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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1.Creutzfeldt W. Regul Pept. 2005; 128:87-91.2.Bayliss WM et al. J Phystol. 1902;28:325-353.3.La Barre J. B
2、ull Acad R. Med Belg. 1932;120:620-634.4.McIntyre N et al. Lancet. 1964;41:20-21.5.Elrick H et al. J Clin Endocr. 1964;24:1076-1082.6.Hopsu-Havu VK, Glenner GG. Histochemle. 1966;7(3):197-201.7.Nauck M et al. Diabetologia. 1986;29:46-52.8.Kreymann B et al. Lancet. 1987;2:1300-1304.9.Kieffer TJ et al
3、. Endocrinology. 1995;136;3385-3596.10.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)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;*P0.05;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
4、萄糖（50g）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)Role of Incretin System in Glucose Homeostasis Normoglycaem
5、iaGlucoseuptakebyperipheraltissueAdaptedfromDruckerDJ.CellMetab.2006;3:153-65.HepaticglucoseproductionGlucose-dependentinsulin(GLP-1&GIP)Glucose-dependentglucagon(GLP-1)Pancreas-cells-cellsReleaseofactiveincretinsGLP-1&GIPDPP-4inactivatesGLP-1&GIPGItractIngestionoffoodGLP-1和GIP是两类主要的肠促胰素GLP-1（胰高糖素样肽
6、-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DruckerDJ.DiabetesCare.2003;26:2929-2940.The Incretin Effect is Reduced in Type 2 DiabetesAdapted from Nauck M, et al. Diabetologia. 1986;29:46-52. Oral glucose (50g)IV glucose (variable)Responses t
7、o 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 subjectsControl subjects (N=8)Type 2 diabetic patients (N=14)Oral glucose (50g)IV glucose (variable)V
8、enous plasma glucose (mmol/l)Time (min)Time (min)010151201800160051015512018001600202Venous immunoreactiveinsulin (mU/l)(nmol/l)020406080020406080000.10.30.40.60.50.20.10.30.40.60.50.2*Venous plasma glucose (mmol/l)*P0.05 to the respective value after the oral loadTime (min)Time (min)120180601201806
9、002020101(nmol/l)Venous immunoreactiveinsulin (mU/l)Incretin hormone changesIn patients with type 2 diabetes, levels of GLP-1 released in response to glucose are reduced and GIP activity is decreasedContinuous Infusion of GLP-1 Decreases Fasting Glucose as well as HbA1cAdapted from Zander M, et al.
10、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 HbA1c that was decreased by 1.3% (P=0.003)Patients assigned saline (N=9)Patients assigned GLP-1 (N=10)Glucose co
11、ncentration in plasma (mmol/L)008246082462520151050252015105Week 0Week 1Week 6Time (hr)Time (hr)Glucose concentration in plasma (mmol/L)Exogenous GlucoseDependent Insulinotropic Polypeptide Worsens Postprandial Hyperglycaemia in Type 2 DiabetesAdapted from Chia CW, et al. Diabetes. 2009;58(6):1342-9
12、.GIP given at supraphysiological levels still has an early,short-lived insulinotropic effect in type 2 diabetesTime (min)GIPPlacebo455256528018038080-20Insulin (mg/mL)Glucose (mg/dL)45525656040200Time (min)19011015023028018038080-201401902406040200When compared with placebo, exogenous GIP infusion n
13、ot 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 insulinChanges 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u肠促胰岛素的效应在2型糖尿病患者中减弱u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
