The Journal of Internal Korean Medicine (대한한방내과학회지)

The Society of Internal Korean Medicine (대한한방내과학회)
권호 표지
DOI QR코드

DOI QR Code

Ameliorating Effects of Geumnyeonyijin-tang Water Extract on Obesity-Induced T2DM and Related Complications in Mice

  • Lee, Yoo-na (Dept. of Cardiovascular and Neurologic Diseases of Korean Internal Medicine, Daegu Korean Medical Hospital of Daegu Haany University) ;
  • Baek, Kyungmin (Dept. of Cardiovascular and Neurologic Diseases of Korean Internal Medicine, Daegu Korean Medical Hospital of Daegu Haany University) ;
  • Ku, Sae-kwang (College of Korean Medicine, Daegu Haany University)
  • Received : 2022.08.31
  • Accepted : 2022.10.03
  • Published : 2022.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Objective: The aim of this study was to compare the effects of different doses of Geumnyeonyijin-tang (GNYJT) water extracts with those of metformin (250 mg/kg) in mild diabetic-obese mice. Methods and Results: The 48 mice were divided into 1 normal pellet diet (NFD) group and 5 high-fat diet (HFD) groups. At the end of 12 weeks of oral administration of metformin (250 mg/kg) or GNYJT water extracts (400, 200, or100 mg/kg), the effects were evaluated. The HFD control mice showed noticeable increases in body weight, adipose tissue density, fat pad weight of the periovarian and abdominal wall, and insulin, blood glucose, and HbA1c levels, with decreases in serum HDL levels. Increases in the periovarian and dorsal abdominal fat pad, regions of steatohepatitis, adipocyte hypertrophy, and hepatocyte hypertrophy were also discovered. The HFD group showed a decline in glucose levels and elevation of hepatic gluconeogenesis, suggesting an HFD-induced AMPK downregulation related to glucose dysregulation, as well as lipid metabolism related to obese insulin-resistant type II diabetes, dyslipidemia, and oxidative stress related diabetic hepatopathy (non-alcoholic fatty liver disease, NAFLD). Conclusion: Assessment of the key parameters for inhibition of diabetes and related complications in HFD-fed diabetic-obese mice demonstrated that GNYJT water extracts have favorable ameliorating effects. The effect of GNYJT was manifested through the stimulation of AMPK upregulation of related hepatic glucose enzyme activities and expression of lipid metabolism-related genes. Therefore, appropriate oral dosages of GNYJT could be promising as a new preventive candidate for controlling diabetes and related complications. Further screening of biologically active compounds, elucidation of detailed mechanisms, and more animal studies are warranted.

