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ΙΝΚΡΕΤΙΝΕΣ :
Ο ρόλος του ενζύμου DPP-4 στον Σακχαρώδη Διαβήτη τύπου 2
Δρ Ασημίνα Μητράκου
1
Εκκριση Ινσουλίνης μετά την λήψη τροφής
Νευρογενή
Ερεθίσματα
Sympathetic innervation (β-receptors)
Parasympathetic (cholinergic) innervation
Γλυκόζη
(κι αλλες ουσίες)
ΙΝΣΟΥΛΙΝΗ
ΙΝΚΡΕΤΙΝΕΣ
2
Βασική παρατήρηση: Η έκκριση ινσουλίνης ειναι μεγαλύτερη μετα τηαν
απο του στόματος λήψη γλυκόζης
Blood Glucose
Plasma Insulin
300
Intravenous
250
Plasma Insulin ( pmol/L)
Blood Glucose (mg/dL)
300
Intrajejunal
200
150
100
50
250
200
150
100
50
0
0
-30 -15
0
15
30
45
60
75
Time (min)
McIntyre N, et al. Lancet. 1964;II:20-1.
90 105 120 135
-30 -15
0
15
30
45
60
75
90
105 120 135
Time (min)
3
Φαινόμενο Ινκρετίνης
Oral Glucose Tolerance Test
Glucose (mg/dL)
200
Insulin (pmol/L)
400
50 g glucose
150
300
100
200
50
100
0
0
-30
0
30
60
90 120 150 180 210
Time (min)
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
-30
0
30
60
90 120 150 180 210
Time (min)
4
Φαινόμενο Ινκρετίνης
OGTT and Matched IV Infusion
Glucose (mg/dL)
Insulin (pmol/L)
400
200
Oral
150
300
100
200
50
100
0
0
-30
0
30
60
90 120 150 180 210
Time (min)
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
IV
-30
0
30
60
90
120 150 180 210
Time (min)
5
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.
6
Εκκριση Ινσουλίνης και επίπεδα γλυκόζης με αυξανομένη δόση
γλυκόζης απο του στόματος/ενδοφλεβίως
300
25 g
Oral
200
100 g
100
IV
Glucose (mg/dL)
Glucose (mg/dL)
300
200
25 g
100 g
100
0
0
-30 0 30 60 90 120 150 180 210 240 270 300 330
Time (min)
800
-30 0
800
30 60 90 120 150 180 210 240 270 300 330
Time (min)
Insulin Secretion
(pmol/min)
600
Insulin Secretion
(pmol/min)
600
400
400
200
200
0
0
-30
0
30 60
90 120 150 180 210 240 270 300 330
Time (min)
Tillil H, et al. Am J Physiol. 1988;254:E349-E357.
-30
0
30 60 90 120 150 180 210 240 270 300 330
Time (min)
7
Η εκκριση των Ινκρετινών εξαρτάται απο το μεγεθος του
γεύματος
GIP
GLP-1
160
260 kcal
260 kcal
40
520 kcal
30
20
10
Total GIP (pmol/L)
Total GLP-1 (pmol/L)
50
0
520 kcal
120
80
40
0
-30
0
30
60
90 120 150 180 210
Time (min)
Vilsbøll T, et al. J Clin Endocrinol Metab. 2003;88:2706-13.
-30
0
30
60
90
120 150 180 210
Time (min)
8
Οι ΙΝΚΡΕΤΙΝΕΣ
GLP-1: Glucagon-Like Peptide–1
H A E G T F T S D V S S Y L E G Q A
A
K
A
K
F
L
R
I
V
E
W
G
G
GIP: Glucose-Dependent Insulinotropic Peptide
A
E G T F I S D Y S I A M D K I H
Q
K K G K
A L L W N V F D Q
D
N
W
Q
K
T Q
I
N
H
Y
*Amino acids shown in gold are homologous with the structure of glucagon.
