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第1页，共40页。
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 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.
第2页，共40页。
静脉血浆葡萄糖 (mmol/L)
时间 (分钟)
C-肽 (nmol/L)
11
0
时间 (分钟)
01
60
120
180
02
口服葡萄糖 静脉注射葡萄糖
*
*
*
*
*
*
*
平均值 ± SE; n=6; *P; 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.
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
01
60
120
180
02
肠促胰素效应
第3页，共40页。
Nauck et al. Diabetologia. 1986
2型糖尿病患者肠促胰岛素效应减弱
口服葡萄糖
静脉注射葡萄糖
Time (min)
Insulin (mU/l)
80
60
40
20
0
180
60
120
0
Time (min)
Insulin (mU/l)
80
60
40
20
0
180
60
120
0
肠促胰岛素效应
非糖尿病组 (n=8)
2型糖尿病组 (n=14)
第4页，共40页。
Role of Incretin System in Glucose Homeostasis
Normoglycaemia
­ Glucose uptake by peripheral tissue
Adapted from Drucker DJ. Cell Metab. 2006;3:153-65.
¯ Hepatic glucose production
Glucose- dependent
­ insulin
(GLP-1 & GIP)
Glucose-
dependent
¯ glucagon
(GLP-1)
Pancreas
-cells
-cells
Release of
active incretins
GLP-1 & GIP
DPP-4
inactivates
GLP-1 & GIP
GI tract
Ingestion of food
第5页，共40页。
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）
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β细胞增殖
是
是
促进胰岛素生物合成
是
是
Drucker DJ. Diabetes Care. 2003;26:2929-2940.
第6页，共40页。
The Incretin Effect is Reduced in Type 2 Diabetes
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 type 2 diabetics and healthy subjects
Control subjects (N=8)
Type 2 diabetic patients (N=14)
Oral glucose (50g)
IV glucose (variable)
Venous plasma glucose (mmol/l)
Time (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
*
*
*
*
*
*
*
*
*
*
Venous plasma glucose (mmol/l)
*P≤ to the respective value after the oral load
Time (min)
Time (min)
120
180
60
120
180
60
02
02
01
01
(nmol/l)
Venous immunoreactive
insulin (mU/l)
第7页，共40页。
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
第8页，共40页。
Continuous Infusion of GLP-1 Decreases Fasting Glucose 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 mmol/l and mmol/l (P<), and HbA1c that was decreased by % (P=)
Patients assigned saline (N=9)
Patients assigned GLP-1 (N=10)
Glucose concentration in plasma (mmol/L)
0
0
8
2
4
6
0
8
2
4
6
25
20
15
10
5
0
25
20
15
10
5
Week 0
Week 1
Week 6
Time (hr)
Time (hr)
Glucose concentration in plasma (mmol/L)
第9页，共40页。
Exogenous Glucose–Dependent Insulinotropic Polypeptide Worsens Postprandial Hyperglycaemia in Type 2 Diabetes
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 diabetes
Time (min)
GIP
Placebo
45
5
25
65
280
180
380
80
-20
Insulin (mg/mL)
Glucose (mg/dL)
45
5
25
65
60
40
20
0
Time (min)
190
110
150
230
280
180
380
80
-20
140
190
240
60
40
20
0
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)
Changes in insulin
Changes in glucose
*
*
*
*
*
*
*
*P< vs placebo
第10页，共40页。