Keywords

References

  1. Jaacks LM, Vandevijvere S, Pan A, McGowan CJ, Wallace C, Imamura F, et al. The obesity transition: stages of the global epidemic. The lancet Diabetes & endocrinology 2019;7(3):231-40. doi:10.1016/s2213-8587(19)30026-9 [published Online First: 2019/02/02]
  2. Lovic D, Piperidou A, Zografou I, Grassos H, Pittaras A, Manolis. The Growing Epidemic of Diabetes Mellitus. Current vascular pharmacology 2020;18(2):104-9. https://doi.org/10.2174/1570161117666190405165911
  3. Lim S, Meigs JB. Ectopic fat and cardiometabolic and vascular risk. International journal of cardiology 2013;169(3):166-76. https://doi.org/10.1016/j.ijcard.2013.08.077
  4. Khan SH, Shahid R, Fazal N, Ijaz A. Comparison of Various Abdominal Obesity Measures for Predicting Metabolic Syndrome, Diabetes, Nephropathy, and Dyslipidemia. Journal of the College of Physicians and Surgeons-Pakistan : JCPSP 2019;29(12):1159-64.
  5. Sahakyan KR, Somers VK, Rodriguez-Escudero JP, Hodge DO, Carter RE, Sochor O, et al. Normal-Weight Central Obesity: Implications for Total and Cardiovascular Mortality. Annals of internal medicine 2015;163(11):827-35. https://doi.org/10.7326/M14-2525
  6. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature reviews Immunology 2006;6(10):772-83. https://doi.org/10.1038/nri1937
  7. Padhi S, Nayak AK, Behera A. Type II diabetes mellitus: a review on recent drug based therapeutics. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2020;131:110708. https://doi.org/10.1016/j.biopha.2020.110708
  8. Choi BR, Kim HJ, Lee YJ, Ku SK. Anti-Diabetic Obesity Effects of Wasabia Japonica Matsum Leaf Extract on 45% Kcal High-Fat Diet-Fed Mice. Nutrients 2020;12(9):2837. https://doi.org/10.3390/nu12092837
  9. Zhang M, Shao Y, Gao B, Chen J, Zhang P, Hu Y, et al. Erchen Decoction Mitigates Lipid Metabolism Disorder by the Regulation of PPARγ and LPL Gene in a High-Fat Diet C57BL/6 Mice Model. Evidence-based complementary and alternative medicine : eCAM 2020;2020:9102475.
  10. Cui X, Qian DW, Jiang S, Shang EX, Zhu ZH, Duan JA, et al. Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway. Int J Mol Sci 2018;19(11):3634. https://doi.org/10.3390/ijms19113634
  11. Flecknell P. Laboratory Animal Anesthesia. United States: Harcourt Brace & Company; 1996.
  12. Choi EH, Chun YS, Kim JK, Ku SK, Jeon SW, Park TS, et al. Modulating lipid and glucose metabolism by glycosylated kaempferol rich roasted leaves of Lycium chinense via upregulating adiponectin and AMPK activation in obese mice-induced type 2 diabetes. Journal of Functional Foods 2020;72:104072. https://doi.org/10.1016/j.jff.2020.104072
  13. Jung YM, Lee SH, Lee DS, You MJ, Chung IK, Cheon WH, et al. Fermented garlic protects diabetic, obese mice when fed a high-fat diet by antioxidant effects. Nutrition research 2011;31(5):387-96. https://doi.org/10.1016/j.nutres.2011.04.005
  14. Kang SJ, Lee JE, Lee EK, Jung DH, Song CH, Park SJ, et al. Fermentation with Aquilariae Lignum enhances the anti-diabetic activity of green tea in type II diabetic db/db mouse. Nutrients 2014;6(9):3536-71. https://doi.org/10.3390/nu6093536
  15. Kim CM, Yi SJ, Cho IJ, Ku SK. Red-koji fermented red ginseng ameliorates high fat diet-induced metabolic disorders in mice. Nutrients 2013;5(11):4316-32. https://doi.org/10.3390/nu5114316
  16. Lee JE, Kang SJ, Choi SH, Song CH, Lee YJ, Ku SK. Fermentation of green tea with 2% Aquilariae lignum increases the anti-diabetic activity of green tea aqueous extracts in the high fat-fed mouse. Nutrients 2015;7(11):9046-78. https://doi.org/10.3390/nu7115447
  17. Davidson AL, Arion WJ. Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity. Archives of Biochemistry and Biophysics 1987;253(1):156-67. https://doi.org/10.1016/0003-9861(87)90648-5
  18. Alegre M, Ciudad CJ, Fillat C, Guinovart JJ. Determination of glucose-6-phosphatase activity using the glucose dehydrogenase-coupled reaction. Analytical biochemistry 1988;173(1):185-9. https://doi.org/10.1016/0003-2697(88)90176-5
