研究生: |
鄭裕文 Cheng, Yu-Wen |
---|---|
論文名稱: |
蛹蟲草水萃物之降血糖機制 Hypoglycemic mechanism of Cordyceps militaris aqueous extracts |
指導教授: |
黎耀基
Lai, Yiu-Kay 張世良 Chang, Shih-Liang |
口試委員: |
張大慈
張晃猷 |
學位類別: |
博士 Doctor |
系所名稱: |
生命科學暨醫學院 - 生物科技研究所 Biotechnology |
論文出版年: | 2013 |
畢業學年度: | 101 |
語文別: | 英文 |
論文頁數: | 110 |
中文關鍵詞: | 蛹蟲草 、糖尿病 、降血糖機轉 、抗膽鹼作用 |
外文關鍵詞: | Cordyceps militaris, diabetes mellitus, hypoglycemic mechanism, anticholinergic effect |
相關次數: | 點閱:3 下載:0 |
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糖尿病會有許多的併發症,以致於造成殘疾或危及生命。先前的研究發現蛹蟲草有降血糖的功能,但是其真正的機轉仍是不明。此研究的目的便是要釐清蛹蟲草的降血糖機轉。本研究分成兩個部分:
第一部分為正常的大鼠以蛹蟲草的水萃取物餵食。最佳的降血糖劑量是10 mg/kg,此劑量比100 mg/kg有更好的效果,所以之後的治療劑量都是10 mg/kg。對於正常大鼠,蛹蟲草餵食30分鐘後可以降低血糖達21.0%,同時可增加54.5%胰島素分泌。如果大鼠先給予腹膜內注射0.1 mg/kg阿托品(atropine)以阻斷膽鹼神經,則蛹蟲草之降血糖與增加胰島素分泌的效果就消失。分析胰島素訊息蛋白時,發現在餵食蛹蟲草後,胰島素受體受質-1 (insulin receptor substrate 1, IRS-1)與葡萄糖運送子-4 (glucose transporter 4, GLUT-4)會增加(與肌動蛋白的比值分別為餵食食鹽水的3.63與2.64倍)。相同的,這些胰島素訊息蛋白的增加也被阿托品所阻斷,同樣的阻斷作用,也可見於事先注射了半膽鹼-3(hemicholinium-3)的大鼠實驗。
第二部分以注射鏈佐黴素(streptozotocin)而誘發糖尿病的大鼠為對象,餵食蛹蟲草可以降低血糖7.2%,但若餵食食鹽水只有降低1.5%。胰島素受體受質-1在蛹蟲草增加2.9倍,食鹽水組只有0.8倍。葡萄糖運送子-4則於蛹蟲草與食鹽水組分別為1.7與0.6倍。若大鼠先以阿托品注射,則蛹蟲草組的降血糖及胰島素訊息蛋白的增加也會被阻斷。
總結而言,蛹蟲草刺激正常大鼠的胰臟分泌胰島素,繼而活化更多肌肉細胞內的胰島素訊息蛋白使血糖下降。在鏈佐黴素誘發糖尿病的大鼠,因為胰島素而降血糖的機制幾乎不存在,但蛹蟲草仍可增加胰島素訊息蛋白並降血糖。兩種動物模型的有效反應,都可被副交感神經拮抗劑所阻斷。所以,蛹蟲草能夠降血糖的機轉可能為啟動膽鹼神經而增加胰島素分泌以及非胰島素依賴的降血糖作用。
There are many diabetic complications which induce patients’ disability or loss their life. Previous study found Cordyceps militaris (CM) had hypoglycemic effect, yet the actual mechanism remains unclear. We would like to explore the mechanism of CM’s hypoglycemia. The experiments were separated into two portions.
In the first one, aqueous extracts of CM was feeding to the normal Wistar rats. The optimal dose of CM for lowering serum glucose was tested first and found that 10 mg/kg CM had a better hypoglycemic effect than a higher dose (100 mg/kg). Such optimal dose was used in following experiments. In the normal rats, CM decreased plasma glucose by 21.0% and induced additional insulin secretion by 54.5% at 30 minute. Additionally, atropine 0.1 mg/kg was injected intraperitoneally as an antagonist to the cholinergic nerve. The hypoglycemic effects of CM vanished and the enhanced insulin secretion was also blocked. In the assay of insulin signaling proteins, a significant rise in the insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT-4) were found in the rats after being fed CM (3.63- and 2.64-fold in comparison with fed saline). However, these rising signaling proteins were blocked by the atropine. And the same responses were found in the hemicholinium-3 (5μg/kg intraperitoneally) pre-treated rats.
The second portion of experiments was performed to the streptozotocin (STZ)- induced diabetic rats. Blood glucose decreased 7.2% in the CM group but only 1.5% in the control group. The IRS-1 signal was 2.9-fold in the CM group but only 0.8-fold in the control group. In GLUT-4 signal, it was 1.7- vs. 0.6-fold, respectively. However, atropine injection made CM-induced hypoglycemia or elevation of IRS-1 and GLUT-4 not significant.
In conclusion, CM stimulates the pancreas of normal rats to secrete additional insulin and activates the insulin signaling proteins via the binding of more insulin to its receptors in the myocyte. In the STZ-induced diabetic rats, the influence of insulin hypoglycemic effect was little, but CM still had the effect of activating insulin signaling proteins in the myocytes. Both reactions were blocked by anti-cholinergic agents. Taken together, the possible mechanisms of CM-induced hypoglycemia in both types of animal models were the induction of insulin secretion and non-insulin dependent hypoglycemic effect mainly triggered by activation of the cholinergic nerve.
