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

2. Diabetes 53:2397;2004 Treatment with Exenatide does not impair the counterregulatory glucagon response

3. 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.

4. Does activation of the GLP-1r improve cardiac function? A new extra-islet target for GLP-1: The Heart

5. 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.

6. Expression of the GLP-1r in CV tissues CardiomyocytesEndocardiumEndothelium/SMC Anti-actin Anti-GLP-1r Nuclear stain K Ban, Circulation 2008

7. Effects of GLP-1r agonists on LVDP before and after ischemia/reperfusion K Ban, Circulation 2008 EquilibIschReperfEquilibIschReperf

8. Effects of GLP-1 peptides on coronary blood flow, ischemic LDH levels, and glucose uptake K Ban, Circulation 2008

9. Effects of IV GLP–1 on Cardiac Metabolism and Function in Experimental CHF Nikolaidis LA, et al. Circulation. 2004;110:955-61. P ≤ 0.05 P ≤ 0.01 P < 0.001 P < 0.005 Stroke Volume Ejection Fx Myocardial Glucose Uptake

10. GLP-1 decreases pyruvate and lactate in the ischemic & non-ischemic porcine myocardium Kavianipour, Peptides 2003

11. Effects of IV GLP–1 on Ventricular Function and Wall Motion Post-MI Ejection fraction Wall motion abnormality 1.5 – 2.0 – 2.5 – 3.0 – rGLP-1 Control Nikolaidis LA, et al. Circulation. 2004;109:962-5. LVEF (%) ASE-RWMSI (%) ASE-Regional Wall Motion Score (IZ–WMSI) ASE-Regional Wall Motion Score (IZ–WMSI) P < 0.01

12. Effect of GLP–1 on Infarct Size in Experimental Ischemia Bose AK, et al. Diabetes. 2005;54:146-51 Bose AK, et al. Diabetes. 2005;54:146-51. Infarct-to-risk ratio (%) * ControlVal-PyrrolGLP-1Exendin-(9-39)

13. Effect of GLP-1 on endothelial-dependent and independent Blood Flow in non-Diabetic humans A Basu, AJP 2007 Endothelial-Dependent Endothelial-Independent

14. E Mannucci, Nutr Metab Cardiovasc Dis, 2008

15. 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.