The Role of Alpha and Beta

7/28/2019 The Role of Alpha and Beta

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THE ROLES OF ALPHA, BETA CELLS AND ISLET CELLS

DYSFUNCTION IN T2DM

Agung PranotoDiabetes and Nutrition Center

Dr Soetomo Hospital, Airlangga University



Topics

Glucose normal Homeostasis

Incretins, DPP-4 Inhibition & Islet Cell

ALPHA, BETA CELLS (Islet Cells Pathofisiology)

in T2DM

Islet Enhancer Vildagliptin and DPP-4 Inhibition







Topics




in T2DM








Effects Upon Insulin Secretion by the Autonomic

Nervous System, Gut Hormones, Amino Acid and Drugs

Leucine

Arginine +

Amino

acids

Depolarization

K+

SulfonylureasDiazodine

SUR

GDHMetabolism

AC

GI

cAMP

GIPGLP I

Gut hormones (Incretins)

VIPGs

Gs

Somatostatin

Galanin

Sympathetic nerves

Norepinephrine

Adrenal medulla

Parasympathetic

nerves

Ach PIPLC

IP3

DAGIP3R

PKC

cAMP

PKA

+

-

G I

Weir et al, 2000



Figure 8. Dose-response relationships for effect of glucose to suppress glucagon and

stimulate insulin release from the perfused rat pancreas. (Copyright 1974 by J Clin

Invest.















INCRETIN

DIABETES

Type 2 Diabetes

Anti-incretin

factors

HypoinsulinemiaA B



Figure 3. Hypothesis as to the mechanism responsible for the control of diabetes after gastric bypass.



Topics


Islet Cell Incretins, DPP-4 Inhibition & Islet Cell


in T2DM




19

Pancreatic Islet Dysfunction Leads to

Hyperglycemia in T2DM

↑ Glucose

Fewer -Cells -CellsHypertrophy

Insufficient

Insulin

Excessive

Glucagon – +

↓ Glucose

Uptake

↑ HGO

+

HGO=hepatic glucose output

Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504 –510; Gomis R, et al. Diabetes Res Clin Pract . 1989; 6: 191 –198.





Insufficient Insulin and Elevated Glucagon in T2DM

( Insulin/Glucagon Ratio)

CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus

Adapted from Müller WA, et al. N Engl J Med . 1970; 283: 109 –115.

CHO meal

0

NGT

T2DM

-60 Time (min)

0 60 120 180 240

Glucose100 200 300 400

m g / d L

0 Insulin50

100 150

μ U / m

L

NGT

T2DM

Glucagon

75 100 125 150

p g / m

L

NGT

T2DM



Insufficient Insulin and Elevated Glucagon in IGT

( Insulin/Glucagon Ratio)

IGT=impaired glucose tolerance; NGT=normal glucose tolerance

Adapted from Mitrakou A, et al. N Engl J Med . 1992; 326: 22 –29.

Glucagon

25 30 35 40 45

p m o l / L

Time (min) -60 0 60 120 180 240 300

NGT

IGT

0

Insulin

200 400

600

p m o l / L

Glucose

Glucose

50 100 150 200 250

m g / d L

NGT

IGT

NGT

IGT



NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus

Adapted from Kelley D, et al. Metabolism. 1994; 43: 1549 –1557.

Suppression of Endogenous Glucose Production Is

Impaired in T2DM

Time (min)

–30 –15 0 30 60 90 120 150 180 210 240 270 300

Meal

2

6

10

14

18

E n d o g e n o u s G

l u c o s e

( µ m o l / m i n / k g )

NGT (n=12)T2DM (n=18)



FPG=fasting plasma glucose; HGP=hepatic glucose production; T2DM=type 2 diabetes mellitus

Adapted from DeFronzo RA. Diabetes. 1988; 37: 667 –687.

1.0

1.5

2.02.5

3.0

3.5

4.0

4.5

50 100 150 200 250 300

FPG (mg/dL)

HGP(mg/kg • min)

Excessive

glucagon-mediated

glucose output

0.8

1.2

1.6

2.0

2.4

2.8

50 100 150 200 250 300

GlucoseClearance

(mL/kg • min)

Impaired

insulin-mediated

glucose disposal

Diagnosis

Decreased Glucose Disposal and Increased HGP

Contribute to Increased FPG in T2DM



25

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus

*P <0.05†GLP-1(7 –36 amide) infused at 1.2 pmol/kg/min for 240 minutes.

Adapted from Nauck MA, et al. Diabetologia. 1993; 36: 741 –744.

GLP-1 Restores Insulin and Glucagon Responses in a

Glucose-Sensitive Manner in Patients with T2DM

0.0

0.5

1.0

1.5

2.0

2.5

3.0

**

*

**

*

*

*

–30 0 30 60 90 120 150 180 210 240

Time (Min)

GLP-1 infusion

C-Peptide (nmol/L)

–30 0 30 60 90 120 150 180 210 240

Time (Min)

0

5

10

15

20

25

30

*

*

* *

GLP-1 infusion

Glucagon (pmol/L)

GLP-1† Placebo

0

50

100

150

200

250

300

*

*

*

*

*

**

–30 0 30 60 90 120 150 180 210 240

Time (Min)

GLP-1 infusion

Glucose (mg/dL)N=10



26

Topics




in T2DM

DPP-4 Inhibition & Islet Enhancer Vildagliptin


http://slidepdf.com/reader/full/the-role-of-alpha-and-beta 27/33VILDAGLIPTIN



28

DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus

Adapted from Unger RH. Metabolism. 1974; 23: 581 –593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65 –73.

Insulin

Glucagon

Improved

glycemic control

Incretinactivity

prolonged

Improved islet

function

DPP-4 inhibitor

Insulin

Glucagon

HyperglycemiaIncretin

response

diminished

Further impaired

islet function

T2DM

Blocking DPP-4 Can Improve Incretin Activity and

Correct the Insulin:Glucagon Ratio in T2DM



29

Vildagliptin: A Potent and Selective DPP-4 Inhibitor

Highly selective DPP-4 inhibitor

Has a high affinity for the human

enzyme

Reversible inhibition

X-ray crystallographic structure of

vildagliptin (green) bound to the active site

(yellow) of human DPP-4

N

O

N

NH

OH

DPP-4=dipeptidyl peptidase-4



Normal glucose homeostasis maintain by healthy alpha & betaislet cell

Incretins, DPP-4 Inhibition & Islet Cell work synergistically tokeep blood glucose concentrations normal

Pathomechanisms of T2DM are insulin resistance, InsufficientInsulin and elevated Glucagon

A new target treatment is pancreatic alpha cell dysfunction

Conclusion

VILDAGLIPTIN



42

UPCOMING EVENT

WORLD DIABETES DAY (14 Nov 2008)



43

UPCOMING EVENT

WORLD DIABETES DAY (14 Nov 2008)



TERIMA KASIH

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The Role of Alpha and Beta

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