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GLP-1 Effectiveness, Mechanisms of Action and Potential

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.

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GLP-1 Effectiveness, Mechanisms of Action and Potential

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

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

  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 • The GLP-1r is expressed in cardiomyocytes and in vascular endothelial cells. • Activation of the GLP-1r in cardiomyocytes in vitro increases cAMP levels and glucose uptake. • GLP-1r knock-out mice have increased ventricular thickness and increased end-diastolic pressure. • In rodents GLP-1 increases HR through a CNS pathway.

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

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

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

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

  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 P< 0.01 P< 0.01 ASE-Regional Wall Motion Score (IZ–WMSI) LVEF (%) 3.0 – 2.5 – ASE-RWMSI (%) LVEF (%) 2.0 – 1.5 – rGLP-1 Control Nikolaidis LA, et al. Circulation. 2004;109:962-5.

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

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

  14. E Mannucci, Nutr Metab Cardiovasc Dis, 2008

  15. Summary • GLP-1 is essential for normal glucose tolerance and the GLP-1r system is useful for treating diabetes. • GLP-1 acts via multiple mechanisms to improve glucose tolerance. • The mechanism of action of GLP-1r agonists and DPP-4 inhibitors includes islet α- and β-cell effects • 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.

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