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系統識別號 U0026-2907201117484900
論文名稱(中文) 尿囊素在第二型糖尿病的降血糖作用之研究
論文名稱(英文) Antihyperglycemic action of allantoin in type 2 diabetes
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 99
學期 2
出版年 100
研究生(中文) 郭玉華
研究生(英文) Yu-Hua Kuo
學號 S26984058
學位類別 碩士
語文別 中文
論文頁數 74頁
口試委員 指導教授-洪正路
口試委員-鄭瑞棠
口試委員-簡伯武
中文關鍵字 咪唑啉  咪唑啉受體  胰島素阻抗 
英文關鍵字 imidazoline  imidazoline receptor  insulin resistance 
學科別分類
中文摘要 糖尿病(diabetes)主要的病徵為高血糖(hyperglycemia),而高血糖會提高相關心血管疾病的罹病機率與致死率,因此,血糖的適當調控對糖尿病而言是重要的。尿囊素(allantoin)為咪唑啉(imidazoline)的結構類似物,過去研究指出,咪唑啉可透過活化第二亞型之咪唑啉受體(I2R)促使β-腦內啡(β-endorphin)釋放量增加,並藉由活化嗎啡μ型受體(opioid-μ receptor)來達到降血糖作用;也可藉由活化I3R而使對ATP敏感之鉀離子(KATP)通道關閉,導致鈣離子(Ca2+)流入,並促使胰島素釋放。因此,本研究即想探討尿囊素是否經由活化咪唑啉受體而具有降血糖之作用。結果顯示,尿囊素可使第二型糖尿病鼠的血糖下降,並增加血中β-腦內啡之含量,但降血糖作用在預先處理I2R拮抗劑(BU224)、嗎啡μ型拮抗劑(cyprodime與naloxonazine),與在腎上腺摘除之第二型糖尿病鼠中,只有部份被抑制,而β-腦內啡之釋放量則無明顯上升;利用對第一型糖尿病鼠預先處理amiloride觀察確認,尿囊素是活化I2AR此次亞型受體;另外,在動物與胰臟β細胞中皆可觀察到尿囊素的促鈣離子流入與促胰島素分泌之作用,且此作用可被I3R拮抗劑(KU14R)部份抑制。從以上結果可得知尿囊素可藉由非胰島素依賴與胰島素依賴兩條路徑而達到降血糖作用,且從飯後血糖測試、給予I2R作用劑2-BFI與預先處理BU224與否觀察HOMA-IR(homeostasis model assessment for insulin resistance)的變化,以及tolbutamide測試的結果可得知,尿囊素確實可以改善胰島素阻抗,且從這些尿囊素所產生的作用,或許可為糖尿病用藥或預防帶來一束曙光。
英文摘要 Diabetes mellitus is mainly characterized by hyperglycemia which is the major cause to elevate the cardiovascular disease risk and mortality. Thus, it is important to control the blood glucose in diabetes patients. Allantoin is an imidazoline derivative, and previous studies have been demonstrated that imidazoline derivatives may activate imidazoline subtype 2 receptor (I2R) to incresase β-endorphin release for activation of opioid-μ receptor, and/or may stimulate imidazoline subtype 3 receptor (I3R) to increase the release of insulin. Both actions are related to the lowering of blood glucose. Therefore, the aim of the present study is to clarify the hypoglycemic action of allantoin relating to imidazoline receptors. The data showed that intravenous injection of allantoin into fructose-fed diabetic rats significantly reduced the blood glucose and increased the levels of β-endorphin. The hypoglycemic action of allantoin was partially blocked by pretreatment of BU224 (I2R antagonist), cyprodime (opioid μ-receptor antagonist), and adrenalectomy, but not by naloxonazine (opioid μ1-receptor antagonist). Also, the increase of β-endorphin was blocked by pretreatment of BU224 and adrenalectomy. Moremver, the glucose-lowering action of allantoin in STZ-diabetic rats was inhibited by low dose of amiloride (I2AR antagonist). Both in vivo and in vitro, allantoin exerts the I3R-mediated insulinotropic action which was induced by increase of calcium influx and it was inhibited by the pretreatment of KU14R (I3R antagonist) in Min6 pancreatic β cells. The above data indicate that allantoin induced-hypoglycemia is via the insulin-independent and insulin-dependent pathways. Furthermore, allantoin has a benefit on insulin resistance from the HOMA-IR (homeostasis model assessment for insulin resistance) identified by 2-BFI, the short-term postprandial blood glucose test, and the toubutamide-test. In conclusion, the hypoglycemic action and the improvement of insulin resistance induced by allantoin suggest this agent is suitable for handling of insulin resistance in the future.