14、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u2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.MAetal.JClinInvest1993,91:301-307Sites of Action of GLP-1BrainGlucose productionNeuroprotectionAppetiteLiverStomachGastric emptyingGI tractInsulin biosynthesis-cell proliferation-cell apoptosisInsulin secretionGlu
15、cagon secretionMuscleHeartCardioprotectionCardiac outputInsulinsensitivityAdapted from Drucker DJ. Cell Metab. 2006;3:153-65.PancreasGLP-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-1Adaptedfrom:FlintA,etal.JClinInvest.1998;101:515-20.HolstJJ.TEM.2005;10:229-35.L
16、ovshinJA,DruckerDJ.NatRevEndocrinol.2009;5:262-9.细胞工作负荷细胞反应胰高血糖素样肽-1(GLP-1)进食后由肠道L细胞分泌GLP-1在进食后数分钟内开始分泌，对食物中脂类和碳水化合物的反应最为明显1.KiefferTJ,etal.EndocrRev.1999;20:876-9132.DruckerDJ.CurrPharmDes.2001;7:1399-412.3.DruckerDJ.MolEndocrinol.2003;17:161-71.在人体和动物体内在动物体内和体外研究中促进葡萄糖刺激的胰岛素分泌抑制胰高血糖素的释放延缓胃排空减少食物的摄
17、入量增强胰岛素基因的转录可能通过以下途径增加细胞数量-刺激新生细胞的形成-抑制细胞凋亡uGLP-1通过其受体（GLP-1R）发挥作用GLP-1R在胰岛细胞上表达，受刺激后，可激活cAMP，以及蛋白激酶A依赖性或非依赖性的作用2型糖尿病(n=10)Adaptedfrom:NauckMA,etal.Diabetologia.1993;36:741-4.-30 060120180240270180900安慰剂*GLP-1葡萄糖(mg/dL)安慰剂GLP-13002001000*GLP-1安慰剂-30 060120180240胰岛素(pmol/L)20100*GLP-1安慰剂-30 060120180
18、240胰高血糖素(pmol/L)时间(分钟)平均值(SE);*P0.05GLP-1以葡萄糖依赖性方式增加胰岛素的分泌T2DM中胰岛细胞对葡萄糖的敏感性降低AGRarg=2-5分钟对精氨酸的平均急性胰高糖素反应；PG50=对AGRarg的抑制达最大值的一半时所需的血糖水平T2DM=2型糖尿病;*健康者平均年龄1829岁NGT*(n=8)T2DM(n=8)180-150-120-90-60-30-0100200300400500600700AGRarg(pg/mL)血糖水平(mg/dL)PG50WardWK,etal.JClinInvest.1984;74:13181328.DunningB,et
19、al.Diabetologia.2005;48:17001713糖尿病前期胰高糖素异常JJHolst,Diabetologia(2009)52:17141723BoAhren,EuropeanJournalofEndocrinology(1997)137127131糖尿病前期状态的病理生理学胰高血糖素受体敲除小鼠血糖水平降低GR-/-GR+/+RWGellingetal.PNAS100:1438-1443,2003血糖(随意饲养)血糖时间(天)T2DM是胰岛素分泌不足和胰高糖素分泌增加致高血糖MllerWA,etal.NEnglJMed.1970;283:109115碳水化合物膳食胰高糖素时间
20、(分钟)7510012515060060120180240pg/mL胰岛素050100150U/mL0血糖100200300400mg/dL正常葡萄糖耐量2型糖尿病正常葡萄糖耐量2型糖尿病正常葡萄糖耐量2型糖尿病GLP-1降低1型糖尿病患者的胰高糖素和血糖水平CreutzfeldtWO,etal.DiabetesCare.1996;19:580-6.Time (min)Glucagon (pmol/L)-300306090 120 150 180 210 240 024681012Time (min)Plasma Glucose (mg/dL)-300306090 120 150 180 21
21、0 240 050100150200250300350*GLP-1P.001PlaceboGLP-1orPlaceboPlaceboGLP-1P.001*GLP-1orPlaceboGLP-1抑制胰高糖素分泌并非由胰岛素介导uGLP-1抑制胰岛细胞功能无残留的1型糖尿病患者的胰高血糖素分泌u在2型糖尿病中，在不足以导致可测出胰岛素分泌的血糖水平下，GLP-1能抑制胰高血糖素的分泌l没有证据显示其他非肠促胰素类降糖药物对人胰高糖素分泌起作用JesperGromadaEndocrineReviews28(1):84116GLP-1在体内快速降解12330GLP-1Des-HA-GLP-1(失活)G
22、LP-1被二肽基肽酶-4（DPP-4）降解失活半衰期1-2分钟12330DPP-4提高GLP-1作用的治疗方法:1)模拟GLP-1作用的药物(肠促胰岛素类似物)2)DPP-4酶抑制剂Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994 DPP4抑制剂作用机理食物摄入胃胃肠道肠增加和延长GLP-1对细胞的影响:细胞：胰腺胰岛素释放净效应：血糖细胞:增加和延长GLP-1和GIP对细胞的作用：DPP4抑制剂胰高血糖素分泌Drucker和Nauck,2006;Idris和Donnelly,2007;Barnet
23、t,2006肠促胰岛素临床药效学:稳定状态下，血浆中不同剂量的DPP-4活性CV181002 (MAD in T2DM), data are means血浆DPP4活性(自基线的变化%)DPP-4抑制剂沙格列汀具有双重作用机制DPP-4抑制剂沙格列汀BrJDiabetesVaseDis2010;10:14-20b-Cell Stimulation by Saxagliptin in Patients with T2DStudy schemaSAXA: saxagliptin; PBO, placebo; BMI: body mass index; T2D: type 2 diabetes.n=
24、156n=46SAXA5 mgPBOScreeningSingle-blind lead-in2 weeksDouble-blindtreatment12 weeksInclusionTreatment naveT2D18-70 years oldHbA1c 6-8%BMI 40 kg/m2Fasting C-peptide1 ng/mLDiet & exerciseplaceboSubjects wereprovided with:Meters tomonitor glucoseBlood glucose self-monitoring instructionn=20n=16Randomis
