1、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-4 61973-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.Bull Acad R.Me
2、d 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.Endocrinology.1995;136;33
3、85-3596.10.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
4、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Nauck et al.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 Normoglycaemia Glucose uptake by pe
5、ripheral tissueAdapted from Drucker DJ.Cell Metab.2006;3:153-65.Hepatic glucose productionGlucose-dependent insulin(GLP-1&GIP)Glucose-dependent glucagon(GLP-1)Pancreas-cells-cellsRelease ofactive incretinsGLP-1&GIPDPP-4inactivates GLP-1&GIPGI tractIngestion of foodGLP-1和GIP 是两类主要的肠促胰素GLP-1（胰高糖素样肽-1）
6、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 DiabetesAdapted from Nauck M,et al.Diabetologia.1986;29:46-52.Oral glucose(50g)IV glucose(variable)Responses to
7、 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)Venous
8、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)120180601201806002020101(nmo
9、l/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.Lancet.2002;359(9
10、309):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 concentration in plasma(mmo
11、l/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.GIP given at supraphysiological
12、 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 not only did not lower postprandial gl
13、ucose 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
14、，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 1993,91:301-307Sites of Action of GLP-1BrainGlucose productionNeuroprotectionAppetiteLiverStomachGastric emptyingGI tractInsulin biosynthesis-cell proliferation-cell apoptosisInsulin secretionGlucagon secretionMuscleHeartCardiop
15、rotectionCardiac 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-1Adapted from:Flint A,et al.J Clin Invest.1998;101:515-20.Holst JJ.TEM.2005;10:229-35.Lovshin JA,Drucker DJ.Nat Rev
16、Endocrinol.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.Kieffer TJ,et al.Endocr Rev.1999;20:876-9132.Drucker DJ.Curr Pharm Des.2001;7:1399-412.3.Drucker DJ.Mol Endocrinol.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入量 增强胰岛素基因的转录可
17、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)Adapted from:Nauck MA,et al.Diabetologia.1993;36:741-4.-30060120180240270180900安慰剂*GLP-1葡萄糖(mg/dL)安慰剂GLP-13002001000*GLP-1安慰剂-30060120180240胰岛素(pmol/L)20100*GLP-1安慰剂-30060120180240胰高血糖素(pmo
18、l/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)PG50Ward WK,et al.J Clin Invest.1984;74:13181328.Dunning B,et al.D
19、iabetologia.2005;48:17001713 糖尿病前期胰高糖素异常J J Holst,Diabetologia(2009)52:17141723Bo Ahren,European Journal of Endocrinology(1997)137 127131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70010001600200024000.02.55.07.510.0*Time of DayBlood Glucose(mM)GR-/-GR+/+RW Gelling et al.PNAS 100:1438-1443,2003血糖(随意饲养)血糖时间(天)T2DM
20、是胰岛素分泌不足和胰高糖素分泌增加致高血糖 Mller WA,et al.N Engl J Med.1970;283:109115碳水化合物膳食胰高糖素时间(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Creutzfeldt WO,et al.Diabetes Care.1996;19:580-6.*GLP-1P .001PlaceboGLP-1 or PlaceboPlaceboG
21、LP-1P .001 *GLP-1 or PlaceboGLP-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Jesper Gromada Endocrine Reviews 28(1):84116GLP-1在体内快速降解1 2 330GLP-1 Des-HA-GLP-1(失活)GLP-1被二肽基肽酶-4（DPP-4）降解失活半衰期1-2分钟1 23 30DPP-4提高 GLP-1作用的治
22、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;Barnett,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
23、T2DM),data are means-100-80-60-40-2002004812162024Time post-dose(h)Plasma DPP4 activity(%change from baseline).Placebo(n=7)2.5 mg(n=6)5 mg(n=5)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Br J Diabetes Vase Dis 2010;10:14-20b-Cell Stimulation by Saxagliptin in Patients with T2DStudy schemaSA
