DOI QR코드

DOI QR Code

Effects of Phytoestrogens on Glucose Metabolism in C57BL/KsOlaHsd-db/db Mice

주요 Phytoestrogen들이 제2형 당뇨 마우스의 당질대사에 미치는 효과

  • Seo, Bo-Hyeon (Department of Food Science and Nutrition, Kyungpook National University) ;
  • Kim, Kwang-Ok (Department of Food Science and Nutrition, Kyungpook National University) ;
  • Lee, Ji-Hye (Department of Food Science and Nutrition, Kyungpook National University) ;
  • Lee, Hye-Sung (Department of Food Science and Nutrition, Kyungpook National University)
  • 서보현 (경북대학교 식품영양학과) ;
  • 김광옥 (경북대학교 식품영양학과) ;
  • 이지혜 (경북대학교 식품영양학과) ;
  • 이혜성 (경북대학교 식품영양학과)
  • Received : 2011.04.08
  • Accepted : 2011.07.27
  • Published : 2011.08.31

Abstract

This study was conducted to evaluate the antihyperglycemic effects of three phytoestrogens, genistein, coumestrol, and enterolactone, in type 2 diabetic animals. Forty male C57BL/KsOlaHsd-db/db mice were used as a diabetic animal model. The animals were divided into four groups and fed a phytoestrogen-free AIN-76 diet (control), or one of three phytoestrogen-supplemented (3.75 mg/100 g diet) AIN-76 diets for six weeks. During the experimental period, fasting blood glucose levels were measured on week 0, 2, 5, and 6 of the experiment, and oral glucose tolerance tests were performed on the 5th week. After the experimental period, blood concentrations of HbA1c, insulin, and glucagon were measured, and hepatic glycogen content and glucose regulating enzyme activities were analyzed. Fasting blood glucose, HbA1c level, and the area under the blood glucose curve in the oral glucose tolerance test were significantly lower in all of the phytoestrogen-supplemented groups compared to the control group. Plasma glucagon levels were also significantly lower in all of the phytoestrogen-supplemented groups compared to the control group. Hepatic glycogen level was significantly higher in the coumestrol-supplemented group compared to the other groups. However, there were no significant differences in the activities of glucokinase and glucose-6-phosphatase between the groups. These results suggest that all of the three major phytoestrogens tested in the present study were effective in lowering blood glucose levels in type 2 diabetic animals. However, further studies need to be conducted to elucidate the exact mechanism for the hypoglycemic effects of phytoestrogens.

본 실험은 주요 phytoestrogen에 속하는 genistein, coumestrol, enterolactone의 식이보충이 제2형 당뇨동물모델에서 당질대사 개선에 미치는 효과를 알아보고자 C57BL/KsOlaHsd-db/db 마우스를 이용하여 내당능, 당화헤모글로빈 농도, 당대사 관련 효소활성, 조직 중 글리코겐과 최종당화산물 수준 등을 측정하였다. 그 결과, phytoestrogen의 보충(3.75 mg/100 g diet)이 당뇨동물의 체중변화, 식이 및 수분 섭취량 그리고 장기무게에는 유의적인 영향을 미치지 않았으나, 모든 phytoestrogen의 보충은 당뇨동물의 공복 혈당, 경구 내당능 검사 시 혈당반응곡선 아래면적 및 혈중 HbA1c 수준을 유의적으로 낮추었다. 또한 모든 phytoestrogen의 보충은 당뇨동물의 혈장 글루카곤 수준을 유의적으로 낮추었으며, coumestrol과 enterolactone의 보충은 간 조직 중 글리코겐 수준을 유의적으로 증가시켰다. 이상의 결과들은 genistein, coumestrol, enterolactone의 3종 phytoestrogen의 식이보충이 제2형 당뇨동물에서 내당능을 개선시킬 수 있음을 시사하였으나 그 기전에 대해서는 향후 추가 연구가 필요하다고 본다.