1. 行政院衛生署國民健康局. 台灣地區高血壓、高血糖、高血脂盛行率調查期末報告. 2003;
2. American Diabetes Association. Standards of Medical Care in Diabetes—2011. Diabetes Care 2011; 34, supplement 1:S11-S61.
3. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2010; 33, supplement 1:S62-69.
4. Creager MA, Luscher TF, Cosentino F and Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation 2003; 108:1527-1532.
5. King H, Aubert RE and Herman WH. Global burden of diabetes, 1995-2025: Prevalence, numerical estimates, and projections. Diabetes Care 1998; 21:1414-1431.
6. 行政院衛生署國民健康局. 2007年台灣地區高血壓、高血糖、高血脂之追蹤調查研究. http://wwwbhpdohgovtw/health91/pdf/3H/07pdf 2007
7. 朱真一. 台灣各族群糖尿病之高盛行率. 台灣醫界 2004; 47:526-528.
8. Parker VE, Savage DB, O'Rahilly S and Semple RK. Mechanistic insights into insulin resistance in the genetic era. Diabetic Med 2011; 28:1476-1486.
9. Adeghate E, Schattner P and Dunn E. An update on the etiology and epidemiology of diabetes mellitus. Ann NY Acad Sci 2006; 1084:1-29.
10. Inoue M, Inoue K and Akimoto K. Effects of age and sex in the diagnosis of type 2 diabetes using glycated haemoglobin in Japan: the yuport medical checkup centre study. PLoS ONE 2012; 7:e40375.
11. Pani LN, Korenda L, Meigs JB, Driver C, Chamany S, Fox CS, et al. Effect of aging on A1C levels in individuals without diabetes: evidence from the Framingham Offspring Study and the National Health and Nutrition Examination Survey 2001-2004. Diabetes Care 2008; 31:1991-1996.
12. Mohan V, Mathur P, Deepa R, Deepa M, Shukla DK, Menon GR, et al. Urban rural differences in prevalence of self-reported diabetes in India--the WHO-ICMR Indian NCD risk factor surveillance. Diabetes Res Clin Pract 2008; 80:159-168.
13. Jeong SC, Jeong YT, Yang BK, Islam R, Koyyalamudi SR, Pang G, et al. White button mushroom (Agaricus bisporus) lowers blood glucose and cholesterol levels in diabetic and hypercholesterolemic rats. Nutr Res 2010; 30:49-56.
14. Hussain A, Rahim MA, Azad Khan AK, Ali SM and Vaaler S. Type 2 diabetes in rural and urban population: diverse prevalence and associated risk factors in Bangladesh. Diabetic Med 2005; 22:931-936.
15. Hara H, Egusa G and Yamakido M. Incidence of non-insulin-dependent diabetes mellitus and its risk factors in Japanese-Americans living in Hawaii and Los Angeles. Diabetic Med 1996; 13(9 Suppl 6):S133-S142.
16. Penn L, White M, Oldroyd J, Walker M, Alberti KG and Mathers JC. Prevention of type 2 diabetes in adults with impaired glucose tolerance: the European Diabetes Prevention RCT in Newcastle upon Tyne, UK. BMC Public Health 2009; 9:342.
17. Sieverdes JC, Sui X, Lee DC, Church TS, McClain A, Hand GA, et al. Physical activity, cardiorespiratory fitness and the incidence of type 2 diabetes in a prospective study of men. Brit J Sports Med 2010; 44:238-244.
18. Balkau B, Mhamdi L, Oppert JM, Nolan J, Golay A, Porcellati F, et al. Physical activity and insulin sensitivity: the RISC study. Diabetes 2008; 57:2613-2618.
19. Lambernd S, Taube A, Schober A, Platzbecker B, Gorgens SW, Schlich R, et al. Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways. Diabetologia 2012; 55:1128-1139.
20. Runge CF. Economic consequences of the obese. Diabetes 2007; 56:2668-2672.
21. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393-403.
22. Heraclides AM, Chandola T, Witte DR and Brunner EJ. Work stress, obesity and the risk of type 2 diabetes: gender-specific bidirectional effect in the Whitehall II study. Obesity 2012; 20:428-433.
23. Cosgrove MP, Sargeant LA, Caleyachetty R and Griffin SJ. Work-related stress and Type 2 diabetes: systematic review and meta-analysis. Occup Med 2012; 62:167-173.
24. Amed S, Dean HJ, Panagiotopoulos C, Sellers EA, Hadjiyannakis S, Laubscher TA, et al. Type 2 diabetes, medication-induced diabetes, and monogenic diabetes in Canadian children: a prospective national surveillance study. Diabetes Care 2010; 33:786-791.
25. Ho J and Pacaud D. Secondary diabetes in children. Can J Diabetes 2004; 28:400-405.
26. Maes BD, Kuypers D, Messiaen T, Evenepoel P, Mathieu C, Coosemans W, et al. Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors. Transplantation 2001; 72:1655-1661.
27. Van Belle T, Coppieters KT and Von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 2011; 91:79-118.
28. Rees DA and Alcolado JC. Animal models of diabetes mellitus. Diabetic Med 2005; 22:359-370.
29. Braganza JM, Lee SH, McCloy RF and McMahon MJ. Chronic pancreatitis. Lancet 2011; 377:1184-1197.
30. Cui Y and Andersen DK. Pancreatogenic diabetes: special considerations for management. Pancreatology 2011; 11:279-294.
