GLP和DPP.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit 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level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,GLP和DPP,糖尿病：一直在探索，从未被解决,各大指南对,GLP-1,和,DPP-4,抑制剂地位的确定,Ebers,公元前,1550,年,公元,1,世纪,伊姆霍特普,公元前,3000,年,),Arateus,第一次使用,“,糖尿病,”(Diabetes),成功提取胰岛素,1920s,1950s,口服药物，如磺脲类、二甲双胍等陆续用于临床,1970s,2000s,2010s,大型研究相继公布，,大血管获益仍不确定,病因认识不断丰富新型药物如,GLP-1,、,DPP-4,抑制剂等用于临床,糖尿病首次分为,1,型和,2,型,2015s,2013s,ADA,年会数据公布，肯定,了,GLP-1,对心血管的益处,出路探索,-,来自,ADA,的声音：,肠促胰素,Bangting,奖,(2014,第,74,届,ADA,年会,),来自胃肠道代谢信息的破译驱动着治疗革新,Deciphering Metabolic Messages from the Gut Drives Therapeutic Innovation,Daniel J.Drucker,教授,肠促胰素,GLP-1,及,GIP,的不断发展,1970,1950,2010,1930,1990,1992-1994,：研究发现外源性,GIP,不降低,2,型糖尿病患者的血糖，但外源性,GLP-1,反之,1,1985,：发现第,2,种肠促胰素：,GLP-1,1,2005,：更多研究表明,GLP-1,的,非葡萄糖依赖性,4,1932,：第,1,次使用“肠促胰素”的概念：来自肠道的一种可以调节进食后胰岛素分泌的物质1,1971,：分离出第,1,种肠促胰素：,GIP,2002:,发现曾经被认为是无活性的,GLP-1(9-36),的代谢产物，具有一定的生物学活性,3,FPO,1986,：发现,T2DM,患者的肠促胰素效应,2,1964-1967,：口服葡萄糖较静脉滴注葡萄糖引起的胰岛素分泌更多。这种差异被称为“肠促胰岛素效应,Kim W et al.,Pharmacol,Rev.2008;60(4):470-512.,2.Nauck M et al.,Diabetologia,.1986;29(1):46-52.,3.Deacon et al.Am J Physiol Endocrinol Metab.2002;282(4):E873-E879.,4.Nikolaidis et al.Am J Physiol Heart Circ Physiol.2005;289(6):H2401-H2408.,肠促胰素效应的发现,一项试验检测,8,名健康受试者口服葡萄糖（,50 g,）和静脉注射葡萄糖的反应，结果，与静脉,注射葡萄糖相比，口服葡萄糖后，患者的血清,C,肽水平更高，由此证实了肠促胰素效应,Nauck J.Clin Endocrinol Metab 1986;63:492-498,.,静脉血浆葡萄糖,(,mmol/L,),时间,(,分钟,),C-,肽,(nmol/L),11,5.5,0,0.0,0.5,1.0,1.5,2.0,时间,(,分钟,),0,1,60,120,180,0,2,口服葡萄糖 静脉注射葡萄糖,*,*,*,*,*,*,*,0,1,-0,2,=,葡萄糖输注时间,0,1,60,120,180,0,2,肠促胰素效应,*P,0.05;,与,静脉注射葡萄糖相比,0,1,-0,2,=,葡萄糖输注时间,2,型糖尿病患者肠促胰素效应减弱,Nauck et al.Diabetologia.1986;29:46-52,口服葡萄糖,静脉注射葡萄糖,胰岛素,(mU/l),80,60,40,20,0,180,60,120,0,时间,(,分,),胰岛素,(mU/l),80,60,40,20,0,180,60,120,0,肠促胰素,效应,非糖尿病组,(n=8),2,型糖尿病组,(n=14),时间,(,分,),Glucose-Dependent Effects of GLP-1,2,型糖尿病,(n=10),Adapted from:Nauck MA,et al.Diabetologia.1993;36:741-4,.,安慰剂,GLP,-1,葡萄糖,(mg/dL,),GLP,-1,安慰剂,胰岛素,(pmol/L,),GLP,-1,安慰剂,胰高血糖素,(pmol/L,),时间,(,分钟,),平均值,(SE);*,P,0.05,GLP-1,对胰岛素和胰高糖素分泌的调节是葡萄糖依赖性的,GLP-1,安慰剂,P,0.05,60,120,1,80,240,-,30,0,60,120,180,240,270,180,90,0,-,30,0,20,10,300,200,100,0,*,-,30,0,60,120,180,240,0,胰腺,心脏,肝,肠,饱腹感,学习能力和保护神经,(,动物实验,),),葡萄糖生成,GLP-1,具有多种重要生理作用,GLP-1,L,细胞分泌,GLP-1,被,DPP-4,分解,胃,大脑,Adapted from Baggio&Drucker,.Gastroenterol,2007;132;213157,心血管保护功能,胃排空,胰岛素合成,葡萄糖依赖性胰岛素分泌,葡萄糖依赖性胰高糖素分泌,出路探索,-,来自,ADA,的声音：,胰高糖素,(2014,第,74,届,ADA,年会,),胰高血糖在,2,型糖尿病患者中重要么？