Blockade of Glucagon-like Peptide 1 Receptor Corrects Postprandial Hypoglycemia After Gastric Bypass

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 146; no. 3; pp. 669 - 680.e2
• Main Authors: Salehi, Marzieh, Gastaldelli, Amalia, D'Alessio, David A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2014
• Subjects: Adult; Blood Glucose - metabolism; Case-Control Studies; Female; Gastric Bypass - adverse effects; Gastroenterology and Hepatology; Glucagon - blood; Glucagon-like Peptide 1; Glucagon-Like Peptide 1 - blood; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells - physiology; Humans; Hyperinsulinemic Hypoglycemia Syndrome; Hypoglycemia - blood; Hypoglycemia - etiology; Hypoglycemia - prevention & control; Insulin - blood; Insulin-Secreting Cells - physiology; Islet Function; Male; Middle Aged; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - drug effects; Roux-en-Y Gastric Bypass Surgery; Treatment Outcome; H-GB; Islet Function; GI; CON; GLP-1; OGIS; ISR; Glucagon-like Peptide 1; MTT; Roux-en-Y Gastric Bypass Surgery; AUC; EGP; GIP; HOMA-IR; Hyperinsulinemic Hypoglycemia Syndrome; Rd; RaOral; A-GB; RaTOT; GB; Ex-9; GLP-1R; oral glucose insulin sensitivity index; asymptomatic after gastric bypass; control subjects; exendin (9-39); meal-derived glucose appearance; homeostatic model assessment of insulin resistