GLP-1 Effectiveness, Mechanisms of Action and Potential
Part 4 of 4
Diabetes 53:2397;2004
Treatment with Exenatide does not impair the counterregulatory glucagon response
Incretin-related Anti-diabetes Drugs and effects on plasma glucagon
• Hyperglucagonemia contributes to abnormal glucose homeostasis in T2DM
• GLP-1r activation reduces fasting and postprandial glucagon concentrations
• Neither DPP-4 inhibition nor Ex-4 interferes with the glucagon response to hypoglycemia.
• GLP-1r activation may sensitize the alpha-cell to regulation by glucose.
Does activation of the GLP-1r improve cardiac function?
A new extra-islet target for GLP-1: The Heart
The GLP-1r and the Heart
1. The GLP-1r is expressed in cardiomyocytes and in vascular endothelial cells.
2. Activation of the GLP-1r in cardiomyocytes in vitro increases cAMP levels and glucose uptake.
3. GLP-1r knock-out mice have increased ventricular thickness and increased end-diastolic pressure.
4. In rodents GLP-1 increases HR through a CNS pathway.
Expression of the GLP-1r in CV tissues
Cardiomyocytes Endocardium Endothelium/SMC
Anti-actinAnti-GLP-1rNuclear stain
K Ban, Circulation 2008
Effects of GLP-1r agonists on LVDP before and after ischemia/reperfusion
K Ban, Circulation 2008
Equilib Isch Reperf Equilib Isch Reperf
Effects of GLP-1 peptides on coronary blood flow, ischemic LDH levels, and glucose uptake
K Ban, Circulation 2008
0
5
10
15
20
Control DCM DCM +GLP–1
Baseline Hyperinsulinemia
0
5
10
15
20
Control DCM DCM +GLP–1
Baseline Hyperinsulinemia
Effects of IV GLP–1 on Cardiac Metabolism and Function in Experimental CHF
Nikolaidis LA, et al. Nikolaidis LA, et al. CirculationCirculation. 2004;110:955-61.. 2004;110:955-61.
PP ≤ 0.05 ≤ 0.05
PP ≤ 0.01 ≤ 0.01
0
10
20
30
Base CHF 24 h 48 h
Mill
ilite
rs
0
10
20
30
Base CHF 24 h 48 h
Mill
ilite
rs
0
10
20
30
40
50
Base CHF 24 h 48 h
Perc
ent
0
10
20
30
40
50
Base CHF 24 h 48 h
Perc
ent
PP < 0.001 < 0.001PP < 0.001 < 0.001
PP < 0.005 < 0.005
Stroke VolumeStroke Volume
Ejection FxEjection Fx
Myo
card
ial G
luco
se U
ptak
eM
yoca
rdia
l Glu
cose
Upt
ake
GLP-1 decreases pyruvate and lactate in the ischemic & non-ischemic porcine myocardium
Kavianipour, Peptides 2003
Effects of IV GLP–1 on Ventricular Function and Wall Motion Post-MI
Ejection fractionEjection fraction Wall motion abnormalityWall motion abnormality
0
10
20
30
40
50
rGLP-1 Control
0
10
20
30
40
50
rGLP-1 Control1.5 –1.5 –
2.0 –2.0 –
2.5 –2.5 –
3.0 –3.0 –
rGLP-1rGLP-1 ControlControl
Nikolaidis LA, et al. Nikolaidis LA, et al. CirculationCirculation. 2004;109:962-5.. 2004;109:962-5.
LVEF
(%)
LVEF
(%)
LVEF
(%)
LVEF
(%)
ASE
-RW
MSI
(%)
ASE
-RW
MSI
(%)
ASE
-Reg
iona
lW
all M
otio
n Sc
ore
(IZ–
WM
SI)
ASE
-Reg
iona
lW
all M
otio
n Sc
ore
(IZ–
WM
SI)
P < 0.01P < 0.01 P < 0.01P < 0.01
0
10
20
30
40
50
pre-rGLP–1 post-rGLP–1
0
10
20
30
40
50
pre-rGLP–1 post-rGLP–11
2
3
pre-rGLP–1 post-rGLP–1
1
2
3
pre-rGLP–1 post-rGLP–1
0
10
20
30
40
50
60
70
A B C D
Effect of GLP–1 on Infarct Size in Experimental Ischemia
Bose AK, et al. Bose AK, et al. DiabetesDiabetes. 2005;54:146-51. 2005;54:146-51.
Infa
rct-t
o-ris
k ra
tio (%
)In
farc
t-to-
risk
ratio
(%)
**
ControlControl Val-PyrrolVal-Pyrrol GLP-1GLP-1 Exendin-(9-39)Exendin-(9-39)
Effect of GLP-1 on endothelial-dependent and independent Blood Flow in non-Diabetic
humans
A Basu, AJP 2007
Endothelial-Dependent Endothelial-Independent
E Mannucci, Nutr Metab Cardiovasc Dis, 2008
Summary
1. GLP-1 is essential for normal glucose tolerance and the GLP-1r system is useful for treating diabetes.
2. GLP-1 acts via multiple mechanisms to improve glucose tolerance.
3. The mechanism of action of GLP-1r agonists and DPP-4 inhibitors includes islet α- and β-cell effects
4. Effects of GLP-1r signaling on cardiovascular function are still under investigation but there is experimental evidence that this could be another beneficial component of pharmacology.