1、沙格列汀的作用機(jī)制,主講人：,腸促胰島激素簡(jiǎn)史,1902-首次觀察到藏到對(duì)胰島分泌的影響1,2,1932-首次確定腸促胰島素3,1964-證實(shí)倉促胰島素效應(yīng)1,4,5,1966-首次描述DPP-4 6,1973-GIP被確定為一種人類長促胰島素1,1986-證實(shí)了長促胰島素在2型糖尿病患者中的作用7,1995-DPP-4被確定為一種滅活GIP和GLP-1的酶 9,10,1987-GLP-1被確定為一種人類長促胰島素,Creutzfeldt W. Regul Pept. 2005; 128:87-91. Bayliss WM et al. J Phystol. 1902;28:325-353.

2、La Barre J. Bull Acad R. Med Belg. 1932;120:620-634. McIntyre N et al. Lancet. 1964;41:20-21. Elrick H et al. J Clin Endocr. 1964;24:1076-1082. Hopsu-Havu VK, Glenner GG. Histochemle. 1966;7(3):197-201. Nauck M et al. Diabetologia. 1986;29:46-52. Kreymann B et al. Lancet. 1987;2:1300-1304. Kieffer T

3、J et al. Endocrinology. 1995;136;3385-3596. Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952-957.,靜脈血漿葡萄糖 (mmol/L),時(shí)間 (分鐘),C-肽 (nmol/L),0.0,0.5,1.0,1.5,2.0,時(shí)間 (分鐘),口服葡萄糖 靜脈注射葡萄糖,平均值 SE; n=6; *P0.05; 01-02 = 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

4、.,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),腸促胰素效應(yīng),Nauck et al. Diabetologia. 1986,2型糖尿病患者腸促胰島素效應(yīng)減弱,Time (min),Insulin (mU/l),80,60,40,20,0,180,60,120,0,Time (min),Insulin (mU/l),180,60,120,0,非糖尿病組 (n=8),2型糖尿病組 (n=14),Role of Incretin System in Glucose Homeostasis,N

5、ormoglycaemia, Glucose uptake by peripheral tissue,Adapted from Drucker DJ. Cell Metab. 2006;3:153-65., Hepatic glucose production,Glucose- dependent insulin (GLP-1 26:2929-2940.,The Incretin Effect is Reduced in Type 2 Diabetes,Adapted from Nauck M, et al. Diabetologia. 1986;29:46-52.,Responses to

6、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 subjects,Control subjects (N=8),Type 2 diabetic patients (N=14),Venous plasma glucose (mmol/l),Time (mi

7、n),Time (min),0,10,15,120,180,01,60,0,5,10,15,5,120,180,01,60,02,02,Venous immunoreactive insulin (mU/l),(nmol/l),0,20,40,60,80,0,20,40,60,80,0,0,0.1,0.3,0.4,0.6,0.5,0.2,0.1,0.3,0.4,0.6,0.5,0.2,*,*,*,*,*,*,*,*,*,*,Venous plasma glucose (mmol/l),*P0.05 to the respective value after the oral load,Time

8、 (min),Time (min),120,180,60,120,180,60,02,02,01,01,(nmol/l),Venous immunoreactive insulin (mU/l),Incretin hormone changes,In patients with type 2 diabetes, levels of GLP-1 released in response to glucose are reduced and GIP activity is decreased,Continuous Infusion of GLP-1 Decreases Fasting Glucos

9、e as well as HbA1c,Adapted from Zander M, et al. 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 sa

10、line (N=9),Patients assigned GLP-1 (N=10),Glucose concentration in plasma (mmol/L),0,0,Week 0,Week 1,Week 6,Time (hr),Time (hr),Glucose concentration in plasma (mmol/L),Exogenous GlucoseDependent Insulinotropic Polypeptide Worsens Postprandial Hyperglycaemia in Type 2 Diabetes,Adapted from Chia CW,

11、et al. Diabetes. 2009;58(6):1342-9.,GIP given at supraphysiological levels still has an early,short-lived insulinotropic effect in type 2 diabetes,Time (min),Insulin (mg/mL),Glucose (mg/dL),Time (min),140,190,240,60,40,20,0,When compared with placebo, exogenous GIP infusion not only did not lower po

12、stprandial glucose but further worsened hyperglycaemia during late postprandial period (120360 min) in patients with type 2 diabetes (N=22),Changes in insulin,Changes in glucose,*,*,*,*,*,*,*,*P0.05 vs placebo,在2型糖尿病的治療中，針對(duì)GLP-1的藥物更有價(jià)值,腸促胰島素的效應(yīng)在2型糖尿病患者中減弱 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的促胰島素

