沙格列汀的作用机制课件

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,2012/2/27,#,沙格列汀的作用机制,肠促胰岛激素简史,1902-,首次观察到藏到对胰岛分泌的影响,1,2,1932-,首次确定肠促胰岛素,3,1964-,证实仓促胰岛素效应,1,4,5,1966-,首次描述,DPP-4 6,1973-GIP,被确定为一种人类长促胰岛素,1,1986-,证实了长促胰岛素在,2,型糖尿病患者中的作用,7,1995-DPP-4,被确定为一种灭活,GIP,和,GLP-1,的酶,9,10,1987-GLP-1,被确定为一种人类长促胰岛素,Creutzfeldt W.Regul Pept.2005;128:87-91.,Bayliss WM et al.J Phystol.1902;28:325-353.,La Barre J.Bull Acad R.Med Belg.1932;120:620-634.,McIntyre N et al.Lancet.1964;41:20-21.,Elrick H et al.J Clin Endocr.1964;24:1076-1082.,Hopsu-Havu VK,Glenner GG.Histochemle.1966;7(3):197-201.,Nauck M et al.Diabetologia.1986;29:46-52.,Kreymann B et al.Lancet.1987;2:1300-1304.,Kieffer TJ et al.Endocrinology.1995;136;3385-3596.,Deacon CF et al.J Clin Endocrinol Metab.1995;80:952-957.,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,*,*,*,*,*,*,*,平均值,SE;n=6;*P,0.05;01-02=,葡萄糖输注时间,肠促胰,素,效应,的发现,与静脉注射葡萄糖相比，口服葡萄糖,增强了,-,细胞反应,Nauck J.Clin Endocrinol Metab.1986;63:492-8.,检测,8,名健康对照受试者口服葡萄糖（,50 g,）和静脉注射葡萄糖的反应,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,0,1,60,120,180,0,2,肠促胰素效应,Nauck et al.Diabetologia.1986,2,型糖尿病患者肠促胰岛素效应减弱,口服葡萄糖,静脉注射葡萄糖,Time(min),Insulin(mU/l),80,60,40,20,0,180,60,120,0,Time(min),Insulin(mU/l),80,60,40,20,0,180,60,120,0,肠促胰岛素效应,非糖尿病组,(n=8),2,型糖尿病组,(n=14),Role of Incretin System in Glucose Homeostasis,Normoglycaemia,Glucose uptake by peripheral tissue,Adapted from Drucker DJ.Cell Metab.2006;3:153-65.,Hepatic glucose production,Glucose-dependent,insulin,(GLP-1&GIP),Glucose-,dependent,glucagon,(GLP-1),Pancreas,-cells,-,cells,Release of,active incretins,GLP-1&GIP,DPP-4,inactivates,GLP-1&GIP,GI tract,Ingestion of food,GLP-1,和,GIP,是两类主要的肠促胰素,GLP-1,（胰高糖素样肽,-1,）,GIP,（葡萄糖依赖的促胰岛,素释放多肽）,主要合成部位,L,细胞,(,回肠和结肠,),K,细胞,(,十二指肠和空肠,),2,型糖尿病患者中分泌,是,否,餐后胰高糖素,是,否,食物摄入,是,否,延缓胃排空,是,否,促进,细胞增殖,是,是,促进胰岛素生物合成,是,是,Drucker DJ.Diabetes Care.2003;26:2929-2940,.,The Incretin Effect is Reduced in Type 2 Diabetes,Adapted from Nauck M,et al.Diabetologia.1986;29:46-52.,Oral glucose,(50g),IV glucose,(variable),Responses to an oral glucose load of 50 g and intravenous glucose infusion were measured in 14 type 2 diabetic patients and 8 healthy control subjects.,Responses to glucose load in type 2 diabetics and healthy subjects,Control subjects(N=8),Type 2 diabetic patients(N=14),Oral glucose,(50g),IV glucose,(variable),Venous plasma glucose,(mmol/l),Time,(min),Time,(min),0,10,15,120,180,0,1,60,0,5,10,15,5,120,180,0,1,60,0,2,0,2,Venous