Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass

Abstract

Background & aims: Postprandial glycemia excursions increase after gastric bypass surgery; this effect is even greater among patients with recurrent hypoglycemia. These patients also have increased postprandial levels of insulin and glucagon-like peptide 1 (GLP-1). We performed a clinical trial to determine the role of GLP-1 in postprandial glycemia in patients with hyperinsulinemic hypoglycemia syndrome after gastric bypass.

Methods: Nine patients with recurrent hypoglycemia after gastric bypass (H-GB), 7 patients who were asymptomatic after gastric bypass (A-GB), and 8 healthy control subjects underwent a mixed-meal tolerance test (350 kcal) using a dual glucose tracer method on 2 separate days. On 1 day they received continuous infusion of the GLP-1 receptor antagonist exendin (9-39) (Ex-9), and on the other day they received a saline control. Glucose kinetics and islet and gut hormone responses were measured before and after the meal.

Results: Infusion of Ex-9 corrected hypoglycemia in all patients with H-GB. The reduction in postprandial insulin secretion by Ex-9 was greater in the H-GB group than in the other groups (H-GB, 50% ± 8%; A-GB, 13% ± 10%; controls, 14% ± 10%) (P < .05). The meal-derived glucose appearance was significantly greater in subjects who had undergone gastric bypass compared to the controls and in the H-GB group compared to the A-GB group. Ex-9 shortened the time to reach peak meal-derived glucose appearance in all groups without a significant effect on overall glucose flux. Postprandial glucagon levels were higher among patients who had undergone gastric bypass than controls and increased with administration of Ex-9.

Conclusions: Hypoglycemia after gastric bypass can be corrected by administration of a GLP-1 receptor antagonist, which might be used to treat this disorder. These findings are consistent with reports that increased GLP-1 activity contributes to hypoglycemia after gastric bypass. ClinicalTrials.gov, Number: NCT01803451.

Keywords: Glucagon-like Peptide 1; Hyperinsulinemic Hypoglycemia Syndrome; Islet Function; Roux-en-Y Gastric Bypass Surgery.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Blood glucose (A), plasma insulin (B), and insulin secretion (C) responses to meal ingestion in GB subjects, with (Hypoglycemic-GB, left) and without (Asymptomatic-GB, middle) recurrent hypoglycemia, and non-surgical controls (right) during studies with (dashed line, white bar) and without (solid line, black bar) Ex-9 infusion Corresponding AUC for 0–60 and 0–180 min are shown as inset figures, * p

Figure 2

The rates of meal-derived glucose appearance (A), endogenous glucose appearance (B), and glucose disappearance (C) in GB subjects, with (Hypoglycemic-GB, left) and without (Asymptomatic-GB, middle) recurrent hypoglycemia, and non-surgical controls (right) during studies with (dashed line) and without (solid line) Ex-9 infusion AUCRaOral for 0–30 and 0–120 min are shown as inset figures, # p<0.05 compared to non-surgical controls, † p<0.05 compared with A-GB.

Figure 3

Circulatory C-peptide levels across blood glucose values and β-cell glucose sensitivity in GB subjects with (A, D) and without (B, E) hypoglycemia syndrome, and non-surgical subjects (C, F) during MTT studies with (open circle, dashed line) and without (close circle, solid line) Ex-9 infusion (0–120 min for GB subjects and 0–180 min for healthy controls) Black arrows show the initial phase of the MTT (increasing glucose) and white arrow the latter phase of the MTT (decreasing glucose); * p

Figure 4

Plasma glucagon (A), GLP-1 (B), and GIP (C) responses to meal ingestion in GB subjects, with (Hypoglycemic-GB, left) and without (Asymptomatic-GB, middle) recurrent hypoglycemia, and non-surgical controls (right) during studies with (dashed line, white bar) and without (solid line, black bar) Ex-9 infusion Corresponding AUC are shown as inset figures, * p