9
Synthesis and Secretion of GLP-1 and GIP
K-Cell
(jejunum)
L-Cell
(ileum)
ProGIP
Proglucagon
GLP-1 [7-37]
GIP [1-42]
GLP-1 [7-36NH2]
10
Mεταβολισμός GLP-1 και GIP
Active Hormones
GLP-1 [7-36NH2]
GIP [1-42]
Capillary
Inactive Metabolites
Dipeptidyl peptidase-4 (DPP-4)
GLP-1 [9-36NH2]
GIP [3-42]
Ubiquitous, specific protease
Cleaves N-terminal dipeptide
Inactivates > 50% of GLP-1 ~ 1 min
> 50% of GIP in ~ 7 min
11
Μεταβολισμός GLP-1 και GIP
L-Cell
K-Cell
Proglucagon
ProGIP
GLP-1 [7-37]
Capillary
Capillary
GIP [1-42]
GLP-1 [7-36NH2]
GLP-1[7-36NH2]
ACTIVE
GIP [1-42]
ACTIVE
DPP-4
DPP-4
GLP-1 [9-36NH2]
INACTIVE
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
GIP [3-42]
INACTIVE
12
30-Minute Εκκριση Total and Intact GLP-1 and GIP in σε Υγιη Ατομα
GIP
GLP-1
3
2
1
12
9
(0-30min)
(pmol*min/L)
15
6
AUC
AUC
(0-30min)
(pmol*min/L)
4
3
0
0
Total
Intact
Vilsbøll T, et al. J Clin Endocrinol Metab. 2003;88:2706-13.
Total
Intact
13
Τόπος Δράσης
-Cell
ATP
GLP-1
Ac
Ac
Gs
-cell
Adipocyte
Brain
Stomach
Small intestine
ATP
cAMP cAMP
PKA
Insulin
GIP
Gs
-cell
Adipocyte
Brain
Adrenal
Pituitary
14
Glucose-Dependent Insulinotropic Effect of GLP-1 and GIP in
Healthy Subjects
Test Infusion
Test Infusion
250
1000
GL
Saline
GLP-1
GIP
150
100
600
400
50
200
0
0
-50
-25
0
25
50
Time (min)
Kreymann B, et al. Lancet. 1987;2:1300-4.
75
Saline
GLP-1
GIP
800
Insulin (pmol/L)
Glucose (mg/dL)
200
GL
100
-50
-25
0
25
50
75
100
Time (min)
15
Impaired Glucose Tolerance in GLP-1 Receptor Knockout Mice
105
*
*
Wild Type
GLP-1 r -/-
**
360
*
*
*
**
180
0
*
Insulin (pmol/L)
Blood Glucose (mg/dL)
540
70
35
0
0
30
60
90
Time (min)
120
Wild Type
GLP-1r -/-
+/+ -/0 min
+/+ -/30 min
+/+ -/60 min
Time (min)
**P < .01, *P < .05
Scrocchi LA, et al. Nat Med. 1996;2:1254-8.
16
Impaired Glucose Tolerance in GIP Receptor Knockout Mice
500
Blood Glucose (mg/dL)
*
Wild Type
GIPr -/-
**
400
300
200
100
Plasma Insulin (pmol/L)
245
Wild Type
GIP r -/-
210
175
140
***
*
105
70
35
0
0
0
30
60
90
120
Time (min)
0
15
30
60
Time (min)
***P < .001, **P < .01, *P < .05.
Miyawaki K, et al. Proc Natl Acad Sci U S A. 1999;96:14843-7.
17
GLP-1 Decreases Glucagon and Glucose Levels in Patients with Type 1
Diabetes
12
350
GLP-1 or Placebo
GLP-1 or Placebo
300
Placebo
8
P < .001
6
4
*
*
2
*
*
*
*
*
*
GLP-1
0
Plasma Glucose (mg/dL)
Glucagon (pmol/L)
10
Placebo
250
200
*
150
*
100
50
*
* *
GLP-1
*
*
P < .001
0
-30
0
30
60 90 120 150 180 210 240
Time (min)
Creutzfeldt WO, et al. Diabetes Care. 1996;19:580-6.