24、XA:saxagliptin;PBO,placebo;BMI:body mass index;T2D:type 2 diabetes.n=156n=46SAXA5 mgPBOScreeningSingle-blind lead-in2 weeksDouble-blindtreatment12 weeksInclusion Treatment nave T2D 18-70 years old HbA1c 6-8%BMI 40 kg/m2 Fasting C-peptide1 ng/mLDiet&exerciseplaceboSubjects wereprovided with:Meters to
25、monitor glucose Blood glucose self-monitoring instructionn=20n=16RandomisationAdapted 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 1.0 ng/mLu未服用药物的患者uBMI 40 kg/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:CV18104
26、1 3.3.1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。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:CV181041 3.5.1.1研究 041b-Cell Stimulation by Saxagliptin in Patients with
27、 T2DMethodsSAXA:saxagliptin;PBO:placebo;IV:intravenous.*Glucose infusion to achieve 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-s
28、pecified intervals.Sequential IV-Oral hyperglycaemic clamp and arginine stimulation testPlasma glucose(mg/dL)4001005052004503002804805151801200-30Time(min)75 g oralglucosechallengeStartglucoseinfusion*SAXAorPBOIV hyperglycaemic clampIV-Oral hyperglycaemic clampArgininestimulation testSamplesGlucoseI
29、nsulinGlucagonGLP-1GIP0Adapted from Henry R,et al.Poster presented 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:CV181041 Figure 7.1(App.5.3.4)研究 041胰岛素分泌率平均值 (pmol/kg*min)分钟胰岛素分泌率平均值 (pmol/kg*min)分钟10沙格列汀 5
30、mg安慰剂10主要和次要有效性终点Source:CV181041 Table 7.1研究 041有效性终点(12 周)沙格列汀 5 mgn=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)2817.73687.0 12 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1815 基线几何平均值446.3593.5 24周 LOCF几何平
31、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*估值=100*exp(校正后自基线的自然对数平均值的变化)-1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-Cell Stimulation by Saxagliptin in Patients with T2DInsulin secretion rates in the postprandial stateSAXA 5 mg(n=16)PBO
32、(n=15)30-101020Geometric mean%changefrom baseline-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.-2.2-12.49.315.94.229.0Insulin secretion rate during IV-O
33、ral hyperglycaemic clamp:adjusted%change from baseline at Week 12(LOCF)Insulin secretion rate(pmol/kg)*Baseline28183687Week 12(LOCF)33033564Adjusted%difference PBO(95%CI):18.5(1.3,38.7)P=0.035Adapted from Henry R,et al.Poster presented at EASD.Sep 27-Oct 1,2009.Vienna,Austria.422HQ09NP101b-Cell Stim
34、ulation by Saxagliptin 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.-4.1-17.41
35、1.222.67.240.4Insulin 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 baselineAdapted
36、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=16)(n=14)Baselin
37、e,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:placebo;IV,intravenous;T2D:type 2 diabetes.Adapte
38、d 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:CV181041 Section 7.4.3.1(App.5.6.3)研究 041单位:pg*min/mL沙格列汀 5 mgn=20安慰剂n=16统计学结果 病例数1714 基线平均值
39、(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,-333 p-值0.0308a 沙格列汀5 mg与安慰剂自基线变化的差异 b 估值=沙格列汀 5 mg校正后平均值变化 安慰剂校正后平均值变化
40、Henry et al.Diabetes,Obesity and Metabolism 2011;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 concentrations during IV-Oral hyperglycaemic c
41、lamp360Time(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 mg-Week 12PBO-Week 12PBO-BaselineSAXA 5 mg-Baseline80
42、6040201024021018075 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)422HQ09NP101A1C Changes from Baseline at Week 12(LOCF)Source:CV181
43、041 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(0.094)Adjusted from baseline Mean(SE)-0.14(0.118)0.02(0.125)95%two-sided CI-0.38,0.10
44、-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 041Mean Change from Baselinewith 95%CIGlucose AUC During OGTT Changes from Baseline at Week 12(LOCF)Study 041Mean Change from Baselinewith 95%CISAXA 5 mgPBOn=1615Baseline Mean(mgmin/dL)5910850473Source:CV181041 Section 7.4.1.3(App.5.4.7)