31. 林世崇. 糖尿病治療的新策略. 台灣醫界 2010; 53:16-23.
32. Nathan DM, Buse JB, Davinson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 2009; 32:193-203.
33. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28:103-117.
34. Holman RR, Paul SK, Bethel MA, Matthews DR and Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577-1589.
35. Kansagara D, Fu R, Freeman M, Wolf F and Helfand M. Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med 2011; 154:268-282.
36. Chen L. A literature review of intensive insulin therapy and mortality in critically ill patients. Clin Nurse Specialist 2010; 24:80-86.
37. The NICE-SUGAR Study Investigators. Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med 2009; 360:1283-1297.
38. Mayfield JA and White RD. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. Am Fam Physician 2004 70:
39. 劉松臻, 王朝弘 and 簡銘男. 長效型胰島素類似物在第2型糖尿病人的應用. 內科學誌 2010; 21:109-116.
40. Krentz AJ and Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 2005; 65:385-411.
41. Combettes MM. GLP-1 and type 2 diabetes: physiology and new clinical advances Curr Opin Pharmacol 2006; 6:598-605.
42. Wang Q. The present situation of TCM treatment for diabetes and its researches. J Tradit Chin Med 2003; 23:67-73.
43. Yin J, Zhang H and Ye J. Traditional Chinese Medicine in Treatment of Metabolic Syndrome. Endocr Metab Immune Disord Drug Targets 2008; 8:99-111.
44. Kimura M, Waki I, Chujo T, Kikuchi T, Hiyama C, Yamazaki K, et al. Effects of hypoglycemic components in ginseng radix on blood insulin level in alloxan diabetic mice and on insulin release from perfused rat pancreas. J Pharmacobiodyn 1981; 4:410-417.
45. Lee WK, Kao ST, Liu IM and Cheng JT. Increase of insulin secretion by ginsenoside Rh2 to lower plasma glucose in Wistar rats. Clin Exp Pharmacol Physiol 2006; 33:27-32.
46. Xie JT, Mchendale S and Yuan CS. Ginseng and diabetes. Am J Chin Med 2005; 33:397-404.
47. Arun N and Nalini N. Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats. Plant Foods Hum Nutr 2002; 51:41-45.
48. Srinivasan K. Plant foods in the management of diabetes mellitus: Spices as beneficial antidiabetic food adjuncts. Int J Food Sci Nutr 2005; 56:399-414.
49. Yin J, Xing H and Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 2008; 57:712-717.
50. Pan GY, Wang GJ, Sun JG, Huang ZJ, Zhao XC, Gu Y, et al. Inhibitory action of berberine on glucose absorption. Yao Hsueh Hsueh Pao - Acta Pharmaceutica Sinica 2003 38:911-914.
51. Liang F and Koya D. Acupuncture: is it effective for treatment of insulin resistance? Diabetes Obes Metab 2010; 12:555-569.
52. Wu W and Li C. Diabetes mellitus treated by massage. J Tradi Chin Med 1998; 18:64-65.
53. Chang SL, Lin JG, Chi TC, Liu IM and Cheng JT. An insulin-dependent hypoglycaemia induced by electroacupuncture at the Zhongwan (CV12) acupoint in diabetic rats. Diabetologia 1999; 42:250-255.
54. Lin JG, Chang SL and Cheng JT. Release of beta-endorphin from adrenal gland to lower plasma glucose by the electroacupuncture at Zhongwan acupoint in rats. Neurosci Lett 2002; 326:17-20.
55. Chang SL, Tsai CC, Lin JG, Hsieh CL, Lin RT and Cheng JT. Involvement of serotonin in the hypoglycemic response to 2 Hz electroacupuncture of Zusanli acupoint (ST36) in rats. Neurosci Lett 2005; 379:69-73.
56. Chang SL, Lin KJ, Lin RT, Hung PH, Lin JG and Cheng JT. Enhanced insulin sensitivity using electroacupuncture on bilateral Zusanli acupoints (ST 36) in rats. Life Sci 2006; 79:967-971.
57. Lee YC, Li TM, Tzeng CY, Chen YI, Ho WJ, Lin JG, et al. Electroacupuncture at the Zusanli (ST-36) Acupoint Induces a Hypoglycemic Effect by Stimulating the Cholinergic Nerve in A Rat Model of Streptozotocine-induced Insulin-dependent Diabetes Mellitus. Evid-based Complement Altern Med 2010; 7:169-176.
58. Lin RT, Tzeng CY, Lee YC, Ho WJ, Cheng JT, Lin JG, et al. Acute effect of electroacupuncture at the Zusanli acupoints on decreasing insulin resistance as shown by lowering plasma free fatty acid levels in steroid-background male rats. BMC Complement Altern Med 2009; 9:26.
59. Ilhan A, Rasul S, Dimitrov A, Handisurya A, Gartner W, Baumgartner-Parzer S, et al. Plasma neuropeptide Y levels differ in distinct diabetic conditions. Neuropeptides 2010; 44:485-489.
60. Lee JD, Jang MH, Kim EH and Kim CJ. Acupuncture decreases neuropeptide Y expression in the hypothalamus of rats with Streptozotocin-induced diabetes. Acupunct Electrother Res 2004; 29:73-82.
61. Zhao M, Liu Z, Su J and The time-effect relationship of central action in acupuncture treatment for weight reduction. J Tradit Chin Med 2000; 20:26-29.