-30
0
30 60 90 120 150 180 210 240
Time (min)
18
GLP-1 Decreases Gastric Emptying of a Solid Meal in Healthy Subjects
100
Gastric Emptying
(% remaining in stomach)
90
80
70
60
50
GLP-1
Saline
40
30
20
10
0
0
20
40
60
80
100
120
140
160
180
Time (min)
Näslund E, et al. Am J Physiol. 1999;277:R910-R916.
19
Effect of GLP-1 on -Cell Mass
in Diabetic Rats
-Cell
Proliferation
-Cell Mass
-Cell Apoptosis
16
30
2,5
P < .001
1,5
1
0,5
20
P < .05
10
Control
GLP-1
Treated
Farilla L, et al. Endocrinology. 2002;143:4397-408.
12
8
4
0
0
0
-Cell Mass (mg)
2
% Apoptotic -Cells
% Proliferating -Cells
P < .01
Control
GLP-1
Treated
Control
GLP-1
Treated
20
Comparison of Physiology
of GLP-1 and GIP
GLP-1
GIP
L-cells in ileum and colon
K-cells in duodenum and jejunum
Indirect/neuronal
Direct
Inhibits glucagon
Yes
No
Slows gastric emptying
Yes
No
Stimulation of -cell growth/mass
Yes
Yes
-cell, -cell, stomach, nervous
system
-cell, adipose tissue
Exendin [9-39]
GIP [7-30]
Yes, with IGT
Yes, with IGT
Site of production
Response to stimuli
Major target tissues
Antagonist
Receptor KO mice
21
Το Φαινόμενο Ινκρετίνης στον ΣΔ τύπου 2
22
Το φαινόμενο Ινκρετίνης στον ΣΔ τύπου 2
Plasma Glucose (mg/dL)
240
180
90
0
0
30
C-Peptide (nmol/L)
Type 2 DM
60
120
20
*
*
180
90
0
0
60
120
180
0
60
120
180
30
*P < .05
10
240
180
C-Peptide (nmol/L)
Plasma Glucose (mg/dL)
Control
* *
*
* *
*
0
IV
Oral
20
10
0
0
60
120
Time (min)
Nauck M, et al. Diabetologia. 1986;29:46-52.
180
Time (min)
23
Εκκριση Ινκρετινών μετα απο γευμα σε ασθενεις με ΣΔ τυπου 2
GIP
GLP-1
P < 0.001
2,0
1,0
GIP AUC (nmol/L*240 min)
GLP-1 AUC (nmol/L*240 min)
3,0
20
P = 0.095
15
10
5
0
0,0
NGT
IGT
Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-23.
T2DM
24
Διαφορετική ινσουλινοτρόπος δραση των ινκρετινών στον ΣΔ τυπου 2
C-Peptide (pmol/L)
8000
Hyperglycemic Clamp
Saline or GIP or GLP-1
6000
4000
GLP-1
GIP
Saline
2000
0
-15 -10
0
5
10 15
20
30
45
60 75
90 105 120 150
Time (Min)
Vilsböll T, et al. Diabetologia. 2002;45:1111-9.
25
IV χορηγηση GLP-1 σε ασθενεις με ΣΔ τυπου 2
Glucose (mg/dL)
300
C-Peptide (nmol/L)
3,0
250
2,5
200
2,0
150
1,5
100
50
0
-30 0
*
*
*
GLP-1
Saline
* *
*
30 60 90 120 150 180 210 240
30
GLP-1 Infusion
GLP-1 Infusion
*
Glucagon (pmol/L)
GLP-1 Infusion
25
* *
*
*
*
*
*
20
*
15
1,0
10
0,5
5
0,0
-30 0
Time (min)
(Min)
*P < .05
Nauck MA, et al. Diabetologia. 1993;36:741-4.
