Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Anti-diabetic Effect and Mechanism of Korean Red Ginseng in C57BL/KsJ db/db Mice

  • Yuan, Hai-Dan (Pharmacology and Clinical Pharmacy Lab, College of Pharmacy, Kyung Hee University) ;
  • Shin, Eun-Jung (Pharmacology and Clinical Pharmacy Lab, College of Pharmacy, Kyung Hee University) ;
  • Chung, Sung-Hyun (Pharmacology and Clinical Pharmacy Lab, College of Pharmacy, Kyung Hee University)
  • Published : 2008.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

The present study was designed to investigate the anti-diabetic effect and mechanism of Korean red ginseng in C57BL/KsJ db/db mice. The db/db mice were divided into three groups: diabetic control group (DC), Korean red ginseng group (KRG, 100 mg/kg) and metformin group (MET, 300 mg/kg), and treated with drugs once per day for 10 weeks. Compared to the DC group, fasting blood glucose levels were decreased by 19.8% in KRG-, 67.7% in MET-treated group. With decreased plasma glucose and insulin levels, the insulin resistance index of the KRG-treated group was reduced by 27.6% compared to the DC group. The HbA1c levels in KRG and MET-treated groups were also decreased by 11.0% and 18.9% compared to that of DC group, respectively. Plasma triglyceride and non-esterified fatty acid levels were decreased by 18.8% and 16.8%, respectively, and plasma adiponectin and leptin levels were increased by 20.6% and 12.1%, respectively, in the KRG-treated group compared to those in DC group. Histological analyses of the liver and fat tissue of mice treated with KRG revealed significantly decreased number of lipid droplets and decreased size of adipocytes compared to the DC group. From the pancreatic islet double-immunofluorescence staining, we observed KRG has increased insulin contents, but decreased glucagon production. To elucidate action mechanism of KRG, effects on AMP-activated protein kinase (AMPK) and its downstream target proteins responsible for fatty acid oxidation and gluconeogenesis were explored in the liver. KRG activated AMPK and acetyl-coA carboxylase (ACC) phosphorylations, resulting in stimulation of fatty acid oxidation. KRG also caused to down regulation of SREBP1a and its target gene expressions such as FAS, SCD1 and GPAT. In summary, our results suggest that KRG exerted the anti-diabetic effect through AMPK activation in the liver of db/db mice.