62. Zeng Z and Li Y. Effects of electroacupuncture at weiwanxiashu and zusanli points on blood glucose and plasma pancreatic glucagon contents in diabetic rabbits. J Tradit Chin Med 2002; 22:134-136.
63. Reinhart KM, Talati R, White CM and Coleman CI. The impact of garlic on lipid parameters: a systematic review and meta-analysis. Nutr Res Rev 2009; 22:39-48.
64. Ried K, Frank OR, Stocks NP, Fakler P and Sullivan T. Effect of garlic on blood pressure: a systematic review and meta-analysis. BMC Cardiovasc Disord 2008; 8:13.
65. Ajabnoor MA. Effect of aloes on blood glucose levels in normal and alloxan diabetic mice. J Ethnopharmacol 1990; 28:215-220.
66. Birdee GS and Yeh G. Complementary and Alternative Medicine Therapies for Diabetes: A Clinical Review. Clin Diabetes 2010; 28:147-155.
67. Shibib BA, Khan LA and Rahman R. Hypoglycaemic activity of Coccinia indica and Momordica charantia in diabetic rats: depression of the hepatic gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase and elevation of both liver and red-cell shunt enzyme glucose-6-phosphate dehydrogenase. Biochem J 1993; 292:267-270.
68. Ng TB, Wong CM, Li WW and Yeung HW. Insulin-like molecules in Momordica charantia seeds. J Ethnopharmacol 1986; 15:107-117.
69. Aljasir B, Bryson M and Al-shehri B. Yoga Practice for the Management of Type II Diabetes Mellitus in Adults: A systematic Review. Evid Based Complement Altern Med 2010; 7:399-408.
70. Innes KE and Vincent HK. The Influence of Yoga-Based Programs on Risk Profiles in Adults with Type 2 Diabetes Mellitus: A Systematic Review. Evid Based Complement Altern Med 2007; 4:469-486.
71. Yang K, Bernardo LM, Sereika SM, Conroy MB, Balk J and Burke LE. Utilization of 3-Month Yoga Program for Adults at High Risk for Type 2 Diabetes: A Pilot Study. Evid Based Complement Altern Med 2011; Article ID 257891,doi:10.1093/ecam/nep117:
72. Tsujiuchi T, Kumano H, Yoshiuchi K, He D, Tsujiuchi Y, Kuboki T, et al. The effect of Qi-gong relaxation exercise on the control of type 2 diabetes mellitus: a randomized controlled trial. Diabetes Care 2002; 25:241-242.
73. Song R, Ahn S, Roberts BL, Lee EO and Ahn YH. Adhering to a t'ai chi program to improve glucose control and quality of life for individuals with type 2 diabetes. J Altern Complement Med 2009; 15:627-632.
74. Lam P, Dennis SM, Diamond TH and Zwar N. Improving glycaemic and BP control in type 2 diabetes. The effectiveness of tai chi. Aust Fam Physician 2008; 37:884-887.
75. Yeh SH, Chuang H, Lin LW, Hsiao CY, Wang PW and Yang KD. Tai chi chuan exercise decreases A1C levels along with increase of regulatory T-cells and decrease of cytotoxic T-cell population in type 2 diabetic patients. Diabetes Care 2007; 30:716-718.
76. Zhang Y and Fu FH. Effects of 14-week Tai Ji Quan exercise on metabolic control in women with type 2 diabetes. Am J Chin Med 2008; 36:647-654.
77. Chaiopanont S. Hypoglycemic effect of sitting breathing meditation exercise on type 2 diabetes at Wat Khae Nok Primary Health Center in Nonthaburi province. J Med Assoc Thailand 2008; 91:93-98.
78. Hsu CH, Liao YL, Lin SC, Hwang KC and Chou P. The mushroom agaricus blazei murill in combination with metformin and gliclazide improves insulin resistance in type 2 diabetes: a randomized, double-blinded, and placebo-controlled clinical trial. J Altern Complement Med 2007; 13:97-102.
79. Gray AM and Flatt PR. Insulin-releasing and insulin-like activity of Agaricus campestris (mushroom). J Endocrinol 1998; 157:259-266.
80. Takeujchi H, He P and Mooi LY. Reductive effect of hot-water extracts from woody ear (Auricularia auricula-judae Quel.) on food intake and blood glucose concentration in genetically diabetic KK-Ay mice. J Nutr Sci Vitaminol 2004; 50:300-304.
81. Lo HC, Hsu TH, Tu ST and Lin KC. Anti-hyperglycemic Activity of Natural and Fermented Cordyceps sinensis in Rats with Diabetes Induced by Nicotinamide and Streptozotocin. Am J Chin Med 2006; 34:819-832.
82. Zhao CS, Yin WT, Wang JY, Zhang Y, Yu H, Cooper R, et al. CordyMax Cs-4 improves glucose metabolism and increases insulin sensitivity in normal rats. J Altern Complement Med 2002; 8:309-314.
83. Kiho T, Ookubo K, Usui S, Ukai S and Hirano K. Structural features and hypoglycemic activity of a polysaccharide (CS-F10) from the cultured mycelium of Cordyceps sinensis. Biol Pharm Bull 1999; 22:966-970.
84. Zhang HN and Lin ZB. Hypoglycemic effect of Ganoderma lucidum polysaccharides. Acta Pharmacol Sin 2004; 25:191-195.
85. Li F, Zhang Y and Zhong Z. Antihyperglycemic effect of Ganoderma lucidum polysaccharides on streptozotocin-induced diabetic mice. Int J Mol Sci 2011; 12:6135-6145.