13、分泌作用的減弱可能是遺傳因素和環(huán)境因素共同作用引起的 2型糖尿病患者中，GLP-1水平降低，但其作用未受損 開發(fā)提高GLP-1 水平的藥物具有重要的臨床意義,Nauck.MA et al.J Clin Invest 1993,91:301-307,Sites of Action of GLP-1,Brain,Glucose production,Neuroprotection Appetite,Liver,Stomach,Gastric emptying,GI tract,Insulin biosynthesis -cell proliferation -cell apoptosis,Insu

14、lin secretion Glucagon secretion,Muscle,Heart,Cardioprotection Cardiac output,Insulinsensitivity,Adapted from Drucker DJ. Cell Metab. 2006;3:153-65.,Pancreas,GLP-1在人體的作用,促進(jìn)飽腹感， 降低食欲,胃:有助于調(diào)節(jié)胃排空,細(xì)胞:促進(jìn)血糖依賴性胰島素分泌,進(jìn)食后，小腸 開始分泌GLP-1,Adapted from: Flint A, et al. J Clin Invest. 1998;101:515-20. Holst JJ. TE

15、M. 2005;10:229-35. Lovshin JA, Drucker DJ. Nat Rev Endocrinol. 2009;5:262-9.,胰高血糖素樣肽-1 (GLP-1),進(jìn)食后由腸道L細(xì)胞分泌 GLP-1在進(jìn)食后數(shù)分鐘內(nèi)開始分泌，對(duì)食物中脂類和碳水化合物的反應(yīng)最為明顯,Kieffer TJ, et al. Endocr Rev. 1999;20:876-913 Drucker DJ. Curr Pharm Des. 2001;7:1399-412. Drucker DJ. Mol Endocrinol. 2003;17:161-71.,GLP-1通過其受體（GLP-1R）發(fā)

16、揮作用 GLP-1R在胰島細(xì)胞上表達(dá)，受刺激后，可激活cAMP，以及蛋白激酶A依賴性或非依賴性的作用,Glucose-Dependent Effects of GLP-1,2型糖尿病 (n=10),Adapted from: Nauck MA, et al. Diabetologia. 1993;36:741-4.,-30,0,60,120,180,240,270,180,90,0,安慰劑,*,*,*,*,*,*,*,GLP-1,葡萄糖 (mg/dL),安慰劑,GLP-1,300,200,100,0,*,*,*,*,*,*,*,*,GLP-1,安慰劑,-30,0,60,120,180,240,

17、胰島素 (pmol/L),20,10,0,GLP-1,安慰劑,-30,0,60,120,180,240,胰高血糖素 (pmol/L),時(shí)間 (分鐘),平均值(SE); *P0.05,GLP-1以葡萄糖依賴性方式增加胰島素的分泌,T2DM中胰島細(xì)胞對(duì)葡萄糖的敏感性降低,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)所需的血糖水平T2DM = 2型糖尿病; * 健康者平均年齡 1829歲,Ward WK, et al. J Clin Invest. 1984;74:13181328. Dunning B, et al. Diabetol

18、ogia. 2005;48:17001713,糖尿病前期胰高糖素異常,J J Holst, Diabetologia (2009) 52:17141723 Bo Ahren, European Journal of Endocrinology (1997) 137 127131,糖尿病前期狀態(tài)的病理生理學(xué),胰高血糖素受體敲除小鼠血糖水平降低,RW Gelling et al. PNAS 100: 1438-1443, 2003,血糖 (隨意飼養(yǎng)),血糖,時(shí)間 (天),T2DM是胰島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;28

19、3:109115,碳水化合物膳食,胰高糖素,時(shí)間 (分鐘),75,100,125,150,60,0,60,120,180,240,pg/mL,胰島素,0,50,100,150,U/mL,0,血糖,100,200,300,400,mg/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,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-1抑制胰高糖素分泌并非由胰島素介導(dǎo),GLP-1抑制胰島 細(xì)胞功能無殘留的1型糖尿病患者的胰高血糖素分泌 在2型糖尿病中，在不足以導(dǎo)致可測(cè)出胰

20、島素分泌的血糖水平下，GLP-1能抑制胰高血糖素的分泌 沒有證據(jù)顯示其他非腸促胰素類降糖藥物對(duì)人胰高糖素分泌起作用,Jesper Gromada Endocrine Reviews 28 (1): 84116,GLP-1在體內(nèi)快速降解,1 2 3,30,GLP-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分鐘,1 2,3 30,DPP-4,提高 GLP-1作用的治療方法: 模擬 GLP-1作用的藥物 (腸促胰島素類似物) DPP-4 酶抑制劑,Mentlein et al. Eur J Biochem. 1993; Gallwitz et

