沙格列汀的作用机制学习教案

1、会计学1沙格列汀的作用沙格列汀的作用(zuyng)机制机制第一页，共40页。肠促胰岛激素(j s)简史1902-首次观察(gunch)到藏到对胰岛分泌的影响1,21932-首次(shu c)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

2、 et al. J Phystol. 1902;28:325-353.3.La Barre J. Bull 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

3、et al. Lancet. 1987;2:1300-1304.9.Kieffer TJ et al. Endocrinology. 1995;136;3385-3596.10.Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952-957.第1页/共40页第二页，共40页。静脉(jngmi)血浆葡萄糖 (mmol/L)时间(shjin) (分钟)C-肽 (nmol/L)115.500.00.51.01.52.0时间(shjin) (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

4、 = 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016012018002肠促胰素效应第2页/共40页第三页，共40页。Nauck et al. Diabetologia. 19862型糖尿病患者肠促胰岛素效应(xioyng)减弱口服葡萄糖静脉注射葡萄糖Time (min)Insulin (mU/l)8060402001

5、80601200Time (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)第3页/共40页第四页，共40页。Normoglycaemia Glucose uptake by peripheral tissueAdapted from Drucker DJ. Cell Metab. 2006;3:153-65. Hepatic glucose productionGlucose- dependent insulin(GLP-1 & GIP)Glucose-dependent glucagon(GLP-

6、1) Pancreas-cells-cellsRelease ofactive incretinsGLP-1 & GIPDPP-4inactivates GLP-1 & GIPGI tractIngestion of food第4页/共40页第五页，共40页。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-

7、2940.第5页/共40页第六页，共40页。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

8、type 2 diabetics and healthy subjectsControl subjects (N=8)Type 2 diabetic patients (N=14)Oral glucose (50g)IV glucose (variable)Venous plasma glucose (mmol/l)Time (min)Time (min)010151201800160051015512018001600202Venous immunoreactiveinsulin (mU/l)(nmol/l)020406080020406080000.10.30.40.60.50.20.10

9、.30.40.60.50.2*Venous plasma glucose (mmol/l)*P0.05 to the respective value after the oral loadTime (min)Time (min)120180601201806002020101(nmol/l)Venous immunoreactiveinsulin (mU/l)第6页/共40页第七页，共40页。第7页/共40页第八页，共40页。Adapted from Zander M, et al. Lancet. 2002;359(9309):824-30. Compared to saline, pat

10、ients 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 (mmol/L)008246082462520151050252

11、015105Week 0Week 1Week 6Time (hr)Time (hr)Glucose concentration in plasma (mmol/L)第8页/共40页第九页，共40页。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 diabetesTime (min)GIPPlacebo45525652801803

12、8080-20Insulin (mg/mL)Glucose (mg/dL)45525656040200Time (min)19011015023028018038080-201401902406040200When 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

13、 2 diabetes (N=22)Changes in insulinChanges in glucose*P0.05 vs placebo第9页/共40页第十页，共40页。Nauck.MA et al.J Clin Invest 1993,91:301-307第10页/共40页第十一页，共40页。BrainGlucose productionNeuroprotectionAppetiteLiverStomachGastric emptyingGI tractInsulin biosynthesis-cell proliferation-cell apoptosisInsulin secre

14、tionGlucagon secretionMuscleHeartCardioprotectionCardiac outputInsulinsensitivityAdapted from Drucker DJ. Cell Metab. 2006;3:153-65.Pancreas第11页/共40页第十二页，共40页。促进饱腹感，降低(jingd)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(tioji)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

15、;101:515-20. Holst JJ. TEM. 2005;10:229-35. Lovshin JA, Drucker DJ. Nat Rev Endocrinol. 2009;5:262-9.细胞 工作负荷细胞 反应第12页/共40页第十三页，共40页。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

16、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uGLP-1R在胰岛细胞(xbo)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第13页/共40页第十四页，共40页。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

17、GLPGLP-1安慰剂-30060120180240胰岛素 (pmol/L)20100*GLP-1安慰剂-30060120180240胰高血糖素 (pmol/L)时间(shjin) (分钟)平均值(SE); *P0.05GLP-1以葡萄糖依赖性方式增加(zngji)胰岛素的分泌第14页/共40页第十五页，共40页。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(xutng)水平T2DM = 2型糖尿病; * 健康者平均年龄 1829岁 NGT* (n = 8)T2DM (n = 8)180 -15

18、0 -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. Diabetologia. 2005;48:17001713第15页/共40页第十六页，共40页。J J Holst, Diabetologia (2009) 52:17141723Bo Ahren, European Journal of Endocrinology (1997) 137 127131糖尿病前

19、期(qinq)状态的病理生理学第16页/共40页第十七页，共40页。GR-/-GR+/+RW Gelling et al. PNAS 100: 1438-1443, 2003血糖(xutng) (随意饲养)血糖(xutng)时间 (天)第17页/共40页第十八页，共40页。 Mller WA, et al. N Engl J Med. 1970;283:109115碳水化合物膳食(shnsh)胰高糖素时间(shjin) (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