86. Lo HC, Hsu TH and Chen CY. Submerged culture mycelium and broth of Grifola frondosa improve glycemic responses in diabetic rats. Am J Chin Med 2008; 36:265-285.
87. Matsuur H, Asakawa C, Kurimoto M and Mizutani J. Alpha-glucosidase inhibitor from the seeds of balsam pear (Momordica charantia) and the fruit bodies of Grifola frondosa. Biosci Biotechnol Biochem 2002; 66:1576-1578.
88. Yang BK, Kim DH, Jeong SC, Das S, Choi YS, Shin JS, et al. Hypoglycemic effect of a Lentinus edodes exo-polymer produced from a submerged mycelial culture. Biosci Biotechnol Biochem 2002; 66:937-942.
89. Hwang HJ, Kim SW, Lim JM, Joo JH, Kim HO, Kim HM, et al. Hypoglycemic effect of crude exopolysaccharides produced by a medicinal mushroom Phellinus baumii in streptozotocin-induced diabetic rats. Life Sci 2005; 76:3069-3080.
90. Cho EJ, Hwang HJ, Kim SW, Oh JY, Baek YM, Choi JW, et al. Hypoglycemic effects of exopolysaccharides produced by mycelial cultures of two different mushrooms Tremella fuciformis and Phellinus baumii in ob/ob mice. Appl Microbiol Biotechnol 2007; 75:1257-1265.
91. Kim HM, Kang JS, Kim JY, Park SK, Kim HS, Lee YJ, et al. Evaluation of antidiabetic activity of polysaccharide isolated from Phellinus linteus in non-obese diabetic mouse. Int Immunopharmacol 2010; 10:72-78.
92. Hu SH, Wang JC, Lien JL, Liaw ET and Lee MY. Antihyperglycemic effect of polysaccharide from fermented broth of Pleurotus citrinopileatus. Appl Microbiol Biotechnol 2006; 70:107-113.
93. Khatun K, Mahtab H, Khanam P, A., Sayeed MA and Khan KA. Oyster mushroom reduced blood glucose and cholesterol in diabetic subjects. Mymensingh Med J 2007; 16:94-99.
94. Li TH, Hou CC, Chang CL and Yang WC. Anti-hyperglycemic properties of crude extract and triterpenes from Poria cocos. Evid-Based Complement Altern Med 2011;
95. Kiho T, Kochi M, Usui S, Hirano K, Aizawa K and Inakuma T. Antidiabetic effect of an acidic polysaccharide (TAP) from Tremella aurantia and its degradation product (TAP-H). Biol Pharm Bull 2001; 24:1400-1403.
96. Briscoe VJ and Davis SN. Hypoglycemia in Type 1 and Type 2 Diabetes: Physiology, Pathophysiology, and Management. Clin Diabetes 2006; 24:115-121.
97. United Kingdom Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998; 352:837-852.
98. Zammitt NN and Frier BM. Hypoglycemia in Type 2 Diabetes. Pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care 2005; 28:2948-2961.
99. Glaser N and Kuppermann N. The Evaluation and Management of Children With Diabetic Ketoacidosis in the Emergency Department. Pediatr Emerg Care 2004; 20:477-481.
100. Dunger DBS, M.A., Acerini CL, Bohn DJ, Daneman D, Danne TPA, Glaser NS, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child 2004; 89:188-194.
101. Wolfsdorf J, Glaser N and Sperling MA. Diabetic ketoacidosis in infants, children, and adolescents: a consensus statement from the American Diabetes Association. Diabetes Care 2006; 29:1150-2259.
102. Kitabchi AE, Umpierrez GE, Miles JM and Fisher JN. Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes Care 2009; 32:1335-1343.
103. De Beer K, Michael S, Thacker M, Wynne E, Pattni C, Gomm M, et al. Diabetic ketoacidosis and hyperglycaemic hyperosmolar syndrome - clinical guidelines. Nurs Crit Care 2008; 13:5-11.
104. Cochran JB, Walters S and Losek JD. Pediatric hyperglycemic hyperosmolar syndrome: diagnostic difficulties and high mortality rate. Am J Emerg Med 2006; 24:297-301.
105. Venkatraman R and Singhi SC. Hyperglycemic hyperosmolar nonketotic syndrome. Indian J Pediatr 2006; 73:55-60.
106. Brenner ZR. Management of Hyperglycemic Emergencies. AACN clinic issue 2006; 17:56-65.
107. Scott A. Hyperosmolar hyperglycaemic syndrome. Diabetic Med 2006; 23:1-25.
108. Haratz S and Tanne D. Diabetes, hyperglycemia and the management of cerebrovascular disease. Curr Opin Neurol 2011; 24:81-88.
109. Morel O, Kessler L, Ohlmann P and Bareiss P. Diabetes and the platelet: toward new therapeutic paradigms for diabetic atherothrombosis. Atherosclerosis 2010; 212:367-376.
110. Bejot Y and Giroud M. Stroke in diabetic patients. Diabetes Metab 2010; 36:S84-S87.
111. Kaarisalo MM, Raiha I, Sivenius J, Immonen-Raiha P, Lehtonen A, Sarti C, et al. Diabetes worsens the outcome of acute ischemic stroke. Diabetes Res Clin Pract 2005; 69:293-298.
112. Selvin E, Coresh J, Shahar E, Zhang L, Steffes M and Sharrett A. Glycaemia (haemoglobin A1c) and incident ischaemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Lancet Neurol 2005; 4:821-826.