21、 al. Eur J Biochem. 1994,DPP4抑制劑作用機(jī)理,食物 攝入,胃,胃腸道,腸,增加和延長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,臨床藥效學(xué):穩(wěn)定狀態(tài)下，血漿中不同劑量的DPP-4 活性,CV181002 (MAD in T2DM), data are means,血 漿 DPP4 活 性 ( 自基線的變化% ),DPP-4抑制劑沙

22、格列汀具有雙重作用機(jī)制,DPP-4抑制劑 沙格列汀,Br J Diabetes Vase Dis 2010; 10:14-20,b-Cell Stimulation by Saxagliptin in Patients with T2DStudy schema,SAXA: saxagliptin; PBO, placebo; BMI: body mass index; T2D: type 2 diabetes.,n=156,n=46,SAXA5 mg,PBO,Screening,Single-blind lead-in 2 weeks,Double-blindtreatment 12 week

23、s,Inclusion Treatment nave T2D 18-70 years old HbA1c 6-8% BMI 40 kg/m2 Fasting C-peptide1 ng/mL,Diet 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

24、 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 arginine stimulation test,Plasma glucose (mg/dL),400,100,505,200,450,300,280,480,515,180,120,0,-30,Time (min),75 g oralglucosechallenge,Startglu

25、coseinfusion*,SAXAorPBO,IV hyperglycaemic clamp,IV-Oral hyperglycaemic clamp,Argininestimulation test,0,Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.,T2D: type 2 diabetes,422HQ09NP101,基線和12周(LOCF)時(shí)，高糖鉗夾試驗(yàn)中，在空腹（0-180分鐘）和OGTT后（180-480分鐘）狀態(tài)的胰島素分泌率,Source: C

26、V181041 Figure 7.1 (App. 5.3.4),研究 041,胰島素分泌率平均值 (pmol/kg*min),分鐘,胰島素分泌率平均值 (pmol/kg*min),分鐘,10,沙格列汀 5mg,安慰劑,10,主要和次要有效性終點(diǎn),Source: CV181041 Table 7.1,研究 041,a估值 = 100* exp(校正后自基線的自然對(duì)數(shù)平均值的變化) -1 b 估值= 100*exp (校正后沙格列汀5mg 和安慰劑間自然對(duì)數(shù)平均值變化的差異)-1 * 在alpha=0.05水平有意義時(shí)，比較沙格列汀5mg 和安慰劑,b-Cell Stimulation by Sa

27、xagliptin in Patients with T2DInsulin secretion rates in the postprandial state,SAXA 5 mg (n=16),PBO (n=15),30,-10,10,20,Geometric mean % changefrom baseline,-20,0,-,-,-,-,-,* Values are geometric means; Adjusted % change from baseline, geometric mean and 95% CI (represented by bar)SAXA: saxagliptin

28、; PBO: placebo; T2D: type 2 diabetes; LOCF, last observation carried forward.,-2.2,-12.4,9.3,15.9,4.2,29.0,Insulin secretion rate during IV-Oral hyperglycaemic clamp:adjusted % change from baseline at Week 12 (LOCF),Adjusted % difference PBO (95% CI):18.5 (1.3, 38.7) P=0.035,Adapted from Henry R, et

29、 al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.,422HQ09NP101,b-Cell Stimulation by Saxagliptin in Patients with T2DInsulin secretion rates in the fasting state,40,-10,10,20,-20,0,-,-,-,-,-,* Values are geometric means; Adjusted % change from baseline, geometric mean and 95% CI (r

30、epresented by bar)SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes; LOCF, last observation carried forward.,-4.1,-17.4,11.2,22.6,7.2,40.4,Insulin secretion rate during IV hyperglycaemic clamp:adjusted % change from baseline at Week 12 (LOCF),Adjusted % difference PBO (95% CI):27.9 (4.2, 57.1) P

31、=0.020,30,-,SAXA 5 mg (n=18),PBO (n=15),Geometric mean % changefrom baseline,Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.,422HQ09NP101,b-Cell Stimulation by Saxagliptin in Patients with T2D Insulin secretion following IV arginine,*LOCF: last observation

32、 carried forward. P value vs PBO = 0.074 (Kruskal-Wallis test) SAXA: saxagliptin; PBO: 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 12

33、,422HQ09NP101,靜脈-口服高糖鉗夾試驗(yàn)中，胰高糖素曲線下面積12周 (LOCF) 時(shí)自基線的變化,Source: CV181041 Section 7.4.3.1 (App. 5.6.3),研究 041,a 沙格列汀5 mg與安慰劑自基線變化的差異 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,Henry et al. Diabetes, Obesity and Metabolism 2011;13: 850-858.,沙格列汀單劑治療降低胰高糖素水平,沙格列汀降低胰高糖素水平達(dá) 15.4%,SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes.,b-Cell Stimulation by Saxagliptin in Pati