30 60 90 120 150 180 210 240
Time (min)
0
-30 0
**
**
30 60 90 120 150 180 210 240
Time (min)
26
6 εβδομαδες συνεχους χορηγησης GLP-1 σε ασθενεις με ΣΔ τυπου 2
Patients assigned GLP-1
Patients assigned saline
400
400
Meal
Glucose (mg/dL)
Glucose (mg/dL)
Meal
300
200
100
-0.5
0.5
1.5
2.5
3.5
4.5
300
200
100
-0.5
Time (hr)
Week 0
Zander M, et al. Lancet. 2002;359:824-30.
0.5
1.5
2.5
3.5
4.5
Time (hr)
Week 1
Week 6
27
Effects of 4 Weeks’ Treatment with a DPP-4 Inhibitor in Patients with Type 2
Diabetes
275
16
Placebo
Glucose
14
Placebo
GLP-1
225
Drug
GLP-1 (pmol/L)
Glucose (mg/dL)
Drug
meal
175
12
10
8
6
4
125
2
300
120
Insulin
Glucagon
Glucagon (pmol/L)
Insulin (pmol/L)
250
200
150
100
Placebo
50
0
-30
Drug
0
30
60
Time (min)
Ahren B, et al. JCEM. 2004;(in press).
90
120
150
Placebo
Drug
100
80
60
-30
0
30
60
90
120
150
Time (min)
28
4 εβδομαδες θεραπεια με ινκρετινομιμητικα φαρμακα ( GLP-1
Receptor Agonist ) σε αθενεις με ΣΔ τυπου 2
Placebo
Drug (BD)
Drug (TID)
300
0,0
Placebo
Meal
(%)
-0,2
Change in HbA
1c
Glucose (mg/dL)
-0,4
-0,6
-0,8
-1,0
|
P < .001
-1,2
250
200
|
P < .001
Drug
(all arms)
150
-1,4
BD = before breakfast and dinner
-30
0
30 60 90 120 150 180 210 240 270
Time (min)
Fineman MS, et al. Diabetes Care. 2003;26:2370-7.
29
At 30 Weeks, PPG Remained Low among Patients
Treated with GLP-1 Analogue
Postprandial Plasma Glucose (mmol/L)
Week 30 Meal Tolerance Test*
16
15
14
13
12
Injection
Meal
Placebo (n=23)
5 µg exenatide (n=27)
10 µg exenatide (n=27)
11
10
9
8
7.5
0
0
25
50
75
100
125
150
175
Time (Min)
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.
30
Μεταβολικές δράσεις GLP-1 σε συνεχη χορηγηση επι 6 εβδομαδες σε
ασθενεις με ΣΔ τυπου 2
Zander M, et al. Lancet. 2002;359:824-30.
31
Effect of Bedtime Administration of a Long-acting GLP-1 Derivative in
Patients with T2DM
Breakfast
800
225
Placebo
Drug
Placebo
Drug
Insulin Secretory Rate
(pmol/min)
Plasma Glucose (mg/dL)
Breakfast
600
180
400
135
200
90
0
-2 0
2 4
6 8 10 12 14 16 18
Time (hr)
Juhl CB, et al. Diabetes. 2002;51:424-9.
-2 0
2 4
6 8 10 12 14 16 18
Time (hr)
32
Glucose Tolerance, Insulin, and GLP-1 Levels in DPP-4 Deficient
Mice
270
90
*
100
50
-30
0 30 60 120
180
2
1
0
0
0
*
Plasma GLP-1 (pmol/L)
**
180
Plasma Insulin (pmol/L)
+/+
DPP-4 -/-
***
Blood Glucose (mg/dL)
3
150
+/+
-/-
+/+
-/-
Time (min)
***P < .001, *P < .01, *P < .05
Marguet D, et al. Proc Natl Acad Sci U S A. 2000;97:6874-9.
33
GLP-1 Analogues Enhance Glucagon Secretion in
Hypoglycemic Conditions
300
Glucose Clamp Steps
(mmol/L): 5.0
4.0
*
3.2
2.7
*
Recovery
*
Plasma Glucagon (ng/L)
250
Exenatide† (n=11)
Placebo (n=11)
200
150
100
50
0
–30
0
30
60
90
120 150
180
210 240
270
300 330
360
Time (Min)
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.
