GLP1 Effectiveness Mechanisms of Action and Potential Part

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

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

Incretin-related Anti-diabetes Drugs and effects on plasma glucagon • Hyperglucagonemia contributes to abnormal glucose homeostasis in T 2 DM • GLP-1 r activation reduces fasting and postprandial glucagon concentrations • Neither DPP-4 inhibition nor Ex-4 interferes with the glucagon response to hypoglycemia. • GLP-1 r activation may sensitize the alpha-cell to regulation by glucose.

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

The GLP-1 r and the Heart 1. The GLP-1 r is expressed in cardiomyocytes and in vascular endothelial cells. 2. Activation of the GLP-1 r in cardiomyocytes in vitro increases c. AMP levels and glucose uptake. 3. GLP-1 r 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-1 r in CV tissues Cardiomyocytes Endocardium Endothelium/SMC Anti-actin Anti-GLP-1 r Nuclear stain K Ban, Circulation 2008

Effects of GLP-1 r agonists on LVDP before and after ischemia/reperfusion Equilib Isch Reperf K Ban, Circulation 2008

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

Effects of IV GLP– 1 on Cardiac Metabolism and Function in Experimental CHF Myocardial Glucose Uptake Stroke Volume P ≤ 0. 01 P ≤ 0. 05 P < 0. 001 Ejection Fx P < 0. 005 Nikolaidis LA, et al. Circulation. 2004; 110: 955 -61.

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 fraction Wall motion abnormality ASE-Regional Wall Motion Score (IZ–WMSI) P < 0. 01 ASE-RWMSI (%) LVEF (%) P < 0. 01 3. 0 – 2. 5 – 2. 0 – 1. 5 – r. GLP-1 Control Nikolaidis LA, et al. Circulation. 2004; 109: 962 -5.

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

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

E Mannucci, Nutr Metab Cardiovasc Dis, 2008

Summary 1. GLP-1 is essential for normal glucose tolerance and the GLP-1 r system is useful for treating diabetes. 2. GLP-1 acts via multiple mechanisms to improve glucose tolerance. 3. The mechanism of action of GLP-1 r agonists and DPP-4 inhibitors includes islet α- and β-cell effects 4. Effects of GLP-1 r signaling on cardiovascular function are still under investigation but there is experimental evidence that this could be another beneficial component of pharmacology.