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

GLP-1 Effectiveness, Mechanisms of Action and Potential Part 1. Overview. Physiology of GLP-1 Clinical effects of GLP-1r agonists and DPP-4 inhibitors stemming from incretin action. The role of glucagon in glucose intolerance and effects of GLP-1 based drugs on plasma glucagon.

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

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  1. GLP-1 Effectiveness, Mechanisms of Action and PotentialPart 1

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

  3. 300 Intravenous Intrajejunal 250 200 Blood Glucose (mg/dL) 150 100 50 0 -30 -15 0 15 30 45 60 75 90 105 120 135 Time (min) A Fundamental Observation: Insulin Secretion is Greater with Oral Compared to IV Glucose Blood Glucose Plasma Insulin 300 IV/IJglucose 250 200 Plasma Insulin ( pmol/L) 150 100 50 0 -30 -15 0 15 30 45 60 75 90 105 120 135 Time (min) Adapted from McIntyre N, et al. Lancet. 1964;41:20-21.

  4. Synthesis and Secretion of GLP-1 and GIP K-Cell (jejunum) L-Cell (ileum) ProGIP Proglucagon GIP [1-42] GLP-1 [7-37] GLP-1 [7-36NH2]

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

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

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

  8. H-A GLP-1(7-36)NH2 H-A GLP-1(9-36)NH2 + DPP IV cleavage site of DPP-IV H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R P S S G A P P P S H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G GLP-1(7-36)NH2 Exendin-4 Metabolism of GLP-1 by DPP-4

  9. GLP-1/saline infusion GLP-1(9-36)NH2 and insulin secretion Vahl et al., JCEM 2003

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

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

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

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

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