113. Guerrero-Romero F and Rodriguez-Moran M. Proteinuria is an independent risk factor for ischemic stroke in non-insulin-dependent diabetes mellitus. Stroke 1999; 30:1787-1791.
114. Steg PG, Goldberg RJ, Gore JM, Fox KA, Eagle KA, Flather MD, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 2002; 90:358-363.
115. Libby P, Nathan DM, Abraham K, Brunzell JD, Fradkin JE, Haffner SM, et al. Report of the National Heart, Lung, and Blood Institute–National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation 2005; 111:3489-3493.
116. De Caterina R, Madonna R, Sourij H and Wascher T. Glycaemic control in acute coronary syndromes: prognostic value and therapeutic options. Eur Heart J 2010; 31:1557-1564.
117. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo LA, et al. The 7th report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure. JAMA 2003; 289:2560-2572.
118. Aronson D and Edelman ER. Revascularization for coronary artery disease in diabetes mellitus: angioplasty, stents and coronary artery bypass grafting. Rev Endocr Metab Disord 2010; 11:75-86.
119. Cassar A, Poldermans D, Rihal CS and Gersh BJ. The management of combined coronary artery disease and peripheral vascular disease. Eur Heart J 2010 31:1565-1572.
120. Creager MA. Medical management of peripheral arterial disease. Cardiol Rev 2001; 9:238-245.
121. Petersen KF and Shulman GI. Etiology of insulin resistance. Am J Med 2006; 119:10S-16S.
122. Zhang X, Saaddine JB, Chou CF, Cotch MF, Cheng YJ, Geiss LS, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA 2010; 304:649-656.
123. Melendez-Ramirez LY, Richards RJ and Cefalu WT. Complications of type 1 diabetes. Endocrinol Metab Clin North Am 2010; 39:625-640.
124. Cheung N, Mitchell P and Wong TY. Diabetic retinopathy. Lancet 2010; 376:124-136.
125. Bogdanović R. Diabetic nephropathy in children and adolescents. Pediatr Nephrol 2008; 23:507-525.
126. Garg JP and Bakris GL. Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. Vasc Med 2002; 7:35-43.
127. de Zeeuw D, Parving H and Henning RH. Microalbuminuria as an Early Marker for Cardiovascular Disease. J Am Soc Nephrol 2006; 17:2100-2105.
128. Ruggenenti P and Remuzzi G. Time to abandon microalbuminuria? Kidney Int 2006; 70:1214-1222.
129. Giunti S, Barit D and Cooper ME. Mechanisms of Diabetic Nephropathy Role of Hypertension. Hypertension 2006; 48:519-526.
130. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010; 33:2285-2293.
131. Barrett AM, Lucero MA, Le T, Robinson RL, Dworkin RH and Chappell AS. Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: a review. Pain Med 2007; 8 Suppl 2:S50-62.
132. Lindsay TJ, Rodgers BC, Savath V and Hettinger K. Treating diabetic peripheral neuropathic pain. Am Fam Physician 2010; 82:151-158.
133. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care 2010; 33:434-441.
134. Beaumont H and Boeckxstaens G. Recent developments in esophageal motor disorders. Curr Opin Gastroenterol 2007; 23:416-421.
135. Tang DM and Friedenberg FK. Gastroparesis: approach, diagnostic evaluation, and management. Disease-A-Month 2011; 57:74-101.
136. Brown JS, Wessells H, Chancellor MB, Howards SS, Stamm WE, Stapleton AE, et al. Urologic complications of diabetes. Diabetes Care 2005; 28:177-185.
137. Vickers MA and Wright EA. Erectile dysfunction in the patient with diabetes mellitus. Am J Manag Care 2004; 10, Suppl 1:S3-11.
138. Czyzyk A and Szczepanik Z. Diabetes mellitus and cancer. Eur J Int Med 2000; 11:245-252.
139. Noto H, Osame K, Sasazuki T and Noda M. Substantially increased risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis of epidemiologic evidence in Japan. J Diabetes Complicat 2010; 24:345-353.
140. Vigneri P, Frasca F, Sciacca L, Pandini G and Vigneri R. Diabetes and cancer. Endocr-relat Cancer 2009; 16:1103-1123.
141. Giouleme O, Diamantidis MD and Katsaros MG. Is diabetes a causal agent for colorectal cancer? Pathophysiological and molecular mechanisms. World J Gastroenterol 2011; 17:444-448.
142. El-Serag HB, Hampel H and Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol H 2006; 4:369-380.
143. El-Serag HB, Tran T and Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126:460-468.
144. Lai MS, Hsieh MS, Chiu YH and Chen THH. Type 2 Diabetes and Hepatocellular Carcinoma: A Cohort Study in High Prevalence Area of Hepatitis Virus Infection. Hepatology 2006; 43:1295-1302.
145. Everhart J and Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 1995; 273:1605-1609.
146. Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F and Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Brit J Cancer 2005; 92:2076-2083.
147. Pannala R, Basu A, Petersen GM and Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol 2009; 10:88-95.
148. Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M and Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005; 129:504-511.
149. Larsson SC and Wolk A. Diabetes mellitus and incidence of kidney cancer: a meta-analysis of cohort studies. Diabetologia 2011; 54:1013-1018.
150. Larsson SC, Orsini N, Brismar K and Wolk A. Diabetes mellitus and risk of bladder cancer: a meta-analysis. Diabetologia 2006; 49:2819-2823.
