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Diabetologia

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01-03-2017 | Article

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia

Authors: Colleen M. Craig, Li-Fen Liu, Carolyn F. Deacon, Jens J. Holst, Tracey L. McLaughlin

Published in: Diabetologia | Issue 3/2017

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

Available only for authorised users

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Title: Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia
Authors: Colleen M. Craig
Li-Fen Liu
Carolyn F. Deacon
Jens J. Holst
Tracey L. McLaughlin
Publication date: 01-03-2017
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 3/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-016-4179-x

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