沙格列汀的作用机制ppt课件

1、沙格列汀的作用机制,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1,2,1932-首次确定肠促胰岛素3,1964-证实仓促胰岛素效应1,4,5,1966-首次描述DPP-4 6,1973-GIP被确定为一种人类长促胰岛素1,1986-证实了长促胰岛素在2型糖尿病患者中的作用7,1995-DPP-4被确定为一种灭活GIP和GLP-1的酶 9,10,1987-GLP-1被确定为一种人类长促胰岛素,Creutzfeldt W. Regul Pept. 2005; 128:87-91. Bayliss WM et al. J Phystol. 1902;28:325-353. La

2、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 TJ e

3、t al. Endocrinology. 1995;136;3385-3596. Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952-957.,2,静脉血浆葡萄糖 (mmol/L),时间 (分钟),C-肽 (nmol/L),0.0,0.5,1.0,1.5,2.0,时间 (分钟),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.

4、,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,肠促胰素效应,3,Nauck et al. Diabetologia. 1986,2型糖尿病患者肠促胰岛素效应减弱,Time (min),Insulin (mU/l),80,60,40,20,0,180,60,120,0,Time (min),Insulin (mU/l),180,60,120,0,非糖尿病组 (n=8),2型糖尿病组 (n=14),4,Role of Incretin System in Glucose Homeostasi

5、s,Normoglycaemia, 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

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

7、(min),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,T

8、ime (min),Time (min),120,180,60,120,180,60,02,02,01,01,(nmol/l),Venous immunoreactive insulin (mU/l),7,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 G

9、lucose 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 assign

10、ed saline (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),9,Exogenous GlucoseDependent Insulinotropic Polypeptide Worsens Postprandial Hyperglycaemia in Type 2 Diabetes,Adapted from Ch

11、ia 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 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 l

12、ower postprandial 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,10,在2型糖尿病的治疗中，针对GLP-1的药物更有价值,肠促胰岛素的效应在2型糖尿病患者中减弱 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

13、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 2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.MA et al.J Clin Invest 1993,91:301-307,11,Sites of Action of GLP-1,Brain,Glucose production,Neuroprotection Appetite,Liver,Stomach,Gastric emptying,GI tract,Insulin biosynthesis -cell proliferation -cell a

14、poptosis,Insulin secretion Glucagon secretion,Muscle,Heart,Cardioprotection Cardiac output,Insulinsensitivity,Adapted from Drucker DJ. Cell Metab. 2006;3:153-65.,Pancreas,12,GLP-1在人体的作用,促进饱腹感， 降低食欲,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-1,Adapted from: Flint A, et al. J Clin Invest. 1998;101:515-

15、20. Holst JJ. TEM. 2005;10:229-35. Lovshin JA, Drucker DJ. Nat Rev Endocrinol. 2009;5:262-9.,13,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,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.,

16、GLP-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,14,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,安慰剂,*,*,*,*,*,*,*,GLP-1,葡萄糖 (mg/dL),安慰剂,GLP-1,300,200,100,0,*,*,*,*,*,*,*,*,GLP-1,安慰剂

17、,-30,0,60,120,180,240,胰岛素 (pmol/L),20,10,0,GLP-1,安慰剂,-30,0,60,120,180,240,胰高血糖素 (pmol/L),时间 (分钟),平均值(SE); *P0.05,GLP-1以葡萄糖依赖性方式增加胰岛素的分泌,15,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,Ward WK, et al. J Clin Invest. 1984;74:13181328. D

18、unning B, et al. Diabetologia. 2005;48:17001713,16,糖尿病前期胰高糖素异常,J J Holst, Diabetologia (2009) 52:17141723 Bo Ahren, European Journal of Endocrinology (1997) 137 127131,糖尿病前期状态的病理生理学,17,胰高血糖素受体敲除小鼠血糖水平降低,RW Gelling et al. PNAS 100: 1438-1443, 2003,血糖 (随意饲养),血糖,时间 (天),18,T2DM是胰岛素分泌不足和胰高糖素分泌增加致高血糖,Mlle

19、r 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),75,100,125,150,60,0,60,120,180,240,pg/mL,胰岛素,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,19,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.,20,GLP-1抑制胰高糖素分泌并非由胰岛素介导,GLP-1抑制胰岛 细胞

20、功能无残留的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 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): 84116,21,GLP-1在体内快速降解,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分钟,1 2,3 30,DPP-4,提高 GLP-1作用的治疗方法: 模拟 GLP-1作用的药物 (肠促胰岛素类似物) DPP-4 酶抑制剂,Mentl

21、ein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994,22,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,23,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),

22、data are means,血 浆 DPP4 活 性 ( 自基线的变化% ),24,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; 10:14-20,25,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,Sin

23、gle-blind lead-in 2 weeks,Double-blindtreatment 12 weeks,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 adju

24、sted 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 arginine stimulation test,Plasma glucose (mg/dL),400,100,505,200,450,300,280,480,515,180,

25、120,0,-30,Time (min),75 g oralglucosechallenge,Startglucoseinfusion*,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,422HQ09NP101,29,基线和12周(LOCF)

26、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 5mg,安慰剂,10,30,主要和次要有效性终点,Source: CV181041 Table 7.1,研究 041,a估值 = 100* exp(校正后自基线的自然对数平均值的变化) -1 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)-

27、1 * 在alpha=0.05水平有意义时，比较沙格列汀5mg 和安慰剂,31,b-Cell Stimulation by Saxagliptin 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,

28、 geometric mean and 95% CI (represented by bar)SAXA: saxagliptin; 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 % differenc

29、e PBO (95% CI):18.5 (1.3, 38.7) P=0.035,Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.,422HQ09NP101,32,b-Cell Stimulation by Saxagliptin in Patients with T2DInsulin secretion rates in the fasting state,40,-10,10,20,-20,0,-,-,-,-,-,* Values are geometric m

30、eans; 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,-17.4,11.2,22.6,7.2,40.4,Insulin secretion rate during IV hyperglycaemic clamp:adjusted % change from baseline at W

31、eek 12 (LOCF),Adjusted % difference PBO (95% CI):27.9 (4.2, 57.1) P=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.,422HQ09NP101,33,b-Cell Stimulation by Saxagliptin in Patients wi

32、th T2D Insulin secretion following IV arginine,*LOCF: last observation 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.,Ins

33、ulin secretion following IV arginine: changes from baseline at Week 12,422HQ09NP101,34,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,a 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,35,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%,36,SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes.,b-Cell Stimulation by Saxagliptin in Patient