose: roles of AMPK in pancreatic beta-cell apoptosis. Cell. Signal. 19, 791 (2007). https://doi.org/10.1016/j.cellsig.2006.10.004
  24. Tsuboi, T., da Silva Xavier, G., Leclerc, I. and Rutter, G. A. : 5'- AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics. J. Biol. Chem. 278, 52042 (2003). https://doi.org/10.1074/jbc.M307800200
  25. da Silva Xavier, G., Leclerc, I., Varadi, A., Tsuboi, T., Moule, S. K. and Rutter, G. A. : Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem. J. 371, 761 (2003). https://doi.org/10.1042/BJ20021812
  26. 강재선, 황성우, 이진영, 김강민, 김천규, 홍용근, 최광진, 이상길 : 지질대사 개선효과가 있는 데커신 및 데커시놀안젤레이트를 유효 성분으로 하는 참당귀 및 세발당귀추출물과 그 추출방법, 한국특허 10-2009-0078267, 10-2008-0004122 (2008).