25、ationAdapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101入选标准u2型糖尿病病人u筛选访视时，糖化血红蛋白6.0%和8.0%u空腹C-肽浓度1.0ng/mLu未服用药物的患者uBMI40kg/m2u男性和女性,18和70岁.女性必须是不在哺乳期和妊娠期Source:CV1810413.3.1研究041有效性终点u主要有效性终点主要有效性终点是在肠内给糖的高糖钳夹试验中静脉-口服高糖钳夹试验，180-480分钟，胰岛素分泌率曲线下面积在1
26、2周时自基线变化的百分比。如果没有12周的测量值，将采用12周前基线后的最后一次测量值。u次要有效性终点次要有效性终点是在静脉高糖钳夹试验中（120-180分钟），胰岛素分泌率曲线下面积在12周时自基线变化的百分比。如果没有12周的测量值，将采用12周前基线后的最后一次测量值。Source:CV1810413.5.1.1研究041b-Cell Stimulation by Saxagliptin in Patients with T2DMethodsSAXA: saxagliptin; PBO: placebo; IV: intravenous.* Glucose infusion to ac
27、hieve and maintain hyperglycaemia = 280 mg/dL from 0 - 480 min. At 480 min, infusion adjusted to maintain hyperglycaemia = 450 mg/dL. Arginine 5 g (10% solution, 50 mL IV over 30 sec) administered at 505 min. Samples drawn at protocol-specified intervals.Sequential IV-Oral hyperglycaemic clamp and a
28、rginine stimulation testPlasma glucose (mg/dL)4001005052004503002804805151801200-30Time (min)75 g oralglucosechallengeStartglucoseinfusion*SAXAorPBOIV hyperglycaemic clampIV-Oral hyperglycaemic clampArgininestimulation testSamplesGlucoseInsulinGlucagonGLP-1GIP0Adapted from Henry R, et al. Poster pre
29、sented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.T2D: type 2 diabetes422HQ09NP101基线和12周(LOCF)时，高糖钳夹试验中，在空腹（0-180分钟）和OGTT后（180-480分钟）状态的胰岛素分泌率Source:CV181041Figure7.1(App.5.3.4)研究041060120 180 240 300 360 420 48005101520基基线线12周周 (LOCF)胰岛素分泌率平均值(pmol/kg*min)分钟060120 180 240 300 360 420 48005101520基
30、基线线 12周周 (LOCF)胰岛素分泌率平均值(pmol/kg*min)分钟10沙格列汀5mg安慰剂10主要和次要有效性终点Source:CV181041Table7.1研究041有效性终点(12周)沙格列汀5mgn=20安慰剂n=16静脉-口服钳夹试验中胰岛素分泌(pmol/kg)(180-480分钟)病例数1615基线平均值(SE)2817.73687.012周LOCF平均值3303.13564.3校正后自基线的几何平均值的变化%a15.9-2.2校正后与安慰剂的差异%b18.5与安慰剂对照的P-值*0.0350*静脉钳夹试验中胰岛素分泌(pmol/kg)(120-180分钟)病例数18
31、15基线几何平均值446.3593.524周LOCF几何平均值552.1563.1校正后自基线的几何平均值的变化%a22.6-4.1校正后与安慰剂的区别%b27.9与安慰剂对照的P-值*0.0204*a a估值=100*exp(校正后自基线的自然对数平均值的变化)-1b b 估值=100*exp(校正后沙格列汀5mg和安慰剂间自然对数平均值变化的差异)-1*在alpha=0.05水平有意义时，比较沙格列汀5mg和安慰剂b-CellStimulationbySaxagliptininPatientswithT2DInsulinsecretionratesinthepostprandialstat
32、eSAXA5mg(n=16)PBO(n=15)30-101020Geometricmean%changefrombaseline-200-*Valuesaregeometricmeans;Adjusted%changefrombaseline,geometricmeanand95%CI(representedbybar)SAXA:saxagliptin;PBO:placebo;T2D:type2diabetes;LOCF,lastobservationcarriedforward.-2.2-12.49.315.94.229.0InsulinsecretionrateduringIV-Oralh
33、yperglycaemicclamp:adjusted%changefrombaselineatWeek12(LOCF)Insulin secretion rate (pmol/kg)*Baseline28183687Week 12 (LOCF)33033564Adjusted%differencePBO(95%CI):18.5(1.3,38.7)P=0.035AdaptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vienna,Austria.422HQ09NP101b-Cell Stimulation by Saxaglip
34、tin in Patients with T2DInsulin secretion rates in the fasting state40-101020-200-* Values are geometric means; Adjusted % change from baseline, geometric mean and 95% CI (represented by bar)SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes; LOCF, last observation carried forward.-4.1-17.411.222
