沙格列汀的作用機(jī)制學(xué)習(xí)教案

1、會(huì)計(jì)學(xué)1沙格列汀的作用沙格列汀的作用(zuyng)機(jī)制機(jī)制第一頁(yè)，共40頁(yè)。腸促胰島激素(j s)簡(jiǎn)史1902-首次觀察(gunch)到藏到對(duì)胰島分泌的影響1,21932-首次(shu c)確定腸促胰島素31964-證實(shí)倉(cāng)促胰島素效應(yīng)1,4,51966-首次描述DPP-4 61973-GIP被確定為一種人類(lèi)長(zhǎng)促胰島素11986-證實(shí)了長(zhǎng)促胰島素在2型糖尿病患者中的作用71995-DPP-4被確定為一種滅活GIP和GLP-1的酶 9,101987-GLP-1被確定為一種人類(lèi)長(zhǎng)促胰島素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頁(yè)/共40頁(yè)第二頁(yè)，共40頁(yè)。靜脈(jngmi)血漿葡萄糖 (mmol/L)時(shí)間(shjin) (分鐘)C-肽 (nmol/L)115.500.00.51.01.52.0時(shí)間(shjin) (分鐘)016012018002口服葡萄糖 靜脈注射葡萄糖*平均值 SE; n=6; *P0.05; 01-02

4、 = 葡萄糖輸注時(shí)間腸促胰素效應(yīng)的發(fā)現(xiàn)與靜脈注射葡萄糖相比，口服葡萄糖增強(qiáng)了 -細(xì)胞反應(yīng)Nauck J. Clin Endocrinol Metab. 1986;63:492-8.檢測(cè)8名健康對(duì)照受試者口服葡萄糖（50 g）和靜脈注射葡萄糖的反應(yīng)與靜脈注射葡萄糖相比，口服葡萄糖后，患者的血清C肽水平更高，由此證實(shí)了腸促胰素效應(yīng)016012018002腸促胰素效應(yīng)第2頁(yè)/共40頁(yè)第三頁(yè)，共40頁(yè)。Nauck et al. Diabetologia. 19862型糖尿病患者腸促胰島素效應(yīng)(xioyng)減弱口服葡萄糖靜脈注射葡萄糖Time (min)Insulin (mU/l)8060402001

5、80601200Time (min)Insulin (mU/l)806040200180601200腸促胰島素效應(yīng)非糖尿病組 (n=8)2型糖尿病組 (n=14)第3頁(yè)/共40頁(yè)第四頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第五頁(yè)，共40頁(yè)。GLP-1（胰高糖素樣肽-1）GIP（葡萄糖依賴(lài)的促胰島素釋放多肽）主要合成部位L 細(xì)胞(回腸和結(jié)腸)K 細(xì)胞 (十二指腸和空腸) 2型糖尿病患者中分泌是否 餐后胰高糖素是否 食物攝入是 否延緩胃排空是 否促進(jìn)細(xì)胞增殖是是促進(jìn)胰島素生物合成是是Drucker DJ. Diabetes Care. 2003;26:2929-

7、2940.第5頁(yè)/共40頁(yè)第六頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第七頁(yè)，共40頁(yè)。第7頁(yè)/共40頁(yè)第八頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第九頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第十頁(yè)，共40頁(yè)。Nauck.MA et al.J Clin Invest 1993,91:301-307第10頁(yè)/共40頁(yè)第十一頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第十二頁(yè)，共40頁(yè)。促進(jìn)飽腹感，降低(jingd)食欲細(xì)胞: 餐后胰高血糖素分泌肝臟: 胰高血糖素減少肝糖輸出胃:有助于調(diào)節(jié)(tioji)胃排空細(xì)胞:促進(jìn)血糖依賴(lài)性胰島素分泌進(jìn)食后，小腸開(kāi)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.細(xì)胞 工作負(fù)荷細(xì)胞 反應(yīng)第12頁(yè)/共40頁(yè)第十三頁(yè)，共40頁(yè)。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. 在人體和動(dòng)物體內(nèi)在動(dòng)物體內(nèi)和體外研究中促進(jìn)葡萄糖刺

