M S Svane1,2, N B Jørgensen1,2, K N Bojsen-Møller1,2, C Dirksen1,2, S Nielsen1, V B Kristiansen3, S Toräng2,4, N J Wewer Albrechtsen2,4, J F Rehfeld5, B Hartmann2,4, S Madsbad1,2, J J Holst2,4. 1. Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. 2. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. 3. Department of Surgical Gastroenterology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. 4. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Abstract
BACKGROUND/ OBJECTIVES: Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY3-36. SUBJECTS/ METHODS:Appetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1, nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2, 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYY3-36 and (4) Ex-9/sitagliptin combined. RESULTS: In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY3-36 increased food intake by ~20% in RYGB patients, whereas neither GLP-1 receptor blockage nor DPP-4 inhibition alone affected food intake, perhaps because of concomitant marked increases in the unblocked hormone. CONCLUSIONS: Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY3-36, resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.
RCT Entities:
BACKGROUND/ OBJECTIVES: Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY3-36. SUBJECTS/ METHODS: Appetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1, nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2, 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYY3-36 and (4) Ex-9/sitagliptin combined. RESULTS: In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY3-36 increased food intake by ~20% in RYGB patients, whereas neither GLP-1 receptor blockage nor DPP-4 inhibition alone affected food intake, perhaps because of concomitant marked increases in the unblocked hormone. CONCLUSIONS: Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY3-36, resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.
Authors: N B Jørgensen; S H Jacobsen; C Dirksen; K N Bojsen-Møller; L Naver; L Hvolris; T R Clausen; B S Wulff; D Worm; D Lindqvist Hansen; S Madsbad; J J Holst Journal: Am J Physiol Endocrinol Metab Date: 2012-04-24 Impact factor: 4.310
Authors: Julie Berg Schmidt; Nikolaj Ture Gregersen; Sue D Pedersen; Johanne L Arentoft; Christian Ritz; Thue W Schwartz; Jens Juul Holst; Arne Astrup; Anders Sjödin Journal: Am J Physiol Endocrinol Metab Date: 2014-04-15 Impact factor: 4.310
Authors: C Verdich; A Flint; J P Gutzwiller; E Näslund; C Beglinger; P M Hellström; S J Long; L M Morgan; J J Holst; A Astrup Journal: J Clin Endocrinol Metab Date: 2001-09 Impact factor: 5.958
Authors: Rachel L Batterham; Michael A Cowley; Caroline J Small; Herbert Herzog; Mark A Cohen; Catherine L Dakin; Alison M Wren; Audrey E Brynes; Malcolm J Low; Mohammad A Ghatei; Roger D Cone; Stephen R Bloom Journal: Nature Date: 2002-08-08 Impact factor: 49.962
Authors: J B Schmidt; S D Pedersen; N T Gregersen; L Vestergaard; M S Nielsen; C Ritz; S Madsbad; D Worm; D L Hansen; T R Clausen; J F Rehfeld; A Astrup; J J Holst; A Sjödin Journal: Int J Obes (Lond) Date: 2013-08-25 Impact factor: 5.095
Authors: C Dirksen; M Damgaard; K N Bojsen-Møller; N B Jørgensen; U Kielgast; S H Jacobsen; L S Naver; D Worm; J J Holst; S Madsbad; D L Hansen; J L Madsen Journal: Neurogastroenterol Motil Date: 2013-01-29 Impact factor: 3.598
Authors: T D Müller; B Finan; S R Bloom; D D'Alessio; D J Drucker; P R Flatt; A Fritsche; F Gribble; H J Grill; J F Habener; J J Holst; W Langhans; J J Meier; M A Nauck; D Perez-Tilve; A Pocai; F Reimann; D A Sandoval; T W Schwartz; R J Seeley; K Stemmer; M Tang-Christensen; S C Woods; R D DiMarchi; M H Tschöp Journal: Mol Metab Date: 2019-09-30 Impact factor: 7.422
Authors: Tina Jorsal; Nicolai A Rhee; Jens Pedersen; Camilla D Wahlgren; Brynjulf Mortensen; Sara L Jepsen; Jacob Jelsing; Louise S Dalbøge; Peter Vilmann; Hazem Hassan; Jakob W Hendel; Steen S Poulsen; Jens J Holst; Tina Vilsbøll; Filip K Knop Journal: Diabetologia Date: 2017-09-28 Impact factor: 10.122
Authors: Marco Antonio Zappa; Alberto Aiolfi; Cinzia Musolino; Maria Paola Giusti; Giovanni Lesti; Andrea Porta Journal: Obes Surg Date: 2017-08 Impact factor: 4.129
Authors: Lærke S Gasbjerg; Mikkel B Christensen; Bolette Hartmann; Amalie R Lanng; Alexander H Sparre-Ulrich; Maria B N Gabe; Flemming Dela; Tina Vilsbøll; Jens J Holst; Mette M Rosenkilde; Filip K Knop Journal: Diabetologia Date: 2017-09-25 Impact factor: 10.122
Authors: Robert E Steinert; Christine Feinle-Bisset; Lori Asarian; Michael Horowitz; Christoph Beglinger; Nori Geary Journal: Physiol Rev Date: 2017-01 Impact factor: 37.312
Authors: Kellie M Hyde; Ginger D Blonde; Marco Bueter; Carel W le Roux; Alan C Spector Journal: Am J Physiol Regul Integr Comp Physiol Date: 2020-02-21 Impact factor: 3.619