1 / 13

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.

girardk
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related