glp-1 effectiveness, mechanisms of action and potential part 1
TRANSCRIPT
GLP-1 Effectiveness, Mechanisms of Action and Potential
Part 1
Overview
1. Physiology of GLP-1 2. Clinical effects of GLP-1r agonists and DPP-4
inhibitors stemming from incretin action.3. The role of glucagon in glucose intolerance and
effects of GLP-1 based drugs on plasma glucagon.
4. Cardiovascular effects of GLP-1.
A Fundamental Observation: Insulin Secretion is Greater with Oral Compared to IV Glucose
Adapted from McIntyre N, et al. Lancet. 1964;41:20-21.
IV/IJ glucose
Blood Glucose Plasma Insulin
0
50
100
150
200
250
300
-30 -15 0 15 30 45 60 75 90 105 120 135
Time (min)
Blo
od
Glu
co
se
(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)
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]
Vilsboll T, et al. Vilsboll T, et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab. 2003;88:2706-13.. 2003;88:2706-13.
Secretion of Incretins After MealsGLP–1 GIP50 –
Tota
l GLP
–1 (p
mol
/L)
Tota
l GLP
–1 (p
mol
/L)
10 –
20 –
30 –
40 –
Tota
l GIP
(pm
ol/L
)To
tal G
IP (p
mol
/L)
0 –
200 –
50 –
100 –
150 –
0 –
|
−20|
40|
100|
160
Inta
ct G
IP (p
mol
/L)
Inta
ct G
IP (p
mol
/L)
Time (min)Time (min)
0 –
100 –
20 –
40 –
60 –
80 –
20 –
Inta
ct G
LP–1
(pm
ol/L
)In
tact
GLP
–1 (p
mol
/L)
|
−20|
40|
100|
160Time (min)Time (min)
15 –
0 –
5 –
10 –
Distribution of Incretin Receptors
Gs
AcATP
cAMPGs
AcATP
cAMP
PKA
Insulin
-Cell
Heart / VascCNS / PNS
GI tract
Adipocyte Brain
Adrenal
GLP-1 GIP
0
200
400
600
800
1000
-50 -25 0 25 50 75 100
Time (min)
Insu
lin (
pm
ol/L
)
0
200
400
600
800
1000
-50 -25 0 25 50 75 100
Time (min)
Insu
lin (
pm
ol/L
)
Kreymann B, et al. Kreymann B, et al. Lancet.Lancet. 1987;2:1300-4. 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
cose
(m
g/d
L)
0
50
100
150
200
250
-50 -25 0 25 50 75 100
Time (min)
Glu
cose
(m
g/d
L)
GLSalineSaline
GLP–1GLP–1
GIPGIP
SalineSaline
GLP–1GLP–1
GIPGIP
GL
Test InfusionTest InfusionTest InfusionTest Infusion
Metabolism of GLP-1 by DPP-4
H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R
H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S
cleavage site of DPP-IV
Exendin-4
GLP-1(7-36)NH2
GLP-1(7-36)NH2 GLP-1(9-36)NH2H-A H-A +
DPP IV
GLP-1(9-36)NH2 and insulin secretion
Vahl et al., JCEM 2003
Minutes
-40 -20 0 20 40 60 80 100 120 140 160 180 200
Glu
cos
e (m
g/d
l)
0
50
100
150
200
250
300
350Saline GLP-1(7-36) GLP-1(9-36)
GLP-1/saline infusion
Actions of GLP-1 that Regulate Blood Glucose Concentrations
1. Stimulate β-cell function- insulin secretion/synthesis- cell growth/antiapoptosis
2. Inhibit glucagon release3. Delay gastric emptying4. Diminish food intake5. Extrapancreatic effects on glucose
- promote glucose uptake- suppress HGP
0 20 40 60 80 100 120 140
2
4
6
8
10
12
14
16
ControlExendin-(9-39)
Glucose mM
Minutes
Glucose
Mice
0 30 60 90 120 150 1803
4
5
6
7
ControlExendin-(9-39)
Glucose (mM)
Minutes
Glucose
Primates
-20 0 20 40 60 80 100 120 140 160 180 200
4
5
6
7
8
9
ControlExendin-(9-39)
Glucose mM
Minutes
Glucose
Humans
Interruption of GLP-1r signaling causes glucose intolerance
Scrocchi et alNature Med, 1996
Edwards et alDiabetes, 1999
D’Alessio et alJCI, 1996
Incretin effect of GLP-1 in healthy humans
0 30 60 90 120 150 180 210 240 270 300
80
105
130
155
180
SalineExendin-(9-39)
Intravenous glucose infusion at variable rate
Exendine-(9-39) or Saline infusion
Oral glucose consumption
Time (minutes)
Blo
od
glu
cose
(m
g/d
L)
M Salehi et al, JCEM, 2008
Glucose GIR
Insulin C-peptide
Effects of GLP-1r blockade on meal-induced glucagon release and gastric emptying
M Salehi, JCEM 2008
Glucagon Gastric Emptying