Glucose

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Glucose

Meta CR 郭 怡 婷


+

Insulin *

(plasma concentration)

Glucose

(plasma concentration)


+


Glucagon *

(plasma concentration)

*Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input.

Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998: 822–847.


Fewer

β-cells

α-cells

Hypertrophy

Insufficient

Insulin

+


Excessive

Glucagon

+

Glucose

Uptake

Glucose

↑ HGO

Ohneda A, et al. J Clin Endocrinol Metab. 1978;46:504–510

Gomis R, et al. Diabetes Res Clin Pract. 1989;6:191–198.


Age,life style, environmental factors

Diabetes onset

Insulin resistance

Islet cell function

NGT

Prediabetes

(IFG / IGT)

Diabetes

International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.


1902, Moore and colleagues demonstrated that

administration of gut extracts reduces the

amount of urine sugars in patients with

diabetes

In 1929, La Barre purified the glucose-lowering

element from gut extracts, and named it

incretin (INtestine seCRETtion Insulin)


200

Oral Glucose Tolerance Test and Matched IV Infusion

400

Plasma Glucose (mg/dL)

150

100

50

50 g Glucose

Plasma Insulin (pmol/L)

300

200

100

N=6

0

–30 0 30 60 90 120 150 180 210

Time (min)

Oral

0

–30 0 30 60 90 120 150 180 210

Time (min)

IV

Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.


GLP-1: Glucagon-like Peptide-1 (30/31 amino acid peptide)

H A E G T F T S D V S

K

G

R G V

L

S Y

W

L

A

E

I

G Q A A

F K

E

GIP: Glucose-dependent Insulinotropic Peptide

(42 amino acid peptide)

Y A E G T F S

I D

Y I S A M D K H I Q

D K G K A L N V F Q

W N K Q L W D

K

H N I T

Q

Amino acids shown in orange are homologous with the structure of glucagon.


L-cell

(ileum)

Proglucagon

ProGIP

GLP-1 [7–37]

GIP [1–42]

GLP-1 [7–36 NH 2

]

K-cell

(jejunum)

Drucker DJ. Diabetes Care. 2003;26:2929–2940.


D. Yabe, Y. Seino , Progress in Biophysics and Molecular Biology 107 (2011) 248-256


D. Yabe, Y. Seino , Progress in Biophysics and Molecular Biology 107 (2011) 248-256


Glucose

dependent

manner!

D. Yabe, Y. Seino , Progress in Biophysics and Molecular Biology 107 (2011) 248-256


N=10

Glucose (mg/dL)

C-peptide (nmol/L)

Glucagon (pmol/L)

300

GLP-1 infusion

3.0

GLP-1 infusion

30

GLP-1 infusion

250

2.5

25

200

150

*

*

2.0

1.5

*

*

*

*

*

*

*

*

20

15

100

50

*

*

*

*

*

1.0

0.5

10

5

*

*

* *

0

–30 0 30 60 90 120 150 180 210 240

Time (min)

0.0

–30 0 30 60 90 120 150 180 210 240

Time (min)

0

–30 0 30 60 90 120 150 180 210 240

Time (min)

*P


In non-diabetic subjects, the incretin effect is

responsible for 50-70% oral glucose

administration

In type 2 diabetes patients, the incretin effect is

impaired and contributes to only 20-35% of insulin

response to oral glucose

Possible an early phenomenon during the

development of type 2 diabetes and not a

defect that precedes the onset of the disease


No major defect in GIP secretion is evident in

type 2 diabetes

Variable response of GLP-1 secretion in type 2

diabetes


The insulinotropic action of GIP has

convincingly and repeatedly been

demonstrated to be reduced in type 2 diabetes

1. Down-regulation of GIP receptor with poor

beta cell recognition of GIP

2. Defective post-receptor signaling

3. Generalized beta cell dysfunction


The insulin response to GLP-1 is reduced but

more preserved in type 2 diabetes

Hyperglycemia, hyperlipidemia and insulin

resistance associated with impaired beta cell

function

This is the basis of the success of incretin therapy

GLP-1 resistance due to a genetic defect

impairing the beta-cell signaling function of

GLP-1

TCF7L2 & WSF1


Ingestion of

food

GI tract

Release of

incretins from

the gut

Pancreas

β-cells

α-cells

Glucose dependent

Insulin

from beta cells

(GLP-1 and GIP)

Insulin

increases

peripheral

glucose

uptake

Improved Physiologic

Glucose Hyperglycemia Control

DPP-4

Inhibitor

X

DPP-4

Enzyme

Inactive

incretins

Glucagon

from alpha cells

(GLP-1)

Glucose dependent

DPP-4 = dipeptidyl peptidase 4

↑insulin and

↓glucagon

reduce hepatic

glucose

output

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab

Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.


DPP IV inhibitor


Direct injection of

GLP-1

Gila monster( 希 拉 毒 蜥 )


Druker The journal of clinical investigation, 117(2007) 24-32


GLP-1 analogs

Improve pancreatic islet glucose

sensing, slow gastric emptying,

improve satiety

Biguanides

Increase glucose uptake

and decreases hepatic

glucose production

Sulfonylureas

Increase insulin secretion

from pancreatic β-cells

Glinides

Increase insulin secretion

from pancreatic β-cells

DPP-4 inhibitors

Prolong GLP-1 action leading to

improved pancreatic islet glucose

sensing, increase glucose uptake

Thiazolidinediones

Increase glucose uptake in

skeletal muscle and

decrease glucose

production in liver

α-glucosidase inhibitors

Delay intestinal carbohydrate

absorption

Cheng AY, et al. CMAJ. 2005;172:213–226.

Ahrén B, et al. Int J Clin Pract. 2008; 62: 8–14.


2012 糖 尿 病 臨 床 照 護 指 引 . 中 華 民 國 糖 尿 病 學 會


Sjostrom et al. N Engl J Med 2004;351:2683-93.


The Lower Intestinal Hypothesis:

decreased GI tract transit time

The Upper Intestinal

Hypothesis:

Decreased

anti-incretin effect


Proliferation

Anti-apoptosis

D. Yabe, Y. Seino , Progress in Biophysics and Molecular Biology 107 (2011) 248-256


Incretin (GIP and GLP-1) have impacts on

glucose homeostasis

Diminished incretin effect was observed on T2DM

DPPIV-I and GLP-1 agonist are available in

clinical usage

Bariatric surgery can significantly improve

glucose control, partly due to gut hormone

mechanism

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