ΙΝΚΡΕΤΙΝΕΣ : Ο ρόλος του ενζύμου DPP-4 στον Σακχαρώδη...
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Transcript of ΙΝΚΡΕΤΙΝΕΣ : Ο ρόλος του ενζύμου DPP-4 στον Σακχαρώδη...
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ΙΝΚΡΕΤΙΝΕΣΙΝΚΡΕΤΙΝΕΣ : Ο ρόλος του ενζύμου DPP-4 στον Σακχαρώδη Διαβήτη τύπου 2
Δρ Ασημίνα Μητράκου
2
Εκκριση Ινσουλίνης μετά την λήψη τροφής
Γλυκόζη(κι αλλες ουσίες) ΙΝΣΟΥΛΙΝΗ
ΙΝΚΡΕΤΙΝΕΣ
Νευρογενή
ΕρεθίσματαSympathetic innervation (β-receptors)
Parasympathetic (cholinergic) innervation
3
Βασική παρατήρηση: Η έκκριση ινσουλίνης ειναι μεγαλύτερη μετα τηαν απο του στόματος λήψη γλυκόζης
0
50
100
150
200
250
300
-30 -15 0 15 30 45 60 75 90 105 120 135
Time (min)
Blo
od
Glu
cose
(m
g/d
L) Intravenous
Intrajejunal
0
50
100
150
200
250
300
-30 -15 0 15 30 45 60 75 90 105 120 135
Time (min)
Pla
sm
a I
ns
uli
n (
pm
ol/
L)
McIntyre N, et al. Lancet. 1964;II:20-1.
Blood Glucose Plasma Insulin
4
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Φαινόμενο Ινκρετίνης
Oral Glucose Tolerance TestOral Glucose Tolerance Test
Glucose (mg/dL)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Insulin (pmol/L)
50 g glucose
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
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Φαινόμενο Ινκρετίνης
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Glucose (mg/dL)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Oral
IV
Insulin (pmol/L)
OGTT and Matched IV InfusionOGTT and Matched IV Infusion
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
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Ορισμός της Ινκρετίνης
Εκκρινεται κατα την απορόφηση τροφής
Αυξάνει την έκκριση ινσουλίνης
Οι ινσουλινοτρόπος δράση τους είναι γλυκοζοεξαρτωμένη
Creutzfeldt Wl. Diabetologia. 1979;16:75-85.
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0
200
400
600
800
-30 0 30 60 90 120 150 180 210 240 270 300 330
Tim e (m in)
Insu
lin S
ecre
tion
(pm
ol/m
in)
Tillil H, et al. Am J Physiol. 1988;254:E349-E357.
Εκκριση Ινσουλίνης και επίπεδα γλυκόζης με αυξανομένη δόση γλυκόζης απο του στόματος/ενδοφλεβίως
0
100
200
300
-30 0 30 60 90 120 150 180 210 240 270 300 330Tim e (m in)
Glu
cose
(mg/
dL) 25 g
100 g
IV
0
200
400
600
800
-30 0 30 60 90 120 150 180 210 240 270 300 330Tim e (m in)
Insu
lin S
ecre
tion
(pm
ol/m
in)
0
100
200
300
-30 0 30 60 90 120 150 180 210 240 270 300 330Tim e (m in)
Glu
cose
(mg/
dL) 25 g
100 g
OralOral
0
100
200
300
-30 0 30 60 90 120 150 180 210 240 270 300 330Tim e (m in)
Glu
cose
(mg/
dL) 25 g
100 g
Oral
8
Η εκκριση των Ινκρετινών εξαρτάται απο το μεγεθος του γεύματος
0
10
20
30
40
50
-30 0 30 60 90 120 150 180 210
Time (min)
To
tal G
LP
-1 (
pm
ol/L
) 260 kcal
520 kcal
GLP-1 GIP
0
40
80
120
160
-30 0 30 60 90 120 150 180 210
Time (min)
To
tal G
IP (
pm
ol/L
)
260 kcal
520 kcal
Vilsbøll T, et al. J Clin Endocrinol Metab. 2003;88:2706-13.
