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

2. Overview 1.Physiology of GLP-1 2.Clinical effects of GLP-1r agonists and DPP-4 inhibitors stemming from incretin action. 3.The role of glucagon in glucose intolerance and effects of GLP-1 based drugs on plasma glucagon. 4. Cardiovascular effects of GLP-1.

3. A Fundamental Observation: Insulin Secretion is Greater with Oral Compared to IV Glucose Adapted from McIntyre N, et al. Lancet. 1964;41:20-21. IV/IJ glucose Blood GlucosePlasma Insulin 0 50 100 150 200 250 300 -30-150153045607590105120135 Time (min) Blood Glucose (mg/dL) Intravenous Intrajejunal 0 50 100 150 200 250 300 -30-150153045607590105120135 Time (min) Plasma Insulin ( pmol/L)

4. Synthesis and Secretion of GLP-1 and GIP L-Cell (ileum) Proglucagon GLP-1 [7-37] GLP-1 [7-36NH 2 ] K-Cell (jejunum) ProGIP GIP [1-42]

5. Vilsboll T, et al. J Clin Endocrinol Metab. 2003;88:2706-13. Secretion of Incretins After Meals GLP–1 GIP 50 – Total GLP–1 (pmol/L) 10 – 20 – 30 – 40 – Total GIP (pmol/L) 0 – 200 – 50 – 100 – 150 – 0 – | −20 | 40 | 100 | 160 Intact GIP (pmol/L) Time (min) 0 – 100 – 20 – 40 – 60 – 80 – 20 – Intact GLP–1 (pmol/L) | −20 | 40 | 100 | 160 Time (min) 15 – 0 – 5 – 10 –

6. Distribution of Incretin Receptors Gs Ac ATP cAMP Gs Ac ATP cAMP PKA Insulin  -Cell Heart / Vasc CNS / PNS GI tract Adipocyte Brain Adrenal GLP-1 GIP

7. Kreymann B, et al. Lancet. 1987;2:1300-4. Glucose-Dependent Insulinotropic Effect of GLP–1 and GIP in Healthy Subjects GLSalineGLP–1 GIPSalineGLP–1 GIP Test Infusion

8. Metabolism of GLP-1 by DPP-4 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR HGEGTFTSDLSKQMEEEAVRLFIEWLKNGG PSSGAPPPS cleavage site of DPP-IV Exendin-4 GLP-1(7-36)NH 2 GLP-1(9-36)NH 2 H-A + DPP IV

9. GLP-1(9-36)NH 2 and insulin secretion Vahl et al., JCEM 2003 GLP-1/saline infusion

10. Actions of GLP-1 that Regulate Blood Glucose Concentrations 1.Stimulate β-cell function - insulin secretion/synthesis - cell growth/antiapoptosis 2.Inhibit glucagon release 3.Delay gastric emptying 4.Diminish food intake 5.Extrapancreatic effects on glucose - promote glucose uptake - suppress HGP

11. Interruption of GLP-1r signaling causes glucose intolerance Scrocchi et al Nature Med, 1996 Edwards et al Diabetes, 1999 D’Alessio et al JCI, 1996

12. Incretin effect of GLP-1 in healthy humans M Salehi et al, JCEM, 2008 Glucose GIR InsulinC-peptide

13. Effects of GLP-1r blockade on meal-induced glucagon release and gastric emptying M Salehi, JCEM 2008 GlucagonGastric Emptying