16、激的胰島素分泌抑制胰高血糖素的釋放延緩胃排空減少食物的攝入量 增強(qiáng)胰島素基因的轉(zhuǎn)錄可能通過(guò)以下途徑增加 細(xì)胞數(shù)量 - 刺激新生細(xì)胞的形成 - 抑制細(xì)胞凋亡uGLP-1通過(guò)其受體（GLP-1R）發(fā)揮作用uGLP-1R在胰島細(xì)胞(xbo)上表達(dá)，受刺激后，可激活cAMP，以及蛋白激酶A依賴(lài)性或非依賴(lài)性的作用第13頁(yè)/共40頁(yè)第十四頁(yè)，共40頁(yè)。2型糖尿病 (n=10)Adapted from: Nauck MA, et al. Diabetologia. 1993;36:741-4.-30060120180240270180900安慰劑 * * * * * *GLP-1葡萄糖 (mg/dL)安慰劑

17、GLPGLP-1安慰劑-30060120180240胰島素 (pmol/L)20100*GLP-1安慰劑-30060120180240胰高血糖素 (pmol/L)時(shí)間(shjin) (分鐘)平均值(SE); *P0.05GLP-1以葡萄糖依賴(lài)性方式增加(zngji)胰島素的分泌第14頁(yè)/共40頁(yè)第十五頁(yè)，共40頁(yè)。AGRarg= 2-5分鐘對(duì)精氨酸的平均急性胰高糖素反應(yīng)；PG50 = 對(duì)AGRarg的抑制達(dá)最大值的一半時(shí)所需的血糖(xutng)水平T2DM = 2型糖尿病; * 健康者平均年齡 1829歲 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頁(yè)/共40頁(yè)第十六頁(yè)，共40頁(yè)。J J Holst, Diabetologia (2009) 52:17141723Bo Ahren, European Journal of Endocrinology (1997) 137 127131糖尿病前

19、期(qinq)狀態(tài)的病理生理學(xué)第16頁(yè)/共40頁(yè)第十七頁(yè)，共40頁(yè)。GR-/-GR+/+RW Gelling et al. PNAS 100: 1438-1443, 2003血糖(xutng) (隨意飼養(yǎng))血糖(xutng)時(shí)間 (天)第17頁(yè)/共40頁(yè)第十八頁(yè)，共40頁(yè)。 Mller WA, et al. N Engl J Med. 1970;283:109115碳水化合物膳食(shnsh)胰高糖素時(shí)間(shjin) (分鐘)7510012515060060120180240pg/mL胰島素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頁(yè)/共40頁(yè)第十九頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第

21、二十頁(yè)，共40頁(yè)。Jesper Gromada Endocrine Reviews 28 (1): 84116第20頁(yè)/共40頁(yè)第二十一頁(yè)，共40頁(yè)。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分鐘1 23 30DPP-4提高 GLP-1作用(zuyng)的治療方法:模擬 GLP-1作用(zuyng)的藥物 (腸促胰島素類(lèi)似物) DPP-4 酶抑制劑Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994 第21頁(yè)/

22、共40頁(yè)第二十二頁(yè)，共40頁(yè)。食物(shw)攝入胃胃腸道腸增加和延長(zhǎng)(ynchng)GLP-1對(duì)細(xì)胞的影響:細(xì)胞：胰腺胰島素釋放凈效應(yīng)： 血糖細(xì)胞:增加和延長(zhǎng)GLP-1和GIP對(duì)細(xì)胞的作用：DPP4抑制劑胰高血糖素分泌Drucker和Nauck, 2006; Idris和Donnelly, 2007; Barnett, 2006腸促胰島素第22頁(yè)/共40頁(yè)第二十三頁(yè)，共40頁(yè)。CV181002 (MAD in T2DM), data are means血 漿 DPP4 活 性 ( 自基線(jxin)的變化% )第23頁(yè)/共40頁(yè)第二十四頁(yè)，共40頁(yè)。DPP-4抑制劑沙格列汀Br J Diabe