,Glucagon suppression in type 2 diabetes,is it important?,Daniel J.Drucker,教授,血糖,胰岛素,胰高糖素,血糖,胰岛素,胰高糖素,/,细胞对血糖稳态的调节,Cryer PE.Endocrinology.2012;153(3):1039-48.,生理状态下,血糖,血糖,Cryer PE.Endocrinology.2012;153(3):1039-48.,病理状态下,/,细胞对血糖稳态调节“失控”,揭示,细胞,的重要性,病理状态下,血糖,胰岛素,胰高糖素,NO,NO,血糖,血糖,胰岛素,胰高糖素,NO,血糖,GLP-1,针对,和,细胞发挥双重降糖机制,葡萄糖,胰岛素缺乏,高胰高糖素血症,+,葡萄糖,摄取,肝糖输出,+,GLP-1,-,细胞减少,-,细胞肥大,-,细胞功能失调,-,细胞功能失调,GLP-1,Unger.,Metabolism,1974;23:581,糖尿病晚期,GLP-1,仅能发挥部分降糖作用,细胞,细胞,细胞,葡萄糖,葡萄糖,葡萄糖,GLP-1,GLP-1,GLP-1,胰高糖素,胰岛素,生长抑素,胰岛素,GLP-1,类似物,尽早使用，获益更多,两种提高,GLP-1,体内活性的方法,Green BD,et al.Diab Vasc Dis Res.2006 Dec;3(3):159-65,肠促胰素,肠促胰素,肠促胰素,无活性,有活性,有活性,肠促胰素类似物,(,模拟,GLP-1,作用,可抵抗,DPP-4,酶,),DPP-4,抑制剂,(,阻碍,DPP-4,酶作用最小化内源性,活性,GLP-1,的降解,),GLP-1,在体内容易被,DPP-4,酶降解，很快失活,Adapted from Brubaker PL,Drucker DJ,Endocrinology,2004;145:26532659;Zander M et al,Lancet,2002;359:824830;Ahrn B,Curr Diab Rep,2003;3:365372;Buse JB et al.In,Williams Textbook of Endocrinology,.10th ed.Philadelphia,Saunders,2003:14271483.,Hyperglycemia,GLP-1,作用机制：胰岛素促泌与胰高糖素抑制,Release of incretins from the gut,Pancreas,-cells,-cells,Insulinincreases peripheral glucose uptake,Ingestion of food,GI tract,Inactive incretins,DPP-4 Enzyme,DPP-4,Inhibitor,X,DPP-4=dipeptidyl peptidase 4,GLP-1,GIP,Improved Physiologic,Glucose Control,insulin and glucagon reduce hepatic glucose,output,Glucose dependent,Insulin,from beta cells(GLP-1 and GIP),Glucagon,from alpha cells(GLP-1),Glucose dependent,Injuction of,Liraglutide,利拉鲁肽是每日注射一次的人,GLP-1,类似物,Knudsen,et al.J Med Chem,2000;43:16649;Degn,et al.Diabetes,2004;53:118794,天然人,GLP-1,被,DPP-4,降解,利拉鲁肽,C-16,棕榈酰脂肪酸,艾塞那肽,:,第一个上市的,GLP,1,受体激动剂,艾塞那肽,(Exendin-4),人工合成的希拉巨蜥唾液中的一种蛋白质,与人,GLP-1,约有,53,的同源性,体外试验中与人,细胞表面,GLP-1,受体结合,对,GLP-1,受体的激活作用至少和,GLP-1,相近,能抵抗,DPP-4,降解灭活作用,DPP-4,灭活位点,H,G,E G T F T S D,L,S,K Q M,E,E E,A,V R L,F I,E,W L,K N,G,G P S S G A P P P S NH,2,H,A E G,T,F T S D V S,S Y,L,E G Q A A K E F I A W L V K G R NH,2,艾塞那肽,人,GLP-1,Adapted from Nielsen LL,et al.,Regulatory