34
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
35
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.
36
DPP-4 Αναστολείς
37
Inhibition of DPP-4 Increases Active GLP-1
Meal
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
Active
GLP-1
DPP-4
GLP-1
inactive
(>80% of pool)
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1
Adapted 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.
38
Blocking DPP-4 Can Improve Incretin Activity and
Correct the Insulin:Glucagon Ratio in T2DM
T2DM
Incretin
response
diminished
 Insulin
Further impaired
islet function
Hyperglycemia
 Glucagon
DPP-4 inhibitor
Incretin
activity
prolonged
 Insulin
Improved islet
function
Improved
glycemic control
 Glucagon
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.
39
Vildagliptin – a potent and selective DPP-4 inhibitor
H
HO
O
N
N
N
 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
DPP-4=dipeptidyl peptidase-4
40
Vildagliptin Provides Potent and Dose-dependent
Inhibition of DPP-4 in Patients with T2DM
DPP-4 Activity (% baseline)
125
Placebo (n=16)
100
Vilda 10 mg (n=16)
Vilda 25 mg (n=16)
75
Vilda 50 mg (n=16)
50
Vilda 100 mg (n=15)
Vilda 200 mg (n=16)
25
Vilda 400 mg (n=16)
0
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (h)
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus; vilda=vildagliptin
He YL, et al. In press.
41
Vildagliptin Enhances Islet Cell Function by Increasing
Insulin and Decreasing Glucagon Secretion
OGTT 30 Min after Single Oral Dose of Vildagliptin (100 mg)
75 g Glucose
120
Insulin
(pmol/L)
Placebo (n=16)
Vildagliptin 100 mg (n=15)
100
Dose
80
60
40
20
0
−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
300
22.5
Glucose
(mmol/L)
17.5
12.5
7.5
140
Glucagon
(ng/L)
120
100
80
60
OGTT=oral glucose tolerance test
*P <0.01.
He YL, et al. In press.
Time
42
Vildagliptin Enhances GLP-1 Levels in Patients
with T2DM
Meal
Active GLP-1 (pmol/L)
16.0
Placebo (n=16)
*
Vildagliptin 100 mg (n=16)
*
*
12.0
*
*
*
*
*
**
8.0
*
*
*
4.0
0.0
17:00
20:00
GLP-1=glucagon-like peptide-1
*P <0.05
Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
23:00
02:00
05:00
08:00
Time
43
Vildagliptin Suppresses Glucagon Secretion
20
Meal
Placebo (n=16)
Delta Glucagon (ng/L)
10
Vildagliptin 100 mg (n=16)
0
−10
−20
*
−30
*
−40
−50
*
*
*
−60
17:00
*
*
*
20:00
23:00
*P <0.05 vs placebo
Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
02:00
*
05:00
08:00
Time
44
Vildagliptin Suppresses Endogenous Glucose
Production
Time
Meal
Delta EGP (mg/kg/min)
17:00
0
20:00
23:00
02:00
05:00
08:00
−0.3
−0.6
*
−0.9
*
* * ** * * ***
*
−1.2
−1.5
Placebo (n=16)
**
*
* *
****
*
*
*
** * *
Vildagliptin 100 mg (n=16)
*P <0.05 vs placebo
Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
45
Vildagliptin Increases Levels of Active Incretins in
Patients with T2DM
N=9
Intact GIP (pmol/L)
Intact GLP-1 (pmol/L)
35
250
30
200
25
150
20
100
15
//
50
0
–2
10
//
0
2
4
6
//
//
//
//
5
8
10
12
14
16
0
–2
0
2
4
Time (h)
Vildagliptin Day 1
6
8
10
12
14
Time (h)
Vildagliptin Day 28
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
Adapted from Mari A, et al. J Clin Endocrinol Metab. 2005; 90: 4888–4894.
