Colleen M Craig1, Li-Fen Liu2, Carolyn F Deacon3, Jens J Holst3, Tracey L McLaughlin2. 1. Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, 300 Pasteur Drive, Room S025, Stanford, CA, 94305, USA. cmcraig@stanford.edu. 2. Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, 300 Pasteur Drive, Room S025, Stanford, CA, 94305, USA. 3. Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Abstract
AIMS/HYPOTHESIS: Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1). METHODS: We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs). RESULTS: Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion. CONCLUSIONS/ INTERPRETATION:GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02550145.
RCT Entities:
AIMS/HYPOTHESIS: Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1). METHODS: We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs). RESULTS: Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBHparticipants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion. CONCLUSIONS/ INTERPRETATION:GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02550145.
Authors: Lars Sjöström; Anna-Karin Lindroos; Markku Peltonen; Jarl Torgerson; Claude Bouchard; Björn Carlsson; Sven Dahlgren; Bo Larsson; Kristina Narbro; Carl David Sjöström; Marianne Sullivan; Hans Wedel Journal: N Engl J Med Date: 2004-12-23 Impact factor: 91.245
Authors: Geoffrey J Service; Geoffrey B Thompson; F John Service; James C Andrews; Maria L Collazo-Clavell; Ricardo V Lloyd Journal: N Engl J Med Date: 2005-07-21 Impact factor: 91.245
Authors: Todd Andrew Kellogg; John P Bantle; Daniel B Leslie; James B Redmond; Bridget Slusarek; Therese Swan; Henry Buchwald; Sayeed Ikramuddin Journal: Surg Obes Relat Dis Date: 2008 Jul-Aug Impact factor: 4.734
Authors: Francesco Rubino; David M Nathan; Robert H Eckel; Philip R Schauer; K George M M Alberti; Paul Z Zimmet; Stefano Del Prato; Linong Ji; Shaukat M Sadikot; William H Herman; Stephanie A Amiel; Lee M Kaplan; Gaspar Taroncher-Oldenburg; David E Cummings Journal: Diabetes Care Date: 2016-06 Impact factor: 19.112
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: Christopher M Mulla; Allison B Goldfine; Jonathan M Dreyfuss; Sander Houten; Hui Pan; David M Pober; Nicolai J Wewer Albrechtsen; Maria S Svane; Julie B Schmidt; Jens Juul Holst; Colleen M Craig; Tracey L McLaughlin; Mary-Elizabeth Patti Journal: Obes Surg Date: 2019-07 Impact factor: 4.129
Authors: Alejandro J Laguna Sanz; Christopher M Mulla; Kristen M Fowler; Emilie Cloutier; Allison B Goldfine; Brett Newswanger; Martin Cummins; Sunil Deshpande; Steven J Prestrelski; Poul Strange; Howard Zisser; Francis J Doyle; Eyal Dassau; Mary-Elizabeth Patti Journal: Diabetes Technol Ther Date: 2018-02 Impact factor: 6.118
Authors: Ana Raquel Marques; Carolina B Lobato; Sofia S Pereira; Marta Guimarães; Sandra Faria; Mário Nora; Mariana P Monteiro Journal: Obes Surg Date: 2020-01 Impact factor: 4.129
Authors: Christopher M Mulla; Stamatina Zavitsanou; Alejandro Jose Laguna Sanz; David Pober; Lauren Richardson; Pamela Walcott; Ipsa Arora; Brett Newswanger; Martin J Cummins; Steve J Prestrelski; Francis J Doyle; Eyal Dassau; Mary Elizabeth Patti Journal: J Clin Endocrinol Metab Date: 2020-04-01 Impact factor: 5.958