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 1.Glucagon like peptide 1- incretin and satiety factor. 2.Secretion of GLP-1 with bariatric surgery 3.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 M Nauck, Diabetologia, 2010 GLP-2 OXNT PYY

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

5. 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

6. 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

7. 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

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

9. Food Intake in Healthy and Diabetic Men Given IV GLP-1 Gutzwiler et al, AJP, 1999 Gutzwiler et al, Gut, 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 R Peterli, Ann Surg, 2009 RYGB VSG

13. GLP-1 secretion after bariatric surgery 1.L-cell products are increased in RYGB and VSG 2.The elevation of plasma GLP-1 is 5-10 fold > non operated 3.The elevation of plasma GLP-1 after bariatric surgery is persistent 4.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 Rats with RYGB and VSG have elevated GLP-1 A Chambers and D Sandoval, unpublished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 Bariatric surgery in rats improves GTT A Chambers and D Sandoval, unpublished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 GLP-1R blockade has disproportionate effect on glucose tolerance in rats with VSG and RYGB A Chambers and D Sandoval, unpublished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 Clin Endocrinol Metab 2008

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 Augmented GLP-1 effect on insulin secretion after RYGB HG-GB (N=11) NHG-GB (N=12) Control (N=7) M Salehi, unpublished

21. Role of GLP-1 in glucose metabolism after RYGB

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

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

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