46
Vildagliptin Improves First-Phase Insulin Response in
Drug-Naïve T2DM Patients
180
*
*
160
*
Vildagliptin 100 mg daily Week 12
Insulin (pmol/L)
140
Vildagliptin 100 mg daily Week 0
120
100
80
>3-fold increase in AIRg
(P <0.001 vs Week 0, P <0.001 vs placebo)
60
40
−6 −4 −2 0
2
4
6
8 10 12
Time (Min)
AIRg=acute insulin response to glucose; T2DM=type 2 diabetes mellitus
*P <0.05
D’Alessio DA, et al. Poster 454-P presented at ADA 2006.
47
Vildagliptin: Enhances Insulin Sensitivity
Duration: 6 weeks
Vildagliptin vs placebo
Hyperinsulinemic Euglycemic Clamp
Glucose Rd (mg/kg/min)
7.0
6.0
*
6.1
Vildagliptin 100 mg daily (n=8)
5.4
Placebo (n=8)
5.0
4.0
3.0
2.0
1.0
0.0
Rd=rate of disappearance
*P <0.05
Azuma K, et al. Diabetes. 2007 (submitted).
48
Vildagliptin Reduces Postprandial Total Serum
Triglycerides after 4 Weeks of Treatment
Vildagliptin 100 mg daily*
Week 0
Week 4
4.0
Total Serum TG (mmol/L)
4.0
Total Serum TG (mmol/L)
Placebo**
3.5
3.0
2.5
2.0
1.5
1.0
Week 0
Week 4
3.5
3.0
2.5
2.0
1.5
1.0
−1
0
1
2
3 4 5
Time (h)
6
7
8
TG=triglycerides
ITT 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
2
3
4
5
6
7
8
Time (h)
49
Vildagliptin Reduces Chylomicron Tryglycerides after
4 Weeks of Treatment
Vildagliptin 100 mg daily
0.8
Week 0
Chylomicron TG (mmol/L)
Week 4
0.6
0.4
0.2
0.0
-1
0
1
2
3
4
5
6
7
8
Time (h)
TG=triglycerides
Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057.
50
T1/2 (Min) for Gastric Emptying
Vildagliptin: No Effect on Gastric Emptying
150
143
145
Placebo
Vildagliptin 100 mg daily
125
100
75
50
25
0
T1/2=time to empty 50% of stomach contents. Difference not statistically significant
Vella A, et al. Diabetes. 2007: Epub ahead of print.
51
Vildagliptin Enhances -cell Function and Insulin
Sensitivity over 52 Weeks
Insulin
Sensitivity
300
0.050
0.045
*
*
*
0.040
0.035
0.030
0.025
mL · min-1 · m -2
pmol/L 30 min/(mmol/L)
Insulin
Secretion
275
*
*
250
225
200
0 12 24
52
Time (Week)
0 12 24
52
Time (Week)
nmolC-peptide · mmolglucose-1 ·
mL-1 · m-2
Patients on Stable Metformin Therapy
Adaptation
Index
14
12
*
*
†
10
8
6
0 12 24
52
Time (Week)
Vildagliptin 100 mg daily / metformin
Placebo / metformin
*P <0.05 vs placebo; †P <0.01 vs placebo.
Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940.
52
Vildagliptin: Improves β-cell Mass
(Neonatal Rat Pancreatic Growth Model)
Insulin
Vildagliptin
60 mg/kg
21 days
Vehicle
100
80
60
40
20
0
Vehicle
Vilda
2.5
2.0
1.5
P <0.05
1.0
0.5
0.0
Day 7
Vehicle
Vilda
Vilda=vildagliptin
Duttaroy A, et al. Diabetes. 2005; 54 (suppl 1): A141. Abstract 572-P and poster presented at ADA.
-cell Mass (mg)
P <0.001
ApopTag-Positive Cells (%)
BrdU-Positive Cells (%)
120
-cell mass
Apoptosis
Replication
P <0.05
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
Vehicle
Vilda
Day 21
53
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 στομάχου
DPP-4=dipeptidyl peptidase-4; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1
54
ΕΥΧΑΡΙΣΤΩ
Meal
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
Active
GLP-1
DPP-4
GLP-1
inactive
(>80% of pool)
55