Peptides,.2004;117:77-88,分泌能力,胰岛素原,/,胰岛素,第一时相胰岛素分泌,细胞功能,(HOMA-B),细胞量,2,型糖尿病患者,动物实验,体外研究,细胞凋亡,细胞的葡萄糖敏感性,(,胰岛素分泌率,),细胞,Madsbad,et al.Diabetologia,2006;49(Suppl.1):A004;Sturis,et al.Br J Pharmacol,2003;140:12332.,；,Rolin,et al.Am J Physiol Endocrinol Metab,2002;283:E74552;Bregenholt,et al.Diabetologia,2001;44(Suppl.1):A19;Bregenholt,et al.Diabetes,2001:50(Suppl.2):A31;Degn,et al.Diabetes,2004;53:118794;Chang,et al.Diabetes,2003;52:178691,人,GLP-1,类似物利拉鲁肽对,细胞具有多重积极作用,GLP-1,对胰腺,细胞的生理作用,Gastroenterology 2007;132:21312157,GLP-1,受体,胰岛素颗粒,DPP4,抑制剂葡萄糖依赖性降低血糖，低血糖风险低,胰腺,细胞,ATP/ADP,葡萄糖转运蛋白,K/ATP,通道,电压依赖性,Ca,2+,通道,cAMP,ATP,Ca,2+,葡萄糖,Ca,2+,胰岛素释放,血糖水平升高时，触发细胞内一系列反应，最终使囊泡内储存的胰岛素分泌入血（,GSIS,）。,GLP-1,与细胞膜上的受体结合后，刺激,cAMP,产生,然后通过下游信号通路增强,GSIS,。,GLP-1,增强,GSIS,需要足够的葡萄糖浓度。因此胰岛素的分泌需要,GLP-1,和葡萄糖的协同作用,Gromada J,et al.Pflugers Arch Eur J Physiol.1998;435:583-594;,MacDonald PE,et al.Diabetes.2002;51:S434-S442.,GLP-1,GLP-1,对,细胞直接作用的机制,GLP-1,通过激活,cAMP,及,PKA,依赖的,N-type Ca,2+,通道关闭而抑制胰高糖素分泌,Yang Z et al,Cell Metabolism.,2010(11):543-553.,GLP-1,调节,细胞作用的潜在机制,间接作用,细胞,分泌的物质,(,胰岛素,锌,谷氨酸盐,),生长抑素对,细胞,的,抑制作用,通过自主神经系统调控,直接作用,细胞上,GLP-1,的,受体,表达,量不到,细胞上表达量的,0.2,%,GLP-1,对细胞电活动影响甚微，但能选择性地抑制钙通道和胰高糖素的胞外分泌,。,H.Holst.Molecular and Cellular Endocrinology 297(2009)127136,Yang Z.Cell Metabolism 11,543553,June 92010,DPP-4,抑制剂是否仅由直接途径产生降糖效应,Burcelin,et al.Current Opinion in Pharmacology.2009;9:744-52,15,%,25,%,50,%,DPP,-,4,抑制,1,.,5,3,倍,t,:,5,分钟,?,直接途径,细胞,:,胰岛素,细胞,:,胰高糖素,体循环,肠脑轴,100%GLP-1,胰腺,DPP-4,DPP-4,，又被称为,T,细胞表面抗原,CD26,。亦称,ADABP,，,ADCP2,，,DPPIV,，,TP103,，二肽基肽酶,4,，二肽基肽酶,IV,，,T,细胞活化抗原,CD26,的，腺苷脱氨酶络合蛋白,2,是一种细胞表面的丝氨酸蛋白酶。,DPP-4,在肠中高表达，此外于肝脏、胰腺、胎盘、胸腺等也有表达，部分以可溶形式存在于循环血液中。可溶性的,DPP-4,具有酶活性，其主要作用是优先将氨基末端第,2,个氨基酸为丙氨酸（,Ala,）或脯氨酸（,Pro,）的寡肽的氨基末端前两个氨基酸剪切去除。,DPP4,是一种体内的酶，也就是酵素。它主要的作用是在分解体内的蛋白质！其中一种被,DPP4,分解的蛋白质叫做,GLP1,，它是由肠道细胞分泌的荷尔蒙，,GLP-1,可以通过可以刺激胰岛素、抑制升糖素、抑制胃排空和让胰岛细胞重生的方式来降低血糖。导致,DPP4,失活从而不分解,GLP-1,的,DPP4,抑制剂已经成为治疗糖尿病的主攻方向之一。,GLP-1(pmol/L,),时间,(min),T2DM,患者,IGT,NGT,一项糖尿病临床研究，纳入,54,例,T2DM,受试者，,33,例,NGT,受试者和,15,例,IGT,受试者，观察三种人群餐后,GLP-1,水平,结果表明，,T2DM,患者存在餐后,GLP-1,缺乏，*,P,0.05 T2DM,vs,NGT,Toft-Nielsen MB,et al.J Clin Endocrinol Metab.2001;86(8):3717-23.,T2DM,患者存在,GLP-1,缺乏，,GLP-1,成为医治,T2DM,的新靶点,国内外大量研究证实糖尿病患者血液中的,GLP-1,浓度降低而,DPP-4,的活性增强,国内目前有,GLP-1,和,DPP-4,的监测试剂盒,THANK YOU,搜集整理,