Keywords

References

  1. Murkies AL, Wilcox G, Davis SR. Clinical review 92: Phytoestrogens. J Clin Endocrinol Metab 1998; 83(2): 297-303 https://doi.org/10.1210/jc.83.2.297
  2. Lissin LW, Cooke JP. Phytoestrogens and cardiovascular health. J Am Coll Cardiol 2000; 35(6): 1403-1410 https://doi.org/10.1016/S0735-1097(00)00590-8
  3. Ohta N, Kuwata G, Akahori H, Watanabe T. Isolation of a new isoflavone acetyl glucoside, 6"-O-acetyl genistin, from soybeans. Agric Biol Chem 1980; 44(2): 469-470 https://doi.org/10.1271/bbb1961.44.469
  4. Setchell KD, Lawson AM, Conway E, Taylor NF, Kirk DN, Cooley G, Farrant RD, Wynn S, Axelson M. The definitive identification of the lignans trans-2,3-bis (3-hydroxybenzyl)-gammabutyrolactone and 2,3-bis (3-hydroxybenzyl)butane-1,4-diol in human and animal urine. Biochem J 1981; 197(2): 447-458 https://doi.org/10.1042/bj1970447
  5. Shemesh M, Lindner HR, Ayalon N. Affinity of rabbit uterine oestradiol receptor for phyto-oestrogens and its use in a competitive protein-binding radioassay for plasma coumestrol. J Reprod Fertil 1972; 29(1): 1-9 https://doi.org/10.1530/jrf.0.0290001
  6. Prasad K. Hypocholesterolemic and antiatherosclerotic effect of flax lignan complex isolated from flaxseed. Atherosclerosis 2005; 179(2): 269-275 https://doi.org/10.1016/j.atherosclerosis.2004.11.012
  7. de Kleijn MJ, van der Schouw YT, Wilson PW, Grobbee DE, Jacques PF. Dietary intake of phytoestrogens is associated with a favorable metabolic cardiovascular risk profile in postmenopausal U.S. women: the Framingham study. J Nutr 2002; 132 (2): 276-282 https://doi.org/10.1093/jn/132.2.276
  8. Kapiotis S, Hermann M, Held I, Seelos C, Ehringer H, Gmeiner BM. Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells from damage by atherogenic LDL. Arterioscler Thromb Vasc Biol 1997; 17(11): 2868-2874 https://doi.org/10.1161/01.ATV.17.11.2868
  9. Chen Y, Wei X, Xie H, Deng H. Antioxidant 2-phenylbenzofurans and a coumestan from Lespedeza virgata. J Nat Prod 2008; 71(6): 929-932 https://doi.org/10.1021/np800016e
  10. Coward L, Barnes NC, Setchell KDR, Barnes S. Genistein, daidzein, and their ${\beta}$-glycoside conjugates: antitumor isoflavones in soybean foods from American and Asian diets. J Agric Food Chem 1993; 41(11): 1961-1967 https://doi.org/10.1021/jf00035a027
  11. Sarkar FH, Li Y. Soy isoflavones and cancer prevention. Cancer Invest 2003; 21(5): 744-757 https://doi.org/10.1081/CNV-120023773
  12. Lamartiniere CA, Murrill WB, Manzolillo PA, Zhang JX, Barnes S, Zhang X, Wei H, Brown NM. Genistein alters the ontogeny of mammary gland development and protects against chemically-induced mammary cancer in rats. Proc Soc Exp Biol Med 1998; 217(3): 358-364 https://doi.org/10.3181/00379727-217-44245
  13. Ali AA, Velasquez MT, Hansen CT, Mohamed AI, Bhathena SJ. Modulation of carbohydrate metabolism and peptide hormones by soybean isoflavones and probiotics in obesity and diabetes. J Nutr Biochem 2005; 16(11): 693-699 https://doi.org/10.1016/j.jnutbio.2005.03.011
  14. Ohno T, Kato N, Ishii C, Shimizu M, Ito Y, Tomono S, Kawazu S. Genistein augments cyclic adenosine 3'5'-monophosphate (cAMP) accumulation and insulin release in MIN6 cells. Endocr Res 1993; 19(4): 273-285 https://doi.org/10.1080/07435809309026682
  15. Sorenson RL, Brelje TC, Roth C. Effect of tyrosine kinase inhibitors on islets of Langerhans: evidence for tyrosine kinases in the regulation of insulin secretion. Endocrinology 1994; 134 (4): 1975-1978 https://doi.org/10.1210/en.134.4.1975
  16. Liu D, Zhen W, Yang Z, Carter JD, Si H, Reynolds KA. Genistein acutely stimulates insulin secretion in pancreatic ${\beta}$-cells through a cAMP-dependent protein kinase pathway. Diabetes 2006; 55(4): 1043-1050 https://doi.org/10.2337/diabetes.55.04.06.db05-1089
  17. Lee JS. Effects of soy protein and genistein on blood glucose, antioxidant enzyme activities, and lipid profile in streptozotocin-induced diabetic rats. Life Sci 2006; 79(16): 1578-1584 https://doi.org/10.1016/j.lfs.2006.06.030
  18. Park SA, Kim MJ, Jang JY, Choi MS, Yeo J, Lee MK. Effect of genistein and daidzein on antioxidant defense system in C57-BL/KsJ-db/db mice. J Korean Soc Food Sci Nutr 2006; 35(9): 1159-1165 https://doi.org/10.3746/jkfn.2006.35.9.1159
  19. Beguin DP, Kincaid RL. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase activity in chicks fed coumestrol, a phytoestrogen. Poult Sci 1984; 63(4): 686-690 https://doi.org/10.3382/ps.0630686