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Οι ΙΝΚΡΕΤΙΝΕΣ
Y A E GT
FI S D Y
SI
A M D KI
HQ
QDFVNWLLAQKGKKNDW
KH N QTI
GIP: Glucose-Dependent Insulinotropic Peptide
H A E GT F T S D V
SS Y L E G
Q AA
KEFIAWLVKGRG
GLP-1: Glucagon-Like Peptide–1
*Amino acids shown in gold are homologous with the structure of glucagon.
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Synthesis and Secretion of GLP-1 and GIP
L-Cell(ileum)
Proglucagon
GLP-1 [7-37]
GLP-1 [7-36NH2]
K-Cell(jejunum)
ProGIP
GIP [1-42]
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Mεταβολισμός GLP-1 και GIP
Capillary
Dipeptidyl peptidase-4 (DPP-4)Ubiquitous, specific proteaseCleaves N-terminal dipeptideInactivates > 50% of GLP-1 ~ 1 min > 50% of GIP in ~ 7 min
Active Hormones GLP-1 [7-36NH2]
GIP [1-42]
Inactive Metabolites GLP-1 [9-36NH2]
GIP [3-42]
DPP-4
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Μεταβολισμός GLP-1 και GIP
CapillaryCapillary
K-CellL-Cell
GIP [3-42]INACTIVE
DPP-4
GIP [1-42]ACTIVE
GLP-1[7-36NH2]
ACTIVE
GLP-1 [9-36NH2]
INACTIVE
DPP-4
Proglucagon
GLP-1 [7-37]
GLP-1 [7-36NH2]
ProGIP
GIP [1-42]
Dipeptidyl peptidase-4 (DPP-4)•Ubiquitous, specific protease•Cleaves N-terminal dipeptide•Inactivates > 50% of GLP-1 in ~ 1 min > 50% of GIP in ~ 7 min
13Vilsbøll T, et al. J Clin Endocrinol Metab. 2003;88:2706-13.
30-Minute Εκκριση Total and Intact GLP-1 and GIP in σε Υγιη Ατομα
0
1
2
3
4
Total Intact
AU
C (0
-30
min
) (p
mo
l*m
in/L
)
0
3
6
9
12
15
Total Intact
AU
C (0
-30
min
) (p
mo
l*m
in/L
)
GLP-1 GIP
14
Τόπος Δράσης
Gs
AcATP
cAMPGs
AcATP
cAMP
PKA
Insulin
-Cell
-cell Adipocyte Brain Stomach Small intestine
-cell Adipocyte Brain Adrenal Pituitary
GLP-1 GIP
15
0
200
400
600
800
1000
-50 -25 0 25 50 75 100
Time (min)
Ins
uli
n (
pm
ol/
L)
Saline
GLP-1
GIP
Kreymann B, et al. Lancet. 1987;2:1300-4.
Glucose-Dependent Insulinotropic Effect of GLP-1 and GIP in Healthy Subjects
0
50
100
150
200
250
-50 -25 0 25 50 75 100
Time (min)
Glu
co
se
(m
g/d
L)
Saline
GLP-1
GIP
Test Infusion
GL
Test Infusion
GL
16
**P < .01, *P < .05Scrocchi LA, et al. Nat Med. 1996;2:1254-8.
Impaired Glucose Tolerance in GLP-1 Receptor Knockout Mice
0
180
360
540
0 30 60 90 120
Time (min)
Blo
od
Glu
cose
(m
g/d
L)
Wild Type
GLP-1
0
35
70
105
0 min 30 min 60 min
Time (min)
Insu
lin
(p
mo
l/L
)
Wild Type
GLP-1r -/- r -/-
*
* **
* ***
* *
+/+ -/- +/+ -/- +/+ -/-
17
***P < .001, **P < .01, *P < .05.Miyawaki K, et al. Proc Natl Acad Sci U S A. 1999;96:14843-7.
Impaired Glucose Tolerance in GIP Receptor Knockout Mice
0
35
70
105
140
175
210
245
0 15 30 60
Time (min)
Pla
sma
Insu
lin
(p
mo
l/L
)
Wild Type
GIP
0
100
200
300
400
500
0 30 60 90 120
Time (min)
Blo
od
Glu
cose
(m
g/d
L)
Wild Type
GIPr -/- r -/-
****
***
18
GLP-1 Decreases Glucagon and Glucose Levels in Patients with Type 1 Diabetes
Creutzfeldt WO, et al. Diabetes Care. 1996;19:580-6.