論文目次 中文摘要•••••••••••••••••••••••••••••••••••••••••••••••• I
英文摘要•••••••••••••••••••••••••••••••••••••••••••••••• IV
致謝•••••••••••••••••••••••••••••••••••••••••••••••••••• VII
縮寫表•••••••••••••••••••••••••••••••••••••••••••••••••• IX
第一章 緒論•••••••••••••••••••••••••••••••••••••••••••••••••••••• 1
第二章 實驗方法與材料•••••••••••••••••••••••••••••••••••• 10
第三章 實驗結果••••••••••••••••••••••••••••••••••••••••• 23
第四章 討論••••••••••••••••••••••••••••••••••••••••••••• 33
第五章 結論••••••••••••••••••••••••••••••••••••••••••••• 40
參考文獻•••••••••••••••••••••••••••••••••••••••••••••••• 42
附圖•••••••••••••••••••••••••••••••••••••••••••••••••••• 51
自述•••••••••••••••••••••••••••••••••••••••••••••••••••• 74
參考文獻 Ackroyd H. On the presence of allantoin in certain foods. Biochem J. 5: 400-406; 1911.
Akema Fine Chemicals. Allantoin: a safe and effective skin protectant. 2006. Unpublished data.
Akema FineChemicals. Allantoin CTFA. Available at: http://www.akema.it/allantoin.htm. 2009.
American Diabetes Association. Clinical practice recommendations. Diabetes Care. 33: S1-S100; 2010.
American Diabetes Association. Complications of diabetes in the United States. Available at: http://www.diabetes.org/diabetesstatistics/complications.jsp. 2008.
Antonescu CN, Foti M, and Sauvonnet N, et al. Ready, set, internalize: mechanisms and regulation of GLUT4 endocytosis. Biosci Rep. 29: 1-11; 2009.
Aryangat AV, and Gerich JE. Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk. Vasc Health Risk Manag. 6: 145-55; 2010.
Ball BJ, Flatt PR, and McClenaghan NH. Stimulation of insulin secretion in clonal BRIN-BD11 cells by the imidazoline derivatives KU14R and RX801080. Pharmacol Res. 42: 575-579; 2000.
Baron AD. Postprandial hyperglycaemia and α-glucosidase inhibitors. Diabetes Res Clin Pract. 40: S51-S55; 1998.
Barrett-Connor E and Ferrara A. Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men. The Rancho Bernardo study. Diabetes Care. 21: 1236-1239; 1998.
Becker LC, Bergfeld WF, and Belsito DV, et al. Final report of the safety assessment of allantoin and its related complexes. Int J Toxicol. 29: 84S-97S; 2010.
Bonora E, Targher G, and Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of inulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 23: 57-63; 2000.
Calcutt NA, Cooper ME, and Kern TS, et al. Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov. 8: 417-429; 2009.
Ceriello A. The post-prandial state and cardiovascular disease: relevance to diabetes mellitus. Diabetes Metab Res Rev. 16: 125-132; 2000.
Chan SLF, Pallett AL, and Clews J, et al. Characterisation of new efaroxan derivatives for use in purification of imidazoline-binding sites. Eur J Pharmacol. 355: 67-76; 1998.
Chang CH, Wu HT, and Cheng KC, et al. Increase of beta-endorphin secretion by agmatine is induced by activation of imidazoline I(2A) receptors in adrenal gland of rats. Neurosci Lett. 468: 297-9; 2010.
Chapman JC, McClenaghan NH, and Cosgrove KE, et al. ATP-sensitive potassium channels and efaroxan-induced insulin release in the electrofusion-derived BRIN-BD11 beta-cell line. Diabetes. 48: 2349-57; 1999.
Cheng JT, Liu IM, and Tzeng TF, et al. Plasma glucose-lowering effect of beta-endorphin in streptozotocin-induced datbetic rats. Horm Metab Res. 34: 570-576; 2002.
Coupry I, Podevin RA, and Dausse JP, et al. Evidence for imidazoline binding sites in basolateral membranes from rabbit kidney. Biochem Biophys Res Commun. 147: 1055-60; 1987.
Coutinho M, Gerstein HC, and Wang Y, et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 22: 233-40; 1999.
Derave W, Ai H, and Ihlemann J, et al. Dissociation of AMP-activated protein kinase activation and glucose transport in contracting slow-twitch muscle. Diabetes. 49: 1281-1287; 2000.
Diamond GA, Bax L, and Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 147: 578-81; 2007.