Keywords

References

  1. Kim, Y. M., Namkoong, S., Yun, Y. G., Hong, H. D., Lee, Y. C., Ha, K. S., Lee, H., Kwon, H. J., Kwon, Y. G. and Kim, Y. M. : Water extract of Korean red ginseng stimulates angiogenesis by activating the PI3K/Akt dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells. Biol. Pharm. Bull. 30, 1674-1679 (2007) https://doi.org/10.1248/bpb.30.1674
  2. Tuttle, K. R., McGill, J. B., Haney, D. J., Lin, T. E., Anderson, P. W., PKC-DRS., PKC-DMES and PKC-DRS 2 Study Groups : Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin. J. Am. Soc. Nephrol. 2, 631-636 (2007) https://doi.org/10.2215/CJN.00840207
  3. Nammi, S., Boini, M. K., Lodagala, S. D. and Behara, R. B. : The juice of fresh leaves of Catharanthus roseus Linn. reduces blood glucose in normal and alloxan diabetic rabbits. BMC. Complement Altern. Med. 3, 4 (2003) https://doi.org/10.1186/1472-6882-3-4
  4. Stades, A. M., Heikens, J. T., Erkelens, D. W., Holleman, F. and Hoekstra, J. B. : Metformin and lactic acidosis: cause or coincidence? A review of case reports. J. Intern. Med. 255, 179-187 (2004) https://doi.org/10.1046/j.1365-2796.2003.01271.x
  5. Chiang, C. K., Ho, T. I., Peng, Y. S., Hsu, S. P., Pai, M. F., Yang, S. Y., Hung, K. Y. and Wu, K. D. : Rosiglitazone in diabetes control in hemodialysis patients with and without viral hepatitis infection: effectiveness and side effects. Diabetes Care 30, 3-7 (2007) https://doi.org/10.2337/dc06-0956
  6. Kobayashi, M., Iwata, M. and Haruta, T. : Clinical evaluation of pioglitazone. Nippon. Rinsho. 58, 395-400 (2000)
  7. Alarcon-Aguilara, F. J., Roman-Ramos, R., Perez-Gutierrez, S., Aguilar-Contreras, A., Contreras-Weber, C. C. and Flores-Saenz, J. L.: Study of the anti-hyperglycemic effect of plants used as antidiabetics. J. Ethnopharmacol. 61, 101-110 (1998) https://doi.org/10.1016/S0378-8741(98)00020-8
  8. Kim, D. H., Jung, J. S., Moon, Y. S., Sung, J. H., Suh, H. W., Kim, Y. H. and Song, D. K. : Inhibition of intracerebroventricular injection stress-induced plasma corticosterone levels by intracerebroventricularly administered compound K, a ginseng saponin metabolite, in mice. Biol. Pharm. Bull. 26, 1035-1038 (2007) https://doi.org/10.1248/bpb.26.1035
  9. Ryu, J. K., Lee, T., Kim, D. J., Park, I. S., Yoon, S. M., Lee, H. S., Song, S. U. and Suh, J. K. : Free radical-scavenging activity of Korean red ginseng for erectile dysfunction in non-insulin-dependent diabetes mellitus rats. Urology 65, 611-615 (2003) https://doi.org/10.1016/j.urology.2004.10.038
  10. Shin, H. J., Kim, Y. S., Kwak, Y. S., Song, Y. B., Kim, Y. S. and Park, J. D. : Enhancement of antitumor effects of paclitaxel (taxol) in combination with red ginseng acidic polysaccharide (RGAP). Planta. Med. 70, 1033-1038 (2004) https://doi.org/10.1055/s-2004-832643
  11. Wargovich, M. J. : Colon cancer chemoprevention with ginseng and other botanicals. J. Korean Med. Sci. 16, S81-86 (2001) https://doi.org/10.3346/jkms.2001.16.S.S81
  12. Sung, J., Han, K. H., Zo, J. H., Park, H. J., Kim, C. H. and Oh, B. H. : Effects of red ginseng upon vascular endothelial function in patients with essential hypertension. Am. J. Chin. Med. 28, 205-216 (2000) https://doi.org/10.1142/S0192415X00000258
  13. Vuksan, V., Sung, M. K., Sievenpiper, J. L., Stavro, P. M., Jenkins, A. L., Di Buono M., Lee, K. S., Leiter, L. A., Nam, K. Y., Arnason, J. T., Choi, M. and Naeem, A. : Korean red ginseng (Panax ginseng) improves glucose and insulin regulation in well-controlled, type 2 diabetes: results of a randomized, double-blind, placebo-controlled study of efficacy and safety. Nutr. Metab. Cardiovasc. Dis. 18, 46-56 (2008) https://doi.org/10.1016/j.numecd.2006.04.003
  14. Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F. and Turner, R. C. : Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412-419 (1985) https://doi.org/10.1007/BF00280883
  15. Chujo, K., Shima, K., Tada, H., Oohashi, T., Minakuchi, J. and Kawashima, S. : Indicators for blood glucose control in diabetics with end-stage chronic renal disease: GHb vs. glycated albumin (GA). J. Med. Invest. 53, 223-228 (2006) https://doi.org/10.2152/jmi.53.223