151. Tseng CH. Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. Diabetologia 2011; 54:2009-2015.
152. Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CPJ, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011; 34:916-922.
153. Piccinni C, Motola D, Marchesini G and Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care 2011; 34:1369-1371.
154. Tseng CH. Pioglitazone and bladder cancer: a population-based study of Taiwanese. Diabetes Care 2012; 35:278-280.
155. Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care 2003; 26:1752-1758.
156. Wolf I, Sadetzki S, Catane R, Karasik A and Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol 2005; 6:103-111.
157. Friberg E, Mantzoros CS and Wolk A. Diabetes and risk of endometrial cancer: a population-based prospective cohort study. Cancer Epidemiol Biomarkers Prev 2007; 16:276-280.
158. Friberg E, Orsini N, Mantzoros CS and Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007; 50:1365-1374.
159. Folsom AR, Anderson KE, Sweeney C and Jacobs DRJ. Diabetes as a risk factor for death following endometrial cancer. Gynecol Oncol 2004; 94:740-745.
160. He J, Stram DO, Kolonel LN, Henderson BE, Le Marchand L and Haiman CA. The association of diabetes with colorectal cancer risk: the Multiethnic Cohort. Br J Cancer 2010; 103:120-126.
161. Jin T. Why diabetes patients are more prone to the development of colon cancer? Med Hypotheses 2008; 71:241-244.
162. Shrestha B, Zhang WM, Zhang YJ and Liu XZ. The medicinal fungus Cordyceps militaris: research and development. Mycol Progress 2012; 11:599-614.
163. Paterson RR. Cordyceps: a traditional Chinese medicine and another fungal therapeutic biofactory? Phytochemistry 2008; 69:1469-1495.
164. Zhang YJ, Li E, Wang CS, Li YL and Liu XZ. Ophiocordyceps sinensis, the flagship fungus of China: terminology, life strategy and ecology. Mycology 2012; 3:2-10.
165. Wang L, Zhang WM, Hu B, Chen YQ and Qu LH. Genetic variation of Cordyceps militaris and its allies based on phylogenetic analysis of rDNA ITS sequence data. Fungal Divers 2008; 31:147-155.
166. Das SK, Masuda M, Sakurai A and Sakakibara M. Medicinal uses of the mushroom Cordyceps militaris: Current state and prospects. Fitoterapia 2010; 81:961-968.
167. Yu R, Song L, Zhao Y, Bin W, Wang L, Zhang H, et al. Isolation and biological properties of polysaccharide CPS-1 from cultured Cordyceps militaris. Fitoterapia 2004; 75:465-472.
168. Ng TB and Wang HX. Pharmacological actions of Cordyceps, a prized folk medicine. J Pharm Pharmacol 2005; 57:1509-1519.
169. Li SP, Li P, Lai CM, Gong YX, Kan KK, Dong TTX, et al. Simultaneous determination of ergosterol, nucleosides and their bases from natural and cultured Cordyceps by pressurized liquid extraction and highperformance liquid chromatography. J Chromatogr 2004; 1036:239-243.
170. Yu R, Ye B, Yan C, Song L, Zhang Z, Yang W, et al. Fingerprint analysis of fruiting bodies of cultured Cordyceps militaris by high-performance liquid chromatography-photodiode array detection. J Pharm Biomed Anal 2007; 44:818-823.
171. Zhou X, Gong Z, Su Y, Lin J and Tang K. Cordyceps fungi: natural products, pharmacological functions and developmental products. J Pharm Pharmacol 2009; 61:279-291.
172. Zheng P, Xia Y, Xiao G, Xiong C, Hu X, Zhang S, et al. Genome sequence of the insect pathogenic fungus Cordyceps militaris, a valued traditional Chinese medicine. Genome Biol 2011; 12:R116.
173. Chen RY and Ichida M. Infection of the silkworm, Bombyx mori, with Cordyceps militaris. J Insect Biotechnol Sericol 2002; 71:61-63.
174. Hong IP, Kang PD, Kim KY, Nam SH, Lee MY, Choi YS, et al. Fruit body formation on silkworm by Cordyceps militaris. Mycobiology 2010; 38:128-132.
175. Lin QY, Song B and Li TH. Advances in the studies on Cordyceps militaris. Microbiol China 2006; 33:154-157.
176. 任士升. 人工培育蛹蟲草優質高產的技術環節. 中國食用菌 1998; 17:22-23.
177. Jung EC, Kim KD, Bae CH, Kim JC, Kim DK and Kim HH. A mushroom lectin from ascomycete Cordyceps militaris. Biochim Biophys Acta 2007; 1770:833-838.
178. Jung K, Kim IH and Han D. Effect of medicinal plant extracts on forced swimming capacity in mice. J Ethnopharmacol 2004; 93:75-81.
179. Won SY and Park EH. Anti-inflammatory and related pharmacological activities of cultured mycelia and fruiting bodies of Cordyceps militaris. J Ethnopharmacol 2005; 96:555-561.
180. Kim HG, Shrestha B, Lim SY, Yoon DH, Chang WC, Shin DJ, et al. Cordycepin inhibits lipopolysaccharide-induced inflammation by the suppression of NF-kappaB through Akt and p38 inhibition in RAW 264.7 macrophage cells. Eur J Pharmacol 2006; 545:192-199.
181. Yu HM, Wang BS, Huang SC and Duh PD. Comparison of protective effects between cultured Cordyceps militaris and natural Cordyceps sinensis against oxidative damage. J Agric Food Chem 2006; 54:3132-3138.