0
2
4
6
8
10
12
-30 0 30 60 90 120 150 180 210 240
Time (min)
Glu
ca
go
n (
pm
ol/
L)
0
50
100
150
200
250
300
350
-30 0 30 60 90 120 150 180 210 240
Time (min)
Pla
sm
a G
luc
os
e (
mg
/dL
)* * * * * * *
*
GLP-1
P < .001
Placebo
GLP-1 or Placebo
Placebo
GLP-1
P < .001
** * * * * *
GLP-1 or Placebo
19Näslund E, et al. Am J Physiol. 1999;277:R910-R916.
GLP-1 Decreases Gastric Emptying of a Solid Meal in Healthy Subjects
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100 120 140 160 180
Time (min)
Gas
tric
Em
pty
ing
(%
rem
ain
ing
in
sto
mac
h)
GLP-1Saline
20Farilla L, et al. Endocrinology. 2002;143:4397-408.
Effect of GLP-1 on -Cell Mass in Diabetic Rats
0
4
8
12
16
Control GLP-1Treated
-C
ell
Ma
ss
(m
g)
0
0,5
1
1,5
2
2,5
Control GLP-1Treated
% P
roli
fera
tin
g
-Ce
lls
0
10
20
30
Control GLP-1Treated
% A
po
pto
tic
-
Ce
lls
P .001
P .05
P .01
-Cell Mass-Cell Apoptosis-Cell
Proliferation
21
Comparison of Physiology of GLP-1 and GIP
GLP-1 GIP
Site of production L-cells in ileum and colonK-cells in duodenum and
jejunum
Response to stimuli Indirect/neuronal Direct
Inhibits glucagon Yes No
Slows gastric emptying Yes No
Stimulation of -cell growth/mass Yes Yes
Major target tissues-cell, -cell, stomach,
nervous system-cell, adipose tissue
Antagonist Exendin [9-39] GIP [7-30]
Receptor KO mice Yes, with IGT Yes, with IGT
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Το Φαινόμενο Ινκρετίνης στον ΣΔ τύπου 2
23
0 60 120 1800 60 120 180
0 60 120 180
Nauck M, et al. Diabetologia. 1986;29:46-52.
Το φαινόμενο Ινκρετίνης στον ΣΔ τύπου 2
Control Type 2 DM
0 60 120 180
240
180
90
0
240
180
90
0
30
20
10
0
30
20
10
0
Pla
sma
Glu
cose
(m
g/d
L)
C-P
epti
de
(nm
ol/
L)
Pla
sma
Glu
cose
(m
g/d
L)
C-P
epti
de
(nm
ol/
L)
Time (min)Time (min)
**
* ** * * *
IVOral
*P < .05
24
Εκκριση Ινκρετινών μετα απο γευμα σε ασθενεις με ΣΔ τυπου 2
Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-23.
0,0
1,0
2,0
3,0
GL
P-1
AU
C (
nm
ol/
L*2
40
min
)
P < 0.001
0
5
10
15
20
GIP
AU
C (
nm
ol/
L*2
40
min
) P = 0.095
NGT IGT T2DM
GLP-1 GIP
25
0
2000
4000
6000
8000
Time (Min)
C-P
epti
de
(pm
ol/
L)
Vilsböll T, et al. Diabetologia. 2002;45:1111-9.
Διαφορετική ινσουλινοτρόπος δραση των ινκρετινών στον ΣΔ τυπου 2
GLP-1GIPSaline
-15 -10 0 5 10 15 20 30 45 60 75 90 105 120 150
Hyperglycemic Clamp
Saline or GIP or GLP-1
26
*P < .05Nauck MA, et al. Diabetologia. 1993;36:741-4.