Efendic S, Efanov AM, and Berggren PO, et al. Two generations of insulinotropic imidazoline compounds. Diabetes. 51: S448-54; 2002.
Eglen RM, Hudson AL, and Kendall DA, et al. 'Seeing through a glass darkly': casting light on imidazoline 'I' sites. Trends Pharmacol Sci. 19: 381-90; 1998.
Finn DP, Hudson AL, and Kinoshita H, et al. Imidazoline2 (I2) receptor- and alpha2-adrenoceptor-mediated modulation of hypothalamic-pituitary-adrenal axis activity in control and acute restraint stressed rats. J Psychopharmacol. 18: 47-53; 2004.
Food and Drug Administration. Frequency of use of cosmetic ingredients. FDA Database. 2007.
Gottschalck TE, and Bailey JE. International Cosmetic Ingredient Dictionary and Handbook. 12th ed. Washington, DC: CTFA; 2008.
Hammad HM, Hammad MM, and Abdelhadi IN, et al. Effects of topically applied agents on intra-oral wound healing in a rat model: a clinical and histomorphometric study. Int J Dent Hyg. 9: 9-16; 2011.
Head GA, and Mayorov DN. Imidazoline receptors, novel agents and therapeutic potential. Cardiovasc Hematol Agents Med Chem. 4: 17-32; 2006.
Huang S, and Czech MP. The GLUT4 glucose transporter. Cell Metab. 5: 237-52; 2007.
Hwang SL, Liu IM, and Tzeng TF, et al. Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats. Diabetologia. 48: 767-75; 2005.
International Diabetes Federation Diabetes e-Atlas. Available at: http://www. eatlas.idf.org; 2006.
Ishiki M and Klip A. Minireview: recent developments in the regulation of glucose transporter-4 traffic: new signals, locations, and partners. Endocrinology. 146: 5071-5078; 2005.
Jou SB, Liu IM, and Cheng JT. Activation of imidazoline receptor by agmatine to lower plasma glucose in streptozotocin-induced diabetic rats. Neurosci Lett. 358: 111-114; 2004.
Ko WC, Liu IM, and Chung HH, et al. Activation of I2-imidazoline receptors may ameliorate insulin resistance in fructose-rich chow-fed rats. Neurosci Lett. 448: 90-3; 2008.
Lachaud-Pettiti V, Podevin RA, and Chretien Y, et al. Imidazline-guanidinium and alpha 2-denergic binding sites in basolateral membranes from human kidney. Eur J Phunnacol. 206: 23-31; 1991.
Lee MK, Miles PD, and Khoursheed M, et al. Metabolic effects of troglitazone on fructose-induced insulin resistance in the rats. Diabetes. 43: 1435-1439; 1994.
Lee MY, Lee NH, and Jung D, et al. Protective effects of allantoin against ovalbumin (OVA)-induced lung inflammation in a murine model of asthma. Int Immunopharmacol. 10: 474-80; 2010.
LeRoith D, Taylor SI, Olefsky JM (eds). Diabetes mellitus: a fundamental and clinical text, 3rd edn. Lippincott Williams and Wilkins, Philadelphia, PA; 2004.
Livingston SK, and Prince LH. The treatment of chronic osteomylitis. JAMA. 98: 1143-1149; 1932.
MacKay D, and Miller AL. Nutritional support for wound healing. Altern Med Rev. 8: 359-77; 2003.
Madariaga H, Lee PC, and Heitlinger LA, et al. Effects of graded α- glucosidase inhibition on sugar absorption in vivo. Digestive Dis Sci. 33: 1020-1024; 1988.
Maksimovic Z, Malenovic A, and Jancic B, et al. Quantification of allantoin in various Zea mays L. hybrids by RP-HPLC with UV detection. Pharmazie. 59: 524-527; 2004.
Matschinsky FM, Zelent B, and Doliba NM, et al. Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects. Handb Exp Pharmacol. 203: 357-401; 2011.
Mayer G, and Taberner PV. Effects of the imidazoline ligands efaroxan and KU14R on blood glucose homeostasis in the mouse. Eur J Pharmacol. 454: 95-102; 2002.
Mehers KL, Gillespie KM. The genetic basis for type 1 diabetes. Br Med Bull. 88: 115-129; 2008.
Morgan NG, and Chan SL. Imidazoline binding sites in the endocrine pancreas: can they fulfil their potential as targets for the development of new insulin secretagogues? Curr Pharm Des. 7: 1413-31; 2001.
