基于GLP-1的2型糖尿病治疗

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,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,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide No.,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide No.,*,Click to edit Master title style,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Slide No.,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide No.,*,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,Fifth level,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,Date,Slide No.,*,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,Slide No.,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide No.,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide No.,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide No.,*,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,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Slide No.,*,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,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Slide No.,1,人,GLP-1,类似物利拉鲁肽 改善,2,型糖尿病的治疗,Slide No.,2,基于肠促胰素,GLP-1,的治疗机制,人,GLP-1,类似物利拉鲁肽的临床研究结果,利拉鲁肽相比其他基于肠促胰素的治疗优势,主要内容,Slide No.,3,肠促胰素在正常胰岛素应答反应中至关重要,Nauck,et al.Diabetologia,1986;29:4652,健康志愿者,(n=8),口服葡萄糖负荷,静脉输注葡萄糖,血浆葡萄糖,(mmol/L),10,5,60,120,180,10,时间,(,分,),5,0,15,血浆葡萄糖,尽管血浆葡萄糖浓度相似，口服葡萄糖后的胰岛素应答反应要强于静脉输注葡萄糖,胰岛素应答反应,胰岛素,(mU/L),80,60,40,20,10,5,60,120,180,0,时间,(,分,),肠促胰素,效应,Slide No.,4,2,型糖尿病中肠促胰素作用减弱,0,20,40,60,80,胰岛素,(mU/L),0,30,60,90,120,150,180,时间,(min),*,*,*,*,*,*,*,0,20,40,60,80,0,30,60,90,120,150,180,时间,(min),*,*,*,2,型糖尿病患者,正常人,静脉注射葡萄糖,口服葡萄糖,*,与口服后的相应值相比,p.05,Nauck MA,et al.,Diabetologia,.1986;29:46-52.,Slide No.,5,Toft-Nielsen et al.J Clin Endocrinol Metab(2001),进餐,进餐,时间（,min,）,时间（,min,）,T2DM,患者进餐引起的,GLP-1,分泌受损而非,GIP,Slide No.,6,胰腺,胃,心脏,大脑,肝脏,GLP-1,具有更多针对,T2DM,病理生理的作用,Adapted from Baggio&Drucker,.Gastroenterol,2007;132;213157,Intestine,心脏保护心功能,饱腹感,胃排空,葡萄糖输出,胰岛素合成,Beta,细胞量,葡萄糖依赖胰高糖素分泌,葡萄糖依赖胰岛素分泌,Slide No.,7,基于肠促胰素,GLP-1,的治疗机制,人,GLP-1,类似物利拉鲁肽的临床研究结果,利拉鲁肽相比其他基于肠促胰素的治疗优势,主要内容,Slide No.,8,利拉鲁肽与天然,GLP-1,保持高度同源性,Knudsen,et al.J Med Chem,2000;43:16649;Degn,et al.Diabetes,2004;53:118794,34,34,被,DPP-IV,酶降解,从皮下组织缓慢吸收,不被,DPP-IV,酶降解，不从肾脏滤过,血浆半衰期,13,小时，降糖作用,24,小时,26,Slide No.,9,每日一次利拉鲁肽,可达到,GLP-1,类似物高药理学浓度,Agers,et al.Diabetologia,2002;45:195202,单变量模式：,给,药,3,次后达到稳态,血浆利拉鲁肽,(pmol/L),时间,(,天,),2,12,6,8,10,4,6000,4000,2000,8000,9,11,7,3,1,5,13,30,个基准点制成的曲线模型,Slide No.,10,利拉鲁肽具有更多针对,T2DM,病理生理的作用,动物实验,Slide No.,11,单次剂量利拉鲁肽可恢复,细胞的葡萄糖敏感性,试验前,9,小时，对,2,型糖尿病患者注射利拉鲁肽或安慰剂,(,交叉,),检测胰岛素分泌情况,利拉鲁肽可使,细胞对葡萄糖浓度升高的反应性恢复至健康对照水平,胰岛素分泌率,(pmol/min/kg),mmol/L,mg/dL,0,2,4,6,8,10,12,14,4,6,8,10,12,葡萄糖,安慰剂,利拉鲁肽,7.5 g/kg,健康对照,(n=10),80,100,140,180,220,120,200,160,Data are meanSEM;type 2 diabetes patients(n=10).,Chang et al.Diabetes 2003;52:178691,18,Slide No.,12,ATP,敏感性,钾通道,胰岛素释放,胰岛素颗粒,胰岛,细胞,GLP-1,受体,葡萄糖转运蛋白,肠促胰素,-,真正葡萄糖依赖性,依赖葡萄糖产生的,ATP,CAMP,放大促泌,葡萄糖,K,m=7-9mM,葡萄糖,葡萄糖,葡萄糖,葡萄糖,葡萄糖激酶,电压依赖性,Ca,2+,通道,Slide No.,13,N=10 patients,with type 2 diabetes.Patients were studied on two occasions.A regular meal and drug schedule was allowed for one day between the experiments with GLP-1 and placebo.,葡萄糖,(mmol/L),胰高血糖素,(pmol/L),时间,(,分钟,),250,200,150,100,50,15.0,12.5,10.0,7.5,5.0,20,15,10,5,0,60,120,180,240,安慰剂,GLP-1,输注,胰岛素,(pmol/L),*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,当血糖达到正常，,GLP-1,调节胰岛素和胰高糖素效应减弱,Infusion,Nauck MA et al,Diabetologia,1993;36:741744.,*p0.05 GLP-1 vs.,安慰剂,GLP-1,葡萄糖依赖性促进胰岛素分泌，抑制胰高糖素分泌,Slide No.,14,利拉鲁肽在低血糖时不诱导胰岛素分泌,对应的血糖平台水平,mmol/L(mg/dL),胰岛素分泌率,(pmol/kg/min),时间,(,分,),1,0,0,60,120,180,240,4.3,(77),3.7,(,67,),3.0,(54),2.3,(41),利拉鲁肽,数据为平均,SEM;2,型糖尿病患者,(n=11),安慰剂,Nauck et al.Diabetes 2003;52(Suppl.1):A128,19,Slide No.,15,利拉鲁肽在低血糖时不抑制胰高糖素分泌,对应的血糖平台水平,mmol/l(mg/dl),利拉鲁肽,(,体重,7.5 g/kg)(n=11),安慰剂,(n=11),利拉鲁肽不抑制低血糖诱导的胰高糖素分泌,1,利拉鲁肽葡萄糖输注率与安慰剂相同,1,不影响总体低血糖反调节应答,胰高糖素,(pq/ml),分钟,0,60,120,180,240,40,80,120,160,4.3(77),3.7(67),3.0(54),2.3(41),Adapted from:1.Nauck et al.Diabetes 2003;52(Suppl 1):A128,19,.,Data are mean SEM,Slide No.,16,利拉鲁肽对,细胞有多重积极作用,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),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):A3