23、tes Vase Dis 2010; 10:14-20第24頁(yè)/共40頁(yè)第二十五頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第二十六頁(yè)，共40頁(yè)。Source: CV181041 3.3.1研究(ynji) 041第26頁(yè)/共40頁(yè)

25、第二十七頁(yè)，共40頁(yè)。Source: CV181041 3.5.1.1研究(ynji) 041第27頁(yè)/共40頁(yè)第二十八頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第二十九頁(yè)，共40頁(yè)?；€和12周(LOCF)時(shí)，高糖鉗夾試驗(yàn)(shyn)中，在空腹（0-180分鐘）和OGTT后（180-480分鐘

28、）狀態(tài)的胰島素分泌率Source: CV181041 Figure 7.1 (App. 5.3.4)研究(ynji) 04105101520060 120180240300360420480基線基線12周周 (LOCF)胰島素分泌(fnm)率平均值 (pmol/kg*min)分鐘05101520060 120180240300360420480基線基線 12周周 (LOCF)胰島素分泌率平均值 (pmol/kg*min)分鐘10沙格列汀 5mg安慰劑10第29頁(yè)/共40頁(yè)第三十頁(yè)，共40頁(yè)。Source: CV181041 Table 7.1研究(ynji) 041有效性終點(diǎn)( 12 周)沙格

29、列汀 5 mgn = 20安慰劑n = 16靜脈-口服鉗夾試驗(yàn)中胰島素分泌(pmol/kg) (180 - 480 分鐘) 病例數(shù)1615 基線平均值(SE)2817.73687.0 12 周 LOCF平均值3303.13564.3 校正后自基線的幾何平均值的變化%a15.9-2.2 校正后與安慰劑的差異% b18.5 與安慰劑對(duì)照的P-值*0.0350*靜脈鉗夾試驗(yàn)中胰島素分泌(pmol/kg) (120 - 180分鐘) 病例數(shù)1815 基線幾何平均值446.3593.5 24周 LOCF幾何平均值552.1563.1 校正后自基線的幾何平均值的變化% a22.6-4.1 校正后與安慰劑的

30、區(qū)別% b27.9 與安慰劑對(duì)照的P-值*0.0204*第30頁(yè)/共40頁(yè)第三十一頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第三十二頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第三十三頁(yè)，共40頁(yè)。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頁(yè)/共40頁(yè)第三十四頁(yè)，共40頁(yè)。Source: CV181041 Section 7.4.3.1 (App. 5.6.3)研究(ynji) 041單位: pg*min/mL沙格列汀 5 mgn = 20安慰劑n

37、 = 16統(tǒng)計(jì)學(xué)結(jié)果 病例數(shù)1714 基線平均值(SE)14279 (1228.2)11177 (880.2) 12周 LOCF 平均值 (SE)11571 (1112.7)12965 (1272.5) 自基線變化的平均值(SE)-2708 (864.9)1788 (1247.5)校正后自基線的變化 平均值 (SE)-2191 (957.8)1161 (1061.9) 95% 雙側(cè)檢驗(yàn)的可信區(qū)間-4153, -229-1014, 3336與安慰劑的不同a 平均值 (SE)b-3352 (1473.8) 95%雙側(cè)檢驗(yàn)的可信區(qū)間-6371, -333 p-值0.0308a 沙格列汀5 mg與安慰

38、劑自基線(jxin)變化的差異 b 估值 = 沙格列汀 5 mg校正后平均值變化 安慰劑校正后平均值變化第34頁(yè)/共40頁(yè)第三十五頁(yè)，共40頁(yè)。Henry et al. Diabetes, Obesity and Metabolism 2011;13: 850-858.沙格列汀單劑治療降低(jingd)胰高糖素水平沙格列汀降低(jingd)胰高糖素水平達(dá) 15.4%胰高血糖素pg/ml75g口服葡萄糖測(cè)試沙格列汀5mg:基線沙格列汀5mg:12周第35頁(yè)/共40頁(yè)第三十六頁(yè)，共40頁(yè)。SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes.360Time (min)Mean active GLP-1 conce