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The role of GLP-1 in mediating the anorectic and metabolic effects of bariatric surgery.

The role of GLP-1 in mediating the anorectic and metabolic effects of bariatric surgery. David D’Alessio, MD Division of Endocrinology University of Cincinnati Cincinnati VAMC. Overview. Glucagon like peptide 1- incretin and satiety factor. Secretion of GLP-1 with bariatric surgery

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The role of GLP-1 in mediating the anorectic and metabolic effects of bariatric surgery.

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  1. The role of GLP-1 in mediating the anorectic and metabolic effects of bariatric surgery. David D’Alessio, MD Division of Endocrinology University of Cincinnati Cincinnati VAMC

  2. Overview • Glucagon like peptide 1- incretin and satiety factor. • Secretion of GLP-1 with bariatric surgery • GLP-1 and insulin secretion after RYGB 4. Do plasma levels of GLP-1 contribute to reduced food intake after bariatric procedures?

  3. Synthesis and Secretion of GLP-1 L-Cell (ileum) ProG GLP-1 GLP-2 OXNT PYY M Nauck, Diabetologia, 2010

  4. GLP-1 containing L-cells small intestine Jejunum- cross section Jejunum- en face

  5. 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

  6. 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.

  7. 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

  8. The Brain GLP-1 System Brain GLP-1 synthesis CNS access of plasma GLP-1 C Knauf et al, Diabetes, 2008 Key Brain GLP-1r Yamamoto et al, J Neuroscience, 2003 PVN CeA Merchenthaler et al., J Comp Neurol 1999

  9. Food Intake in Healthy and Diabetic Men Given IV GLP-1 Gutzwiler et al, Gut, 1999 Gutzwiler et al, AJP, 1999

  10. Secretion of L-cell products after RYGB B Laferrere, JCEM, 2010

  11. HyperGLP-1emia is persistent following RYGB J Vidal, JCEM, 2009

  12. GLP-1 elevation in VSG is comparable to RYGB RYGB VSG R Peterli, Ann Surg, 2009

  13. GLP-1 secretion after bariatric surgery • L-cell products are increased in RYGB and VSG • The elevation of plasma GLP-1 is 5-10 fold > non operated • The elevation of plasma GLP-1 after bariatric surgery is persistent • Gastric banding is not associated with major changes in circulating GLP-1 (or other GI hormones)

  14. Does elevated GLP-1 contribute to changes in glucose tolerance following bariatric surgery?

  15. Rats with RYGB and VSG have elevated GLP-1 A Chambers and D Sandoval, unpublished

  16. Bariatric surgery in rats improves GTT A Chambers and D Sandoval, unpublished

  17. GLP-1R blockade has disproportionate effect on glucose tolerance in rats with VSG and RYGB A Chambers and D Sandoval, unpublished

  18. Post-RYGB hypoglycemic syndrome is associated with hyperGLP-1/insulinemia Goldfine et al, JCEM, 2007

  19. Measurement of GLP-1 action on insulin secretion in humans Salehi et al. J ClinEndocrinolMetab 2008

  20. Augmented GLP-1 effect on insulin secretion after RYGB Control(N=7) HG-GB (N=11) NHG-GB (N=12) M Salehi, unpublished

  21. Role of GLP-1 in glucose metabolism after RYGB • Improved glucose tolerance • Larger incretin effect • Elevated plasma levels associated with 2-3 fold greater effect on insulin secretion

  22. Does GLP-1 contribute to reduced food intake following bariatric surgery?

  23. Peripheral infusion of GLP-1 to healthy humans decreases food intake Fullness, satiety Hunger No nausea Plasma GLP-1 levels Ad libitum Food Intake P = 0.002 Flint et al, JCI, 1998

  24. Neural mediation of GLP-1 action Holst and Deacon, Diabetologia, 2005

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