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

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.

Keywords: Bariatric complication; GLP-1; Hyperinsulinaemic hypoglycaemia; Hypoglycaemia; Late dumping syndrome; NIPHS; Nesidioblastosis; Neuroglycopenia; Noninsulinoma pancreatogenous hypoglycaemia syndrome; Post-bariatric hypoglycaemia; RYGB; Roux-en-Y gastric bypass.

Figures

Fig. 1

Plasma glucose (a), insulin (b), C-peptide (c) and ISR (d) in response to OGTT in participants with PBH during placebo (solid line, black circles) vs Ex-9 (dashed line, white circles) infusion, compared with NSCs (solid line, black triangles). ISR at sequential timepoints (0, 30, 60 min) as a function of glucose (e) or GLP-1 (f) demonstrates the dose response in ISR for both glucose and GLP-1. Ex-9 decreased ISR. **p<0.01 and ***p<0.001 for PBH participants during Ex-9 vs placebo infusion

Fig. 2

GLP-1 (a), GIP (b) and glucagon (c) responses to an OGTT in PBH participants during placebo (solid line, black circle) vs Ex-9 (dashed line, white circle) infusion. **p<0.01 for PBH participants during Ex-9 vs placebo infusion