35、.67.240.4Insulin secretion rate during IV hyperglycaemic clamp:adjusted % change from baseline at Week 12 (LOCF)Insulin secretion rate (pmol/kg)*Baseline446594Week 12 (LOCF)552563Adjusted % difference PBO (95% CI):27.9 (4.2, 57.1)P=0.02030-SAXA 5 mg (n=18)PBO (n=15)Geometric mean % changefrom baseli
36、neAdapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101b-Cell Stimulation by Saxagliptin in Patients with T2D Insulin secretion following IV arginineInsulin secretion in first 5 minutes following IV arginineSAXA 5 mgPBOAcute insulin response, mU/mL(n
37、=16)(n=14) Baseline, median (Q1, Q3)164 (107, 203)204 (175, 268) Week 12, median (Q1, Q3)172 (136, 228)185 (147, 208) Change from baseline*, median (Q1, Q3)24.0 (-5.8, 71.5)-21.7 (-52.3, 5.3)* LOCF: last observation carried forward.P value vs PBO = 0.074 (Kruskal-Wallis test)SAXA: saxagliptin; PBO:
38、placebo; IV, intravenous; T2D: type 2 diabetes.Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.Insulin secretion following IV arginine: changes from baseline at Week 12422HQ09NP101静脉-口服高糖钳夹试验中，胰高糖素曲线下面积12周(LOCF)时自基线的变化Source:CV181041Section7.4.3.1(App.5.6.3
39、)研究041单位:pg*min/mL沙格列汀5mgn=20安慰剂n=16统计学结果病例数1714基线平均值(SE)14279(1228.2)11177(880.2)12周LOCF平均值(SE)11571(1112.7)12965(1272.5)自基线变化的平均值(SE)-2708(864.9)1788(1247.5)校正后自基线的变化平均值(SE)-2191(957.8)1161(1061.9)95%双侧检验的可信区间-4153,-229-1014,3336与安慰剂的不同a平均值(SE)b-3352(1473.8)95%双侧检验的可信区间-6371,-333p-值0.0308a沙格列汀5mg与
40、安慰剂自基线变化的差异b估值=沙格列汀5mg校正后平均值变化安慰剂校正后平均值变化Henryetal.Diabetes,ObesityandMetabolism2011;13:850-858.沙格列汀单剂治疗降低胰高糖素水平沙格列汀降低胰高糖素水平达15.4%胰高血糖素pg/ml75g口服葡萄糖测试沙格列汀5mg:基线沙格列汀5mg:12周SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes.b-Cell Stimulation by Saxagliptin in Patients with T2D GLP-1 and GIP concen
41、trations during IV-Oral hyperglycaemic clamp360Time (min)Mean active GLP-1 concentrations (pmol/L)0270 300420480GLP-1SAXA 5 mg - Week 12PBO - Week 12PBO - BaselineSAXA 5 mg - Baseline5432124021018075 g oralglucose challenge360Time (min)Mean active GIP concentrations (pmol/L)0270 300420480GIPSAXA 5 m
42、g - Week 12PBO - Week 12PBO - BaselineSAXA 5 mg - Baseline806040201024021018075 g oralglucose challenge305070Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.Active GLP-1 and GIP concentrations during IV-Oral hyperglycemic clamp at baseline and Week 12 (LOCF
43、)422HQ09NP101A1C Changes from Baseline at Week 12 (LOCF)Source: CV181041 Section 7.4.4 (App. 5.7.1)Study 041Unit: PercentSAXA 5 mgn = 20PBOn = 16Summary Statistics n1816 Baseline mean (SE)6.94 (0.117)6.59 (0.144) Week 12 LOCF mean (SE)6.77 (0.155)6.64 (0.167) Mean from baseline (SE)-0.17 (0.133)0.05
44、 (0.094)Adjusted from baseline Mean (SE)-0.14 (0.118)0.02 (0.125) 95% two-sided CI-0.38, 0.10-0.23, 0.28Fasting Plasma Glucose Changes from Baseline at Week 12 (LOCF)Source: CV181041 Section 7.4.1.5 (App. 5.7.2)Study 041-1001020302.412.4-8.50.813.323.9Mean Change from Baselinewith 95% CISAXA 5 mgSAX
45、A 5 mgPBOPBOn =n =18181616Baseline MeanBaseline Mean( (mg/dL)mg/dL)133.2133.2124.7124.7Glucose AUC During OGTT Changes from Baseline at Week 12 (LOCF)Study 041-10000-50000500010000-37712844-9905-350523639193Mean Change from Baselinewith 95% CISAXA 5 mgPBOn =1615Baseline Mean(mgmin/dL)5910850473Source: CV181041 Section 7.4.1.3 (App. 5.4.7)41 以上有不当之处，请大家给与批评指正，以上有不当之处，请大家给与批评指正，谢谢大家！谢谢大家！