IV χορηγηση GLP-1 σε ασθενεις με ΣΔ τυπου 2
0
50
100
150
200
250
300
-30 0 30 60 90 120 150 180 210 240
Time (Min)
0
5
10
15
20
25
30
-30 0 30 60 90 120 150 180 210 240
Time (min)
0
50
100
150
200
250
300
-30 0 30 60 90 120 150 180 210 240
Time (min)
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)
Glucose (mg/dL) C-Peptide (nmol/L) Glucagon (pmol/L)
* * ** * *
**
* * * *GLP-1Saline
GLP-1 Infusion GLP-1 Infusion GLP-1 Infusion
**
**
* * *
27
6 εβδομαδες συνεχους χορηγησης GLP-1 σε ασθενεις με ΣΔ τυπου 2
Zander M, et al. Lancet. 2002;359:824-30.
Week 0 Week 1 Week 6
100
200
300
400
-0.5 0.5 1.5 2.5 3.5 4.5
Time (hr)
Glu
co
se
(m
g/d
L)
100
200
300
400
-0.5 0.5 1.5 2.5 3.5 4.5
Time (hr)
Glu
cose
(mg
/dL
)
MealMeal
Patients assigned saline Patients assigned GLP-1
28
2
4
6
8
10
12
14
16
GL
P-1
(p
mo
l/L)
Placebo
Drug
60
80
100
120
-30 0 30 60 90 120 150
Glu
cag
on
(p
mo
l/L)
Placebo
Drug
0
50
100
150
200
250
300
-30 0 30 60 90 120 150
Insu
lin (
pm
ol/L
)
Placebo
Drug
Ahren B, et al. JCEM. 2004;(in press).
Effects of 4 Weeks’ Treatment with a DPP-4 Inhibitor in Patients with Type 2 Diabetes
125
175
225
275
Glu
cose
(m
g/d
L)
Placebo
DrugGlucose
Insulin
GLP-1
Time (min)Time (min)
Glucagon
meal
29Fineman MS, et al. Diabetes Care. 2003;26:2370-7.
4 εβδομαδες θεραπεια με ινκρετινομιμητικα φαρμακα ( GLP-1 Receptor Agonist ) σε αθενεις με ΣΔ τυπου 2
150
200
250
300
-30 0 30 60 90 120 150 180 210 240 270
Time (min)
Glu
co
se
(m
g/d
L)
MealPlacebo
Drug (all arms)
-1,4
-1,2
-1,0
-0,8
-0,6
-0,4
-0,2
0,0
Placebo Drug (BD) Drug (TID)
Ch
ang
e in
Hb
A1
c (
%)
|P < .001 |
P < .001
BD = before breakfast and dinner
30
At 30 Weeks, PPG Remained Low among Patients Treated with GLP-1 Analogue
Week 30 Meal Tolerance Test*
GLP-1=glucagon-like peptide-1; PPG=postprandial glucose*Exendin-4 or placebo were administered at time zero; subjects in all treatment arms were maintained on metformin-sulfonylurea therapy.Adapted from Kendall DM, et al. Diabetes Care. 2005; 28: 1083–1091.
Time (Min)
16
15
14
13
12
11
10
9
8
0 25 50 75 100 125 150 175
Po
stp
ran
dia
l P
lasm
a G
luco
se (
mm
ol/
L)
InjectionMeal
7.5
0
Placebo (n=23)5 µg exenatide (n=27)10 µg exenatide (n=27)
31Zander M, et al. Lancet. 2002;359:824-30.
Μεταβολικές δράσεις GLP-1 σε συνεχη χορηγηση επι 6 εβδομαδες σε ασθενεις με ΣΔ τυπου 2
-50
-25
0
25
50
75
100
Pe
rce
nt
Ch
an
ge
fro
m W
ee
k 0
32
90
135
180
225
-2 0 2 4 6 8 10 12 14 16 18
Time (hr)
Pla
sma
Glu
cose
(m
g/d
L)
0
200
400
600
800
-2 0 2 4 6 8 10 12 14 16 18
Time (hr)
Insu
lin
Sec
reto
ry R
ate
(pm
ol/
min
)
Juhl CB, et al. Diabetes. 2002;51:424-9.