immunoreactive,insulin,(mU/l),(nmol/l),0,20,40,60,80,0,20,40,60,80,0,0,0.1,0.3,0.4,0.6,0.5,0.2,0.1,0.3,0.4,0.6,0.5,0.2,*,*,*,*,*,*,*,*,*,*,Venous plasma glucose,(mmol/l),*P0.05 to the respective value after the oral load,Time,(min),Time,(min),120,180,60,120,180,60,0,2,0,2,0,1,0,1,(nmol/l),Venous immunoreactive,insulin,(mU/l),Incretin hormone changes,In patients with type 2 diabetes,levels of GLP-1 released in response to glucose are reduced and GIP activity is decreased,Continuous Infusion of GLP-1 Decreases Fasting Glucose as well as HbA,1c,Adapted from Zander M,et al.Lancet.2002;359(9309):824-30.,Compared to saline,patients treated with GLP-1 showed fasting and 8-hour mean plasma glucose that was decreased by 4.3 mmol/l and 5.5 mmol/l(P0,.0001,),and HbA,1c,that was decreased by 1.3%(P=0.003),Patients assigned saline(N=9),Patients assigned GLP-1(N=10),Glucose concentration in plasma,(mmol/L),0,0,8,2,4,6,0,8,2,4,6,25,20,15,10,5,0,25,20,15,10,5,Week 0,Week 1,Week 6,Time,(hr),Time,(hr),Glucose concentration in plasma,(mmol/L),Exogenous GlucoseDependent Insulinotropic Polypeptide Worsens Postprandial Hyperglycaemia in Type 2 Diabetes,Adapted from Chia CW,et al.Diabetes.2009;58(6):1342-9.,GIP given at supraphysiological levels still has an early,short-lived insulinotropic effect in type 2 diabetes,Time,(min),GIP,Placebo,45,5,25,65,280,180,380,80,-20,Insulin,(mg/mL),Glucose,(mg/dL),45,5,25,65,60,40,20,0,Time,(min),190,110,150,230,280,180,380,80,-20,140,190,240,60,40,20,0,When compared with placebo,exogenous GIP infusion not only did not lower postprandial glucose but further worsened hyperglycaemia during late postprandial period(120360 min)in patients with type 2 diabetes(N=22),Changes in insulin,Changes in glucose,*,*,*,*,*,*,*,*P0.05 vs placebo,在,2,型糖尿病的治疗中，,针对,GLP-1,的药物更有价值,肠促胰岛素的效应在,2,型糖尿病患者中减弱,在,2,型糖尿病患者中,GIP,水平正常甚至略微升高，但其作用很小,-GIP,抵抗,GIP,的促胰岛素分泌作用的减弱可能是遗传因素和环境因素共同作用引起的,2,型糖尿病患者中，,GLP-1,水平降低，但其作用未受损,开发提高,GLP-1,水平的药物具有重要的临床意义,Nauck.MA et al.J Clin Invest 1993,91:301-307,Sites of Action of GLP-1,Brain,Glucose production,Neuroprotection,Appetite,Liver,Stomach,Gastric emptying,GI tract,Insulin biosynthesis,-,cell proliferation,-cell apoptosis,Insulin secretion,Glucagon secretion,Muscle,Heart,Cardioprotection,Cardiac output,Insulinsensitivity,Adapted from Drucker DJ.Cell Metab.2006;3:153-65.,Pancreas,GLP,-1,在人体的作用,促进饱腹感，,降低食欲,细胞,:,餐后胰高血糖素分泌,肝脏,:,胰高血糖素,减少肝糖输出,胃,:,有助于调节胃排空,细胞,:,促进血糖依赖性,胰岛素,分泌,进食后，小肠,开始分泌,GLP,-1,Adapted from:Flint A,et al.J Clin Invest.1998;101:515-20.Holst JJ.TEM.2005;10:229-35.