沙格列汀的作用机制

110
-20 80 180 280 380
Time (min)
*P<0.05 vs placebo
Time (min)
GIP given at supraphysiological levels still has an early, short-lived insulinotropic effect in type 2 diabetes
Insulin sensitivity
Insulin secretion Glucagon secretion
Muscle
Adapted from Drucker DJ. Cell Metab. 2006;3:153-65.
GLP-1在人体的作用
进食后，小肠 开始分泌GLP-1
促进饱腹感， 降低食欲
(回肠和结肠)
L 细胞 是 是 是 是
K 细胞 否 否 否 否
促进β细胞增殖
促进胰岛素生物合成
Drucker DJ. Diabetes Care. 2003;26:2929-2940.
是
是
是
是
The Incretin Effect is Reduced in Type 2 Diabetes
Responses to glucose load in type 2 diabetics and healthy subjects
¯ Hepatic glucose production
百度文库
Adapted from Drucker DJ. Cell Metab. 2006;3:153-65.
GLP-1和GIP 是两类主要的肠促胰素
GLP-1
（胰高糖素样肽-1）
GIP
（葡萄糖依赖的促胰岛 素释放多肽）
(十二指肠和空肠)
主要合成部位 2型糖尿病患者中分泌 餐后胰高糖素 食物摄入 延缓胃排空
Time (min)
Time (min)
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.
When compared with placebo, exogenous GIP infusion not only did not lower postprandial glucose but further worsened hyperglycaemia during late postprandial period (120–360 min) in patients with type 2 diabetes (N=22)
Oral glucose (50g) IV glucose (variable)
Control subjects (N=8)
Venous plasma glucose (mmol/l)
15 10 5 0
Type 2 diabetic patients (N=14)
Venous plasma glucose (mmol/l)
*
0 01 02 60 120 180
0.0 01 02 60 120 180
时间 (分钟)
平均值 ± SE; n=6; *P0.05; 01-02 = 葡萄糖输注时间 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
Nauck J. Clin Endocrinol Metab. 1986;63:492-8.
Ingestion of food Release of active incretins GLP-1 & GIP
Pancreas
GI tract
-cells -cells
Normoglycaemia
DPP-4 inactivates GLP-1 & GIP
Glucosedependent ¯ glucagon (GLP-1)
Glucose concentration in plasma (mmol/L)
20 15 10 5 0 0 2 4 Time (hr) 6 8
Adapted from Zander M, et al. Lancet. 2002;359(9309):824-30.
Exogenous Glucose–Dependent Insulinotropic Polypeptide Worsens Postprandial Hyperglycaemia in Type 2 Diabetes
15 10 5 0
*P≤0.05 to the respective value after the oral load
01 02
60
120
180 0.6 0.5
01 02
60
120
180 0.6 0.5
Time (min)
80 60 40 20 0 01 02 60 120 180 * * * *
120
180
Nauck et al. Diabetologia. 1986
Role of Incretin System in Glucose Homeostasis
Glucosedependent ­ insulin (GLP-1 & GIP) ­ Glucose uptake by peripheral tissue
GIP Placebo
Changes in insulin
65 45
Changes in glucose
* *
240
* *
*
*
190 230
65
25
5
0
*
Glucose (mg/dL)
Insulin (mg/mL)
45
20
40
60
190
140
0 20 40 60
25
150
5
-20 80 180 280 380
Continuous Infusion of GLP-1 Decreases Fasting Glucose as well as HbA1c
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 (P<0.0001), and HbA1c that was decreased by 1.3% (P=0.003)
Time (min)
Venous immunoreactive insulin (mU/l)
80 60 40 20 0 01 02 60 120 180 * * *
Venous immunoreactive insulin (mU/l)
(nmol/l)
0.3
0.3 0.2 0.1 0
*
*
0.2 * 0.1 0
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

在人体和动物体内

在动物体内和体外研究中
增强胰岛素基因的转录 β 细胞数量
可能通过以下途径增加
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
β细胞 工作负荷
α 细胞: 餐后胰高血糖素分泌
β细胞 反应
β细胞: 促进血糖依赖性 胰岛素分泌
肝脏: 胰高血糖素减少肝糖输出
胃: 有助于调节胃排空
Adapted 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 Endocrinol. 2009;5:262-9.
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
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
11 2.0 口服葡萄糖 静脉注射葡萄糖
*
静脉血浆葡萄糖 (mmol/L)
1.5
C-肽 (nmol/L)
*
1.0
*
* * 肠促胰素效应 *
5.5
0.5
1973-GIP被确 定为一种人类长 促胰岛素1
1987-GLP-1 被确定为一种 人类长促胰岛 素
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Creutzfeldt W. Regul Pept. 2005; 128:87-91. Bayliss WM et al. J Phystol. 1902;28:325-353. 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 TJ et al. Endocrinology. 1995;136;3385-3596. Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952-957.

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
Sites of Action of GLP-1
Brain Neuroprotection Heart Appetite
沙格列汀的作用机制
肠促胰岛激素简史
1932-首次确 定肠促胰岛素3 1966-首次描 述DPP-4 6 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
1902-首次观察 到藏到对胰岛分 泌的影响1,2
1964-证实仓促 胰岛素效应 1,4,5
Adapted from Nauck M, et al. Diabetologia. 1986;29:46-52.
(nmol/l)
0.4
0.4
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
Gastric emptying
Stomach Cardioprotection Cardiac output
Glucose production
GI tract
Pancreas Insulin biosynthesis -cell proliferation -cell apoptosis
Liver
时间 (分钟)
2型糖尿病患者肠促胰岛素效应减弱
80
非糖尿病组 (n=8)
80
2型糖尿病组 (n=14)
60
60
Insulin (mU/l)
40 20 0 0
肠促胰岛素效应
Insulin (mU/l)
40 20 0
Time (min)
口服葡萄糖 静脉注射葡萄糖
60
120
180
0
Time (min)
60
Patients assigned saline (N=9)
Week 0 Week 1 Week 6
Patients assigned GLP-1 (N=10)
25
25
Glucose concentration in plasma (mmol/L)
20 15 10 5 0 0 2 4 Time (hr) 6 8
Adapted from Chia CW, et al. Diabetes. 2009;58(6):1342-9.
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