Effect of Bedtime Administration of a Long-acting GLP-1 Derivative in Patients with T2DM
Breakfast Breakfast
PlaceboDrug
PlaceboDrug
33
0
90
180
270
Time (min)
Blo
od
Glu
cose
(m
g/d
L)
0
50
100
150
+/+ -/-
Pla
sma
Insu
lin
(p
mo
l/L
) *
0
1
2
3
+/+ -/-
Pla
sma
GL
P-1
(p
mo
l/L
) *
-30 0 30 60 120 180
***
**
+/+DPP-4 -/-
***P < .001, *P < .01, *P < .05
Marguet D, et al. Proc Natl Acad Sci U S A. 2000;97:6874-9.
Glucose Tolerance, Insulin, and GLP-1 Levels in DPP-4 Deficient Mice
34
GLP-1 Analogues Enhance Glucagon Secretion in Hypoglycemic Conditions
–30 0 30 60 90 120 150 180 210 240 270 300 330 360
Glucose Clamp StepsP
lasm
a G
luca
go
n (
ng
/L)
0
50
100
150
200
300
250
(mmol/L): 5.0 4.0 3.2 2.7 Recovery
GLP-1=glucagon-like peptide-1 *P <0.05 †Exenatide infused at .066 pmol/kg/min for 270 minutes.Adapted from Degn KB, et al. Diabetes. 2004; 54: 2397–2403.
* * *
Exenatide† (n=11)
Placebo (n=11)
Time (Min)
35
Συνοπτικά : Φυσιολογία των Ινκρετινών
Φαινόμενο Ινκρετίνης: Εκκριση ινσουλινης μεγαλύτερη μετα απο του στόματος χορήγηση γλυκόζης απο οτι με ενδοφλέβιο χορήγηση
Οι ινκρετίνες : GLP-1 and GIP
Αλλες δράσεις του GLP-1 :
a) μειώνει την έκκριση γλυκαγόνης
b) ελαττώνει την κένωση στομάχου
c) αίσθημα πληρότητας.
Καταβολίζονται γρήγορα απο το ένζυμο DPP-4
Το φαινόμενο ινκρετίνης δεν ειναι φυσιολογικό στον ΣΔ τύπου 2
36
Συνοπτικά : Θεραπείες βασιζόμενες στις Ινκρετίνες
GLP-1 πρέπει να χορηγείται με συνεχή χορήγηση για να ειναι αποτελεσματικο.
GLP-1 receptor agonists που αντιστέκονται στην δράση του DPP-4 βελτιώνουν τον γλυκαιμικό έλεγχο στον ΣΔ τυπου 2
Απο του στόματος χορήγηση αναστολέων DPP-4 επιτυγχάνουν μείωση της υπεργλυκαιμίας.
37
DPP-4 Αναστολείς
38
Inhibition of DPP-4 Increases Active GLP-1
GLP-1inactive
(>80% of pool)
ActiveGLP-1
Meal
DPP-4
IntestinalGLP-1 release
GLP-1 t½=1–2 min
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1Adapted from Rothenberg P, et al. Diabetes. 2000; 49(suppl 1): A39. Abstract 160-OR.Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126-1131.
39
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
Incretin activity
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
40
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
41
Vildagliptin Provides Potent and Dose-dependent Inhibition of DPP-4 in Patients with T2DM
0
25
50
75
100
125
-2 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
DP
P-4
Act
ivity
(% b
asel
ine)
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus; vilda=vildagliptinHe YL, et al. In press.
Placebo (n=16)
Vilda 10 mg (n=16)
Vilda 25 mg (n=16)
Vilda 50 mg (n=16)
Vilda 100 mg (n=15)
Vilda 200 mg (n=16)
Vilda 400 mg (n=16)
42
Vildagliptin Enhances Islet Cell Function by Increasing Insulin and Decreasing Glucagon Secretion
OGTT 30 Min after Single Oral Dose of Vildagliptin (100 mg)
OGTT=oral glucose tolerance test*P <0.01. He YL, et al. In press.