  16. Christopher, D., Saudek, M. D., Rachel, L., Derr, M. D., Rita, R. and Kalyani, M. D. : Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin $A_{1c}$. JAMA 295, 1688-1697 (2006) https://doi.org/10.1001/jama.295.14.1688
  17. Wang, Y., Lam, K. S, Yau, M. H. and Xu, A. : Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem. J. 409, 623-633 (2008) https://doi.org/10.1042/BJ20071492
  18. Aguilera, C. M., Gil-Campos, M., Canete, R. and Gil, A. : Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome. Clin. Sci (Lond). 114, 183-193 (2008) https://doi.org/10.1042/CS20070115
  19. Yamauchi, T., Kamon, J., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., Eto, K., Akanuma, Y., Froguel, P., Foufelle, F., Ferre, P., Carling, D., Kimura, S., Nagai, R., Kahn, B. B. and Kadowaki, T. : Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288-1295 (2002) https://doi.org/10.1038/nm788
  20. Buren, J., Lindmark, S., Renstrom. F. and Eriksson. J. W. : In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients: is cellular insulin resistance caused by glucotoxicity in vivo? Metabolism 52, 239-245 (2003) https://doi.org/10.1053/meta.2003.50041
  21. Fisher, RM., Thorne, A., Hamsten, A. and Arner, P. : Fatty acid binding protein expression in different human adipose tissue depots in relation to rates of lipolysis and insulin concentration in obese individuals. Mol. Cell. Biochem. 239, 1-2 (2002) https://doi.org/10.1023/A:1020591316965
  22. Stich, V. and Berlan, M. : Physiological regulation of NEFA availability: lipolysis pathway. Proc. Nutr. Soc. 63, 369-374 (2004)
  23. Raz, I., Eldor, R., Cernea, S. and Shafrir, E. : Diabetes: insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage. Diabetes Metab. Res. Rev. 21, 3-14 (2005) https://doi.org/10.1002/dmrr.493
  24. Tilg, H. and Kaser, A. : Treatment strategies in nonalcoholic fatty liver disease. Nat. Clin. Pract. Gastroenterol Hepato. 2, 148-155 (2005) https://doi.org/10.1038/ncpgasthep0116
  25. Kim, H. J., Kim, H. J., Lee, K. E., Kim, D. J., Kim, S. K., Ahn, C. W., Lim, S. K., Kim, K. R., Lee, H. C., Huh, K. Ba and Cha, B. S. : Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch. Intern. Med. 164, 2169-2175 (2004) https://doi.org/10.1001/archinte.164.19.2169
  26. Lin, H. Z., Yang, S. Q., Chuckaree, C., Kuhajda, F., Ronnet, G. and Diehl, A. M. : Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat. Med. 6, 998-1003 (2000) https://doi.org/10.1038/79697
  27. Jiang, G. and Zhang, B. B. : Glucagon and regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 284, E671-678 (2003) https://doi.org/10.1152/ajpendo.00492.2002
  28. Velasco, G., Geelen, M. J. and Guzman, M. : Control of hepatic fatty acid oxidation by 5'-AMP-activated protein kinase involves a malonyl-CoA-dependent and a malonyl-CoA-independent mechanism. Arch. Biochem. Biophys. 337, 169-175 (1997) https://doi.org/10.1006/abbi.1996.9784
  29. Yin, H. Q., Kim, M., Kim, J. H., Kong, G., Kang, K. S., Kim, H. L., Yoon, B. I., Lee, M. O. and Lee, B. H. : Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice. Toxicol. Appl. Pharmacol. 223, 225-233 (2007) https://doi.org/10.1016/j.taap.2007.06.018
  30. Horton, J. D., Goldstein, J. L. and Brown, M. S. : SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest., 109, 1125-1131 (2002) https://doi.org/10.1172/JCI0215593
  31. Hardie, D. G. : The AMP-activated protein kinase pathway--new players upstream and downstream. J. Cell. Sci. 117, 5479-5487 (2004) https://doi.org/10.1242/jcs.01540

Cited by

  1. Ethanolic fermentation from red ginseng extract using Saccharomyces cerevisiae and Saccharomyces carlsbergensis vol.20, pp.1, 2011, https://doi.org/10.1007/s10068-011-0018-5
  2. Effects of Red Ginseng Extract on the Epididymal Sperm Motility of Mice Exposed to Ethanol vol.30, pp.4, 2011, https://doi.org/10.1177/1091581811405074
  3. Ginseng Total Saponin Improves Podocyte Hyperpermeability Induced by High Glucose and Advanced Glycosylation Endproducts vol.26, pp.10, 2011, https://doi.org/10.3346/jkms.2011.26.10.1316