Morgan NG, Chan SL, and Mourtada M, et al. Imidazolines and pancreatic hormone secretion. Ann N Y Acad Sci. 881: 217-28; 1999.
Navarro-Cid J, Maeso R, and Perez-Vizcaino F, et al. Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. Hypertension. 26: S1074-S1078; 1995.
Niu CS, Chen W, and Wu HT, et al. Decrease of plasma glucose by allantoin, an active principle of yam (dioscorea spp.), in streptozotocin-induced diabetic rats. J Agric Food Chem. 58: 12031-12035; 2010.
Nyenwe EA, Jerkins TW, and Umpierrez GE, et al. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism. 60: 1-23; 2011.
O'Brien RM, and Granner DK. Regulation of gene expression by insulin. Physiol Rev. 76: 1109-1161; 1996.
Okada S, Yamaguchi-Shima N, and Shimizu T, et al. Centrally administered N-methyl-d-aspartate evokes the adrenal secretion of noradrenaline and adrenaline by brain thromboxane A2-mediated mechanisms in rats. Eur J Pharmacol. 586: 145-150; 2008.
Parini A, Moudanos CG, and Pizzinat N, et al. The elusive family of imidazoline binding sites. Trends Pharmacol Sci. 17: 13-6; 1996.
Park CH, Noh JS, and Tanaka T, et al. The effects of corni fructus extract and its fractions against α-glucosidase inhibitory activities in vitro and sucrose tolerance in normal rats. Am J Chin Med. 39: 367-80; 2011.
Plant TD, and Henquin JC. Phentolamine and yohimbine inhibit ATP-sensitive K+ channels in mouse pancreatic beta-cells. Br J Pharmacol. 101: 115-20; 1990.
Rains JL and Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med. 50: 567-75; 2011.
Ray KK, Seshasai SR, and Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 373: 1765-1772; 2009.
Reaven GM. Role of insulin resistance in human disease. Diabetes 37: 1595- 1607; 1988.
Ruffolo RR Jr, Rosing EL, and Waddell JE. Receptor interactions of imidazolines. I. Affinity and efficacy for alpha adrenergic receptors in rat aorta. J Pharmacol Exp Ther. 209: 429-36; 1979.
Schmitt H, Boissier JR, and Giudicelli JF. Centrally mediated decrease in sympathetic tone induced by 2(2,6-dichlorophenylamino)-2 imidazoline (S.T. 155, Catapresan). Eur J Pharmacol. 2: 147-8; 1967.
Sheker KM, Black HJ, and Lach JL. Silver allantoinate for the topical treatment of burns. Am J Hosp Pharm. 29: 852-855; 1972.
Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 50: 537-546; 2001.
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 25: S5–S20; 2003.
Tominaga M, Eguchi H, and Manaka H, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 22: 920-4; 1999.
van Poelje PD, Potter SC, and Erion MD. Fructose-1, 6-bisphosphatase inhibitors for reducing excessive endogenous glucose production in type 2 diabetes. Handb Exp Pharmacol. 203: 279-301; 2011.
Watson RT, and Pessin JE. GLUT4 translocation: the last 200 nanometers. Cell Signal. 19: 2209-2217; 2007.
Wijesekara N, Thong F, and Antonescu CN, et al. Diverse signals regulate glucose uptake into skeletal muscle. Can J Diabet. 30: 80-88; 2006.
Willital GH, and Heine H. Efficacy of Contractubex gel in the treatment of fresh scars after thoracic surgery in children and adolescents. Int J Clin Pharmacol Res. 14: 193-202; 1994.
Wojtaszewski JF, Jørgensen SB, and Hellsten Y, et al. Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP- activated protein kinase and glycogen synthase activities in rat skeletal muscle. Diabetes. 51: 284-292; 2002.
Wright E Jr, Scism-Bacon JL, and Glass LC. Oxidative stress in type 2 diabetes:the role of fasting and postprandial glycaemia. Int J Clin Pract. 60: 308-314; 2006.
Zaid H, Antonescu CN, and Randhawa VK et al. Insulin action on glucose transporters through molecular switches, tracks and tethers. Biochem J. 413: 201-215; 2008.
Zaitsev SV, Efanov AM, and Efanova IB, et al. Imidazoline compounds stimulate insulin release by inhibition of K(ATP) channels and interaction with the exocytotic machinery. Diabetes. 45: 1610-8; 1996.
Zhang L, Liu Y, and Chen G. Simultaneous determination of allantoin, choline, and larginine in Rhizoma Dioscoreae by capillary electrophoresis. J Chromatog A. 1043: 317-321; 2004.
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