7.5
12.5
17.5
22.5
Glucose (mmol/L)
0
60
80
100
120
40
20
Insulin (pmol/L)
60
80
100
120
140
Glucagon(ng/L)
−90 −60 −30 0 30
60
90
120
150
180
210
240
270
300
−90 −60 −30 0 30
60
90
120
150
180
210
240
270
300
−90 −60 −30 0 30
60
90
120
150
180
210
240
270
300Time
Placebo (n=16)Vildagliptin 100 mg (n=15)
75 g Glucose
Dose
43
Meal
* *
*
*
*
*
** * *
**
*
Placebo (n=16)
Vildagliptin 100 mg (n=16)
Vildagliptin Enhances GLP-1 Levels in Patients with T2DM
GLP-1=glucagon-like peptide-1*P <0.05Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
0.0
4.0
8.0
12.0
16.0
17:00 20:00 23:00 02:00 05:00 08:00
Time
Act
ive
GL
P-1
(p
mo
l/L)
44
Vildagliptin Suppresses Glucagon Secretion
Meal
*
* **
*
*
*
*
*P <0.05 vs placeboBalas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
−60
−50
−40
−30
−20
−10
0
10
20
17:00
Time
Del
ta G
luca
go
n (
ng
/L)
20:00 23:00 02:00 05:00 08:00
Placebo (n=16)
Vildagliptin 100 mg (n=16)
*
45
Vildagliptin Suppresses Endogenous Glucose Production
*P <0.05 vs placeboBalas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
0
−0.3
−0.6
−0.9
−1.2
−1.5
Del
ta E
GP
(m
g/k
g/m
in)
17:00 20:00 23:00 02:00 05:00 08:00
Time
**********
*
*
****************
Placebo (n=16)
Vildagliptin 100 mg (n=16)
Meal
46
Vildagliptin Increases Levels of Active Incretins in Patients with T2DM
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitusAdapted from Mari A, et al. J Clin Endocrinol Metab. 2005; 90: 4888–4894.
Intact GLP-1 (pmol/L)Intact GIP (pmol/L)
0
50
100
150
200
250
–2 0 2 4 6 8 10 12 14 16
Time (h)
Vildagliptin Day 1 Vildagliptin Day 28
0
5
10
15
20
25
30
35
–2 0 2 4 6 8 10 12 14
Time (h)
// //
//////
//
N=9
47
40
60
80
100
120
140
160
180
−6 −4 −2 0 2 4 6 8 10 12
Time (Min)
Insu
lin (
pm
ol/L
)
Vildagliptin 100 mg daily Week 0
Vildagliptin 100 mg daily Week 12
*
*
*
>3-fold increase in AIRg (P <0.001 vs Week 0, P <0.001 vs placebo)
Vildagliptin Improves First-Phase Insulin Response in Drug-Naïve T2DM Patients
AIRg=acute insulin response to glucose; T2DM=type 2 diabetes mellitus *P <0.05D’Alessio DA, et al. Poster 454-P presented at ADA 2006.
48
Vildagliptin: Enhances Insulin Sensitivity
Rd=rate of disappearance*P <0.05Azuma K, et al. Diabetes. 2007 (submitted).
Placebo (n=8)
Vildagliptin 100 mg daily (n=8)
Duration: 6 weeksVildagliptin vs placebo
Hyperinsulinemic Euglycemic Clamp
*
2.0
3.0
4.0
5.0
6.0
7.0
Glu
cose
Rd
(m
g/k
g/m
in) 5.4
6.1
1.0
0.0
49
Vildagliptin Reduces Postprandial Total Serum Triglycerides after 4 Weeks of Treatment
TG=triglyceridesITT population (intention-to-treat).*Adapted from Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057.**Study LAF2217. Data on file, Novartis Pharmaceuticals, 2 December 2005, p.36.
