沙格列汀的作用机制.ppt

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1、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1,21932-首次确定肠促胰岛素31964-证实仓促胰岛素效应1,4,51966-首次描述DPP-461973-GIP被确定为一种人类长促胰岛素11986-证实了长促胰岛素在2型糖尿病患者中的作用71995-DPP-4被确定为一种灭活GIP和GLP-1的酶9,101987-GLP-1被确定为一种人类长促胰岛素CreutzfeldtW.RegulPept.2005;128:87-91.BaylissWMetal.JPhystol.1902;28:325-353.LaBarreJ.B

2、ullAcadR.MedBelg.1932;120:620-634.McIntyreNetal.Lancet.1964;41:20-21.ElrickHetal.JClinEndocr.1964;24:1076-1082.Hopsu-HavuVK,GlennerGG.Histochemle.1966;7(3):197-201.NauckMetal.Diabetologia.1986;29:46-52.KreymannBetal.Lancet.1987;2:1300-1304.KiefferTJetal.Endocrinology.1995;136;338

3、5-3596.DeaconCFetal.JClinEndocrinolMetab.1995;80:952-957.静脉血浆葡萄糖(mmol/L)时间(分钟)C-肽(nmol/L)115.500.00.51.01.52.0时间(分钟)016012018002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NauckJ.ClinEndocrinolMetab.1986;63:492-8.检测8名健康对照受试者口服葡萄糖（50g）和静脉注射

4、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016012018002肠促胰素效应Naucketal.Diabetologia.19862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)806040200180601200Time(min)Insulin(mU/l)806040200180601200肠促胰岛素效应非糖尿病组(n=8)2型糖尿病组(n=14)RoleofIncretinSysteminGlucoseHomeostasisNormoglycae

5、miaGlucoseuptakebyperipheraltissueAdaptedfromDruckerDJ.CellMetab.2006;3:153-65.¯HepaticglucoseproductionGlucose-dependentinsulin(GLP-1&GIP)Glucose-dependent¯glucagon(GLP-1)Pancreas-cells-cellsReleaseofactiveincretinsGLP-1&GIPDPP-4inactivatesGLP-1&GIPGItractIngestionoffoodGLP-1和

6、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β细胞增殖是是促进胰岛素生物合成是是DruckerDJ.DiabetesCare.2003;26:2929-2940.TheIncretinEffectisReducedinType2DiabetesAdaptedfromNauckM,etal.Diabetologia.1986;29:46-52.Oralglucose(50g)IVg

7、lucose(variable)Responsestoanoralglucoseloadof50gandintravenousglucoseinfusionweremeasuredin14type2diabeticpatientsand8healthycontrolsubjects.Responsestoglucoseloadintype2diabeticsandhealthysubjectsControlsubjects(N=8)Type2diabeticpatients(N=14)Oralglucose(50g)IVglucose(variable)

8、Venousplasmaglucose(mmol/l)Time(min)Time