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.

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Presentation transcript:

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 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?

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

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

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

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

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

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

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

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

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

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

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)

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

Rats with RYGB and VSG have elevated GLP-1 A Chambers and D Sandoval, unpublished

Bariatric surgery in rats improves GTT A Chambers and D Sandoval, unpublished

GLP-1R blockade has disproportionate effect on glucose tolerance in rats with VSG and RYGB A Chambers and D Sandoval, unpublished

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

Measurement of GLP-1 action on insulin secretion in humans Salehi et al. J Clin Endocrinol Metab 2008

Augmented GLP-1 effect on insulin secretion after RYGB HG-GB (N=11) NHG-GB (N=12) Control (N=7) M Salehi, unpublished

Role of GLP-1 in glucose metabolism after RYGB

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

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

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