  19. Bentle L, Lardy HA. Interaction of anions and divalent metal ions with phosphoenolpyruvate carboxykinase. Journal of Biological Chemistry 1976;251(10):2916-21. https://doi.org/10.1016/S0021-9258(17)33478-6
  20. Veiga FMS, Graus-Nunes F, Rachid TL, Barreto AB, Mandarim-de-Lacerda CA, Souza-Mello V, et al. Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice. Biochimie 2017;140:106-16. https://doi.org/10.1016/j.biochi.2017.07.003
  21. Kawakami S, Han KH, Nakamura Y, Shimada K, Kitano T, Aritsuka T, et al. Effects of dietary supplementation with betaine on a nonalcoholic steatohepatitis (NASH) mouse model. Journal of nutritional science and vitaminology 2012;58(5):371-5. https://doi.org/10.3177/jnsv.58.371
  22. Kim JW, Lee YS, Seol DJ, Cho IJ, Ku SK, Choi JS, et al. Anti-obesity and fatty liver-preventing activities of Lonicera caerulea in high-fat diet-fed mice. International journal of molecular medicine 2018;42(6):3047-64.
  23. Levene A. Pathological factors influencing excision of tumours in the head and neck. Part I. Clinical Otolaryngology & Allied Sciences 1981;6(2):145-51. https://doi.org/10.1111/j.1365-2273.1981.tb01800.x
  24. Ludbrook J. Update: microcomputer statistics packages. A personal view. Clinical and experimental pharmacology & physiology 1997;24(3-4):294-6. https://doi.org/10.1111/j.1440-1681.1997.tb01823.x
  25. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412-9. https://doi.org/10.1007/BF00280883
  26. Puckrin R, Saltiel MP, Reynier P, Azoulay L, Yu OHY, Filion KB. SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta diabetologica 2018;55(5):503-14. https://doi.org/10.1007/s00592-018-1116-0
  27. Leelakanok N, Holcombe AL, Lund BC, Gu X, Schweizer ML. Association between polypharmacy and death: A systematic review and meta-analysis. Journal of the American Pharmacists Association : JAPhA 2017;57(6):729-38.e10. https://doi.org/10.1016/j.japh.2017.06.002
  28. Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. Journal of hepatology 2013;59(3):550-6. https://doi.org/10.1016/j.jhep.2013.04.027
  29. Chen Cheng, Pei ZY, Chen SW. Taiping huimin heji jufang (太平惠民和劑局方). Beijing: People's Medical Publishing House; 1985.
  30. Xie TH, Li JX, Mao TY, Guo Y, Chen C, Han YF, et al. An ErChen and YinChen decoction ameliorates high-fat-induced nonalcoholic steatohepatitis in rats by regulating JNK1 signaling pathway. Evidence-Based Complementary and Alternative Medicine 2017;2017:4603701.
  31. Xie XJ, Jia X, Li YM, Wu RX, Liao DF, Cheng CL, et al. Effects of the Chinese medicine, modified Erchen decoction, on the lipid metabolism and hepatocyte morphology in ApoE-/-mice. Chinese Journal of Comparative Medicine 2015(4):44-7.
  32. Zhao T, Zhan L, Zhou W, Chen W, Luo J, Zhang L, et al. The Effects of Erchen Decoction on Gut Microbiota and Lipid Metabolism Disorders in Zucker Diabetic Fatty Rats. Frontiers in pharmacology 2021;12:647529. https://doi.org/10.3389/fphar.2021.647529
  33. Lee SM, Lee J, Kang E, Kim HL, Hwang GS, Jung JY. Lipidomic analysis reveals therapeutic effects of Yijin-Tang on high-fat/high-cholesterol diet-induced obese mice. Phytomedicine 2020;74:152936. https://doi.org/10.1016/j.phymed.2019.152936
  34. Choi JS, Kim JW, Park JB, Pyo SE, Hong YK, Ku SK, et al. Blood glycemia-modulating effects of melanian snail protein hydrolysates in mice with type II diabetes. International journal of molecular medicine 2017;39(6):1437-51. https://doi.org/10.3892/ijmm.2017.2967
  35. Fujita H, Fujishima H, Koshimura J, Hosoba M, Yoshioka N, Shimotomai T, et al. Effects of antidiabetic treatment with metformin and insulin on serum and adipose tissue adiponectin levels in db/db mice. Endocrine journal 2005;52(4):427-33. https://doi.org/10.1507/endocrj.52.427
  36. Mitchell M, Armstrong D, Robker R, Norman RJ. Adipokines: implications for female fertility and obesity. Reproduction 2005;130(5):583-97. https://doi.org/10.1530/rep.1.00521
  37. Lebovitz H. Insulin resistance: definition and consequences. Experimental and clinical endocrinology & diabetes 2001;109(Suppl 2):S135-S48. https://doi.org/10.1055/s-2001-18576
