GLP-1 Effectiveness, Mechanisms of Action and Potential Part 4 of 4.

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.