1.0
1.5
2.0
2.5
3.0
3.5
4.0
−1 0 1 2 3 4 5 6 7 8
Time (h)
To
tal
Ser
um
TG
(m
mo
l/L
)
Week 0Week 4
1.0
1.5
2.0
2.5
3.0
3.5
4.0
−1 0 1 2 3 4 5 6 7 8Time (h)
To
tal
Ser
um
TG
(m
mo
l/L
)
Week 0Week 4
Vildagliptin 100 mg daily* Placebo**
50
Vildagliptin Reduces Chylomicron Tryglycerides after 4 Weeks of Treatment
TG=triglyceridesMatikainen N, et al. Diabetologia. 2006; 49: 2049–2057.
Week 0
Week 4
0.0
0.2
0.4
0.6
0.8
-1 0 1 2 3 4 5 6 7 8
Time (h)
Ch
ylo
mic
ron
TG
(m
mo
l/L
)Vildagliptin 100 mg daily
51
Vildagliptin: No Effect on Gastric Emptying
143 145
0
25
50
75
100
125
150
Placebo Vildagliptin 100 mg daily
T1/
2 (M
in)
for
Gas
tric
Em
pty
ing
T1/2=time to empty 50% of stomach contents. Difference not statistically significantVella A, et al. Diabetes. 2007: Epub ahead of print.
52
0 12 24 52
Time (Week)
* * †
0 12 24 52
Time (Week)
* * *
pm
ol/
L 3
0 m
in/(
mm
ol/
L)
0 12 24 52
Time (Week)
* *m
L ·
min
-1 ·
m -2
0.050
0.040
0.045
0.025
0.030
0.035
300
250
275
200
225
14
10
12
6
8
InsulinSecretion
Insulin Sensitivity
AdaptationIndex
Vildagliptin Enhances -cell Function and Insulin Sensitivity over 52 Weeks
Patients on Stable Metformin Therapy
*P <0.05 vs placebo; †P <0.01 vs placebo.Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940.
Vildagliptin 100 mg daily / metformin
Placebo / metforminn
mo
l C-p
epti
de
· m
mo
l glu
cose
-1 ·
m
L-1 ·
m-2
53
Vildagliptin: Improves β-cell Mass(Neonatal Rat Pancreatic Growth Model)
Vilda=vildagliptin Duttaroy A, et al. Diabetes. 2005; 54 (suppl 1): A141. Abstract 572-P and poster presented at ADA.
Replication
-c
ell
Ma
ss
(m
g)
Vehicle Vilda
P <0.05
0.000.020.040.060.080.100.120.14
VehicleBrd
U-P
os
itiv
e C
ell
s (
%)
P <0.001
0
20
40
60
80
100
120
Vilda
Ap
op
Ta
g-P
os
itiv
e C
ell
s (
%)
Vehicle Vilda
P <0.05
0.0
0.5
1.0
1.5
2.0
2.5
Apoptosis -cell mass
Vildagliptin60 mg/kg21 days
Vehicle
Insulin
Day 7 Day 21
54
ΣΥΜΠΕΡΑΣΜΑ
Vildagliptin αναστέλλει DPP-4, με αποτέλεσμα:
επιπέδων GLP-1 και GIP νηστείας και μεταγευματικά
Βελτιώνει την λειτουργία των κυττάρωντων νησιδίων του παγκρέατος:
ευαισθησία γλυκοζοεξαρτωμενης έκκρισης γλυκαγόνης
ευαισθησία γλυκοζοεξαρτωμενης έκκρισης ινσουλίνης
πρώτη φάση έκκρισης ινσουλίνης
δυνατοτητα των παγκρεατικών κυτταρων για έκκριση
Μεταγευματικά τριγλυκερίδια
Αντίσταση στην δράση της ινσουλίνης
Δεν επηρεάζει την κένωση στομάχουDPP-4=dipeptidyl peptidase-4; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1
55
ΕΥΧΑΡΙΣΤΩΕΥΧΑΡΙΣΤΩ
GLP-1inactive
(>80% of pool)
ActiveGLP-1
Meal
DPP-4
IntestinalGLP-1 release
GLP-1 t½=1–2 min