  38. Goldstein BJ. Insulin resistance as the core defect in type 2 diabetes mellitus. The American journal of cardiology 2002;90(5):3-10. https://doi.org/10.1016/S0002-9149(02)02553-5
  39. Larsen ML, Horder M, Mogensen EF. Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus. The New England journal of medicine 1990;323(15):1021-5. https://doi.org/10.1056/NEJM199010113231503
  40. Chen H, Qu Z, Fu L, Dong P, Zhang X. Physicochemical properties and antioxidant capacity of 3 polysaccharides from green tea, oolong tea, and black tea. Journal of food science 2009;74(6):C469-C74. https://doi.org/10.1111/j.1750-3841.2009.01231.x
  41. Angulo P. Nonalcoholic fatty liver disease. New England Journal of Medicine 2002;346(16):1221-31. https://doi.org/10.1056/NEJMra011775
  42. Coope G, Atkinson A, Allott C, McKerrecher D, Johnstone C, Pike KG, et al. Predictive blood glucose lowering efficacy by glucokinase activators in high fat fed female Zucker rats. British journal of pharmacology 2006;149(3):328-35. https://doi.org/10.1038/sj.bjp.0706848
  43. She P, Shiota M, Shelton KD, Chalkley R, Postic C, Magnuson MA. Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. Molecular and cellular biology 2000;20(17):6508-17. https://doi.org/10.1128/MCB.20.17.6508-6517.2000
  44. van Schaftingen E, Gerin I. The glucose-6-phosphatase system. The Biochemical journal 2002;362(Pt 3):513-32. https://doi.org/10.1042/bj3620513
  45. Lin CH, Kuo YH, Shih CC. Effects of BofuTsusho-San on diabetes and hyperlipidemia associated with AMP-activated protein kinase and glucose transporter 4 in high-fat-fed mice. International journal of molecular sciences 2014;15(11):20022-44. https://doi.org/10.3390/ijms151120022
  46. Steinberg GR, Kemp BE. AMPK in health and disease. Physiological reviews 2009;89(3):1025-78. https://doi.org/10.1152/physrev.00011.2008
  47. Hasanvand A, Amini-Khoei H, Hadian MR, Abdollahi A, Tavangar SM, Dehpour AR, et al. Anti-inflammatory effect of AMPK signaling pathway in rat model of diabetic neuropathy. Inflammopharmacology 2016;24(5):207-19. https://doi.org/10.1007/s10787-016-0275-2
  48. Smith BK, Marcinko K, Desjardins EM, Lally JS, Ford RJ, Steinberg GR. Treatment of nonalcoholic fatty liver disease: role of AMPK. American Journal of Physiology-Endocrinology and Metabolism 2016;311(4):E730-E40. https://doi.org/10.1152/ajpendo.00225.2016
  49. Xu H, Wu B, Wang X, Ma F, Li Y, An Y, et al. Cordycepin regulates body weight by inhibiting lipid droplet formation, promoting lipolysis and recruiting beige adipocytes. Journal of Pharmacy and Pharmacology 2019;71(9):1429-39. https://doi.org/10.1111/jphp.13127
  50. Dulloo AG, Seydoux J, Jacquet J. Adaptive thermogenesis and uncoupling proteins: a reappraisal of their roles in fat metabolism and energy balance. Physiology & behavior 2004;83(4):587-602. https://doi.org/10.1016/j.physbeh.2004.07.028
  51. Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R, Goldstein BJ. Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes 2003;52(6):1355-63. https://doi.org/10.2337/diabetes.52.6.1355
  52. Song D, Yin L, Wang C, Wen X. Zhenqing recipe attenuates non-alcoholic fatty liver disease by regulating the SIK1/CRTC2 signaling in experimental diabetic rats. BMC complementary medicine and therapies 2020;20(1):27. https://doi.org/10.1186/s12906-019-2811-2
  53. Liu Y, Song A, Zang S, Wang C, Song G, Li X. Jinlida reduces insulin resistance and ameliorates liver oxidative stress in high-fat fed rats. J Ethnopharmacol 2015;162:244-52. https://doi.org/10.1016/j.jep.2014.12.040
  54. Ding S, Kang J, Tong L, Lin Y, Liao L, Gao B. Erchen Decoction Ameliorates Lipid Metabolism by the Regulation of the Protein CAV-1 and the Receptors VLDLR, LDLR, ABCA1, and SRB1 in a High-Fat Diet Rat Model. Evidence-based complementary and alternative medicine : eCAM2018;2018:5309490.
  55. Saklayen MG. The Global Epidemic of the Metabolic Syndrome. Current hypertension reports 2018;20(2):12. https://doi.org/10.1007/s11906-018-0812-z