182. Li XT, Li HC, Li CB, Dou DQ and Gao MB. Protective effects on mitochondria and anti-aging activity of polysaccharides from cultivated fruiting bodies of Cordyceps militaris. Am J Chin Med 2010; 38:1093-1106.
183. Cheng Z, He W, Zhou X, Lv Q, Xu X, Yang S, et al. Cordycepin protects against cerebral ischemia/reperfusion injury in vivo and in vitro. Eur J Pharmacol 2011; 664:20-22.
184. Yan H, Zhu D, Xu D, Wu J and Bian X. A study on Cordyceps militaris polysaccharide purification, composition and activity analysis. Afr J Biotechnol 2008; 7:4004-4009.
185. Cho HJ, Cho JY, Rhee MH, Lim CR and Park HJ. Cordycepin (3'-deoxyadenosine) inhibits human platelet aggregation induced by U46619, a TXA2 analogue. J Pharm Pharmacol 2006; 58:1677-1682.
186. Lee JS, Kwon JS, Won DP, Lee JH, Lee KE, Lee SY, et al. Study of macrophage activation and structural characteristics of purified polysaccharide from the fruiting body of Cordyceps militaris. J Microbiol Biotechnol 2010; 20:1053-1060.
187. Shin S, Park Y, Kim S, Oh HE, Ko YW, Han S, et al. Cordyceps militaris Enhances MHC-restricted Antigen Presentation via the Induced Expression of MHC Molecules and Production of Cytokines. Immune Netw 2010; 10:135-143.
188. Lee H, Kim YJ, Kim HW, Lee DH, Sung MK and Park T. Induction of apoptosis by Cordyceps militaris through activation of caspase-3 in leukemia HL-60 cells. Biol Pharm Bull 2006; 29:670-674.
189. Park SE, Yoo HS, Jin CY, Hong SH, Lee YW, Kim BW, et al. Induction of apoptosis and inhibition of telomerase activity in human lung carcinoma cells by the water extract of Cordyceps militaris. Food Chem Toxicol 2009; 47:1667-1675.
190. Yoo HS, Yoon J, Lee GH, Lee YW and Cho CK. Best case series program supportive cases of Cordyceps militaris- and Panax notoginseng-based anticancer herbal formula. Integ Cancer Ther 2011; 10:NP1-3.
191. Lin WH, Tsai MT, Chen YS, Hou RC, Hung HF, Li CH, et al. Improvement of sperm production in subfertile boars by Cordyceps militaris supplement. Am J Chin Med 2007; 35:631-641.
192. Chang Y, Jeng KC, Huang KF, Lee YC, Hou CW, Chen KH, et al. Effect of Cordyceps militaris supplementation on sperm production, sperm motility and hormones in Sprague-Dawley rats. Am J Chin Med 2008; 36:849-859.
193. Oh JY, Choi WS, Lee CH and Park HJ. The ethyl acetate extract of Cordyceps militaris inhibits IgE-mediated allergic responses in mast cells and passive cutaneous anaphylaxis reaction in mice. J Ethnopharmacol 2011 135:422-429.
194. Park DK, Choi WS and Park HJ. Antiallergic Activity of Novel Isoflavone Methyl-glycosides from Cordyceps militaris Grown on Germinated Soybeans in Antigen-Stimulated Mast Cells. J Agric Food Chem 2012; 60:2309-2315.
195. Shimada T, Hiramatsu N, Kasai A, Mukai M, Okamura M, Yao J, et al. Suppression of adipocyte differentiation by Cordyceps militaris through activation of the aryl hydrocarbon receptor. Am J Physiol Endocrinol Metab 2008; 295:E859-867.
196. Zhang G, Huang Y, Bian Y, Wong JH, Ng TB and Wang H. Hypoglycemic activity of the fungi Cordyceps militaris, Cordyceps sinensis, Tricholoma mongolicum, and Omphalia lapidescens in streptozotocin-induced diabetic rats. Appl Microbiol Biotechnol 2006; 72:1152-1156.
197. Choi SB, Park CH, Choi MK, Jun DW and Park S. Improvement of insulin resistance and insulin secretion by water extracts of Cordyceps militaris, Phellinus linteus, and Paecilomyces tenuipes in 90% pancreatectomized rats. Biosci Biotechnol Biochem 2004; 68:257-264.
198. Yun Y, Han S, Lee S, Ko S, Lee C, Ha N, et al. Anti-diabetic effects of CCCA, cmESS, and cordycepin from Cordyceps militaris and the immune responses in streptozotocin-induced diabetic mice. Nat Prod Sci 2003; 9:291-298.
199. Argentino DP, Dominici FP, Munoz MC, Al-Regaiey K, Bartke A and Turyn D. Effects of long-term caloric restriction on glucose homeostasis and on the first steps of the insulin signaling system in skeletal muscle of normal and Ames dwarf (Prop1df/Prop1df) mice. Exp Gerontol 2005; 40:27-35.
200. Ferguson SF and Blakely RD. The choline transporter resurfaces: new roles for synaptic vesicles? Mol Interv 2004; 4:22-37.
201. Guo JY, Han CC and Liu YM. A contemporary treatment approach to both diabetes and depression by Cordyceps sinensis, rich in vanadium. Evid Based Complement Alternat Med 2010; 7:387-389.
202. Balon TW, Jasman AP and Zhu JS. A fermentation product of Cordyceps sinensis increases whole-body insulin sensitivity in rats. J Altern Complement Med 2002; 8:315-323.