20、量2型糖尿病正常葡萄糖耐量2型糖尿病第18页/共40页第十九页，共40页。Creutzfeldt WO, et al. Diabetes Care. 1996;19:580-6. 024681012-30 030 60 90 11122 Glucagon (pmol/L)Time (min)050100150200250300350-30 030 60 90 11122 Plasma Glucose (mg/dL)Time (min)*GLP-1P .001PlaceboGLP-1 or PlaceboPlaceboGLP-1P .001 *GLP-1 or Placebo第19页/共40页第

21、二十页，共40页。Jesper Gromada Endocrine Reviews 28 (1): 84116第20页/共40页第二十一页，共40页。1 2 330GLP-1 Des-HA-GLP-1 (失活)GLP-1被二肽基肽酶-4（DPP-4）降解(jin ji)失活半衰期1-2分钟1 23 30DPP-4提高 GLP-1作用(zuyng)的治疗方法:模拟 GLP-1作用(zuyng)的药物 (肠促胰岛素类似物) DPP-4 酶抑制剂Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994 第21页/

22、共40页第二十二页，共40页。食物(shw)摄入胃胃肠道肠增加和延长(ynchng)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肠促胰岛素第22页/共40页第二十三页，共40页。CV181002 (MAD in T2DM), data are means血 浆 DPP4 活 性 ( 自基线(jxin)的变化% )第23页/共40页第二十四页，共40页。DPP-4抑制剂沙格列汀Br J Diabe

23、tes Vase Dis 2010; 10:14-20第24页/共40页第二十五页，共40页。SAXA: saxagliptin; PBO, placebo; BMI: body mass index; T2D: type 2 diabetes.n=156n=46SAXA5 mgPBOScreeningSingle-blind lead-in2 weeksDouble-blindtreatment12 weeksInclusionTreatment naveT2D18-70 years oldHbA1c 6-8%BMI 40 kg/m2Fasting C-peptide1 ng/mLDiet

24、& exerciseplaceboSubjects wereprovided with:Meters tomonitor glucoseBlood glucose self-monitoring instructionn=20n=16RandomisationAdapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101第25页/共40页第二十六页，共40页。Source: CV181041 3.3.1研究(ynji) 041第26页/共40页

25、第二十七页，共40页。Source: CV181041 3.5.1.1研究(ynji) 041第27页/共40页第二十八页，共40页。SAXA: 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

26、, 50 mL IV over 30 sec) administered at 505 min. Samples drawn at protocol-specified intervals.Sequential IV-Oral hyperglycaemic clamp and arginine stimulation testPlasma glucose (mg/dL)4001005052004503002804805151801200-30Time (min)75 g oralglucosechallengeStartglucoseinfusion*SAXAorPBOIV hyperglyc

27、aemic clampIV-Oral hyperglycaemic clampArgininestimulation testSamplesGlucoseInsulinGlucagonGLP-1GIP0Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.T2D: type 2 diabetes422HQ09NP101第28页/共40页第二十九页，共40页。基线和12周(LOCF)时，高糖钳夹试验(shyn)中，在空腹（0-180分钟）和OGTT后（180-480分钟

28、）状态的胰岛素分泌率Source: CV181041 Figure 7.1 (App. 5.3.4)研究(ynji) 04105101520060 120180240300360420480基线基线12周周 (LOCF)胰岛素分泌(fnm)率平均值 (pmol/kg*min)分钟05101520060 120180240300360420480基线基线 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第29页/共40页第三十页，共40页。Source: CV181041 Table 7.1研究(ynji) 041有效性终点( 12 周)沙格

29、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

30、区别% b27.9 与安慰剂对照的P-值*0.0204*第30页/共40页第三十一页，共40页。SAXA 5 mg (n=16)PBO (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 o

31、bservation carried forward.-2.2-12.49.315.94.229.0Insulin secretion rate during IV-Oral 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

32、Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101第31页/共40页第三十二页，共40页。40-101020-200-* 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 o

33、bservation carried forward.-4.1-17.411.222.67.240.4Insulin 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)PB

34、O (n=15)Geometric mean % changefrom baselineAdapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101第32页/共40页第三十三页，共40页。Insulin secretion in first 5 minutes following IV arginineSAXA 5 mgPBOAcute insulin response, mU/mL(n=16)(n=14) Baseline, median (Q1,

35、 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: t

36、ype 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第33页/共40页第三十四页，共40页。Source: CV181041 Section 7.4.3.1 (App. 5.6.3)研究(ynji) 041单位: pg*min/mL沙格列汀 5 mgn = 20安慰剂n

37、 = 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, -333 p-值0.0308a 沙格列汀5 mg与安慰

38、剂自基线(jxin)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第34页/共40页第三十五页，共40页。Henry et al. Diabetes, Obesity and Metabolism 2011;13: 850-858.沙格列汀单剂治疗降低(jingd)胰高糖素水平沙格列汀降低(jingd)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周第35页/共40页第三十六页，共40页。SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes.360Time (min)Mean active GLP-1 conce