  20. Banskota AH, Nguyen NT, Tezuka Y, Nobukawa T, Kadota S. Hypoglycemic effects of the wood of Taxus yunnanensis on streptozotocin-induced diabetic rats and its active components. Phytomedicine 2006; 13(1-2): 109-114 https://doi.org/10.1016/j.phymed.2004.01.015
  21. Velasquez MT, Bhathena SJ, Ranich T, Schwartz AM, Kardon DE, Ali AA, Haudenschild CC, Hansen CT. Dietary flaxseed meal reduces proteinuria and ameliorates nephropathy in an animal model of type II diabetes mellitus. Kidney Int 2003; 64 (6): 2100-2107 https://doi.org/10.1046/j.1523-1755.2003.00329.x
  22. Prasad K. Secoisolariciresinol diglucoside from flaxseed delays the development of type 2 diabetes in Zucker rat. J Lab Clin Med 2001; 138(1): 32-39 https://doi.org/10.1067/mlc.2001.115717
  23. Shim JY, Kim KO, Seo BH, Lee HS. Soybean isoflavone extract improves glucose tolerance and raises the survival rate in streptozotocin-induced diabetic rats. Nutr Res Pract 2007; 1(4): 266-272 https://doi.org/10.4162/nrp.2007.1.4.266
  24. Raba J, Mottola HA. Glucose oxidase as an analytical reagent. Crit Rev Anal Chem 1995; 25(1): 1-42 https://doi.org/10.1080/10408349508050556
  25. Seifter S, Dayton S, Novic B, Muntwyler E. The estimation of glycogen with the anthrone reagent. Arch Biochem 1950; 25(1): 191-200
  26. Davidson AL, Arion WJ. Factors underlying significant underestimations of glucokinase activity in crude liver extracts: Biochem Biophys 1987; 253(1): 156-167 https://doi.org/10.1016/0003-9861(87)90648-5
  27. Swanson MA. Phosphatases of liver. 1. Glucose-6-phosphatase. J Biol Chem 1950; 184(2): 647-659
  28. Zarina S, Zhao HR, Abraham EC. Advanced glycation end products in human senile and diabetic cataractous lenses. Mol Cell Biochem 2000; 210(1-2): 29-34 https://doi.org/10.1023/A:1007015416572
  29. Bradford MM.A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72(1-2): 248-254 https://doi.org/10.1016/0003-2697(76)90527-3
  30. Lee SM, Bustamante S, Flores C, Bezerra J, Goda T, Koldovsky O. Chronic effects of an ${\alpha}$-glucosidase inhibitor (Bay o 1248) on intestinal disaccharidase activity in normal and diabetic mice. J Pharmacol Exp Ther 1987; 240(1): 132-137
  31. Orland MJ, Permutt MA. Quantitative analysis of pancreatic proinsulin mRNA in genetically diabetic (db/db) mice. Diabetes 1987; 36(3): 341-347 https://doi.org/10.2337/diabetes.36.3.341
  32. Stancoven A, McGuire DK. Preventing macrovascular complications in type 2 diabetes mellitus: glucose control and beyond. Am J Cardiol 2007; 99(11A): 5H-11H https://doi.org/10.1016/S0002-9149(07)00800-4
  33. Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med 2003; 163(11): 1306-1316 https://doi.org/10.1001/archinte.163.11.1306
  34. Hanefeld M, Temelkova-Kurktschiev T. Control of post-prandial hyperglycemia-an essential part of good diabetes treatment and prevention of cardiovascular complications. Nutr Metab Cardiovasc Dis 2002; 12(2): 98-107
  35. Rahbar S. An abnormal hemoglobin in red cells of diabetics. Clin Chim Acta 1968; 22(2): 296-298 https://doi.org/10.1016/0009-8981(68)90372-0
  36. Nathan DM, Singer DE, Godine JE, Harrington CH, Perlmuter LC. Retinopathy in older type II diabetics. Association with glucose control. Diabetes 1986; 35(7): 797-801 https://doi.org/10.2337/diabetes.35.7.797
  37. Hers HG. Mechanisms of blood glucose homeostasis. J Inherit Metab Dis 1990; 13(4): 395-410 https://doi.org/10.1007/BF01799497
  38. Barzilai N, Rossetti L. Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin. J Biol Chem 1993; 268(33): 25019-25025
  39. Vedavanam K, Srijayanta S, O'Reilly J, Raman A, Wiseman H. Antioxidant action and potential antidiabetic properties of an isoflavonoid-containing soyabean phytochemical extract (SPE). Phytother Res 1999; 13(7): 601-608 https://doi.org/10.1002/(SICI)1099-1573(199911)13:7<601::AID-PTR550>3.0.CO;2-O

Cited by

  1. Effects of Soybean and DJI Chungkukjang Powder on Blood Glucose and Serum Lipid Reduction in db/db Mice vol.41, pp.8, 2012, https://doi.org/10.3746/jkfn.2012.41.8.1086
  2. Effects of ice creams supplemented with soy isoflavones on diabetic biomarkers in type II model mice vol.23, pp.1, 2014, https://doi.org/10.5934/kjhe.2014.23.1.137
  3. 제2형 당뇨 마우스에서 십조탕(十棗湯)에 의한 혈당 및 신기능 부전 개선효과 vol.32, pp.1, 2017, https://doi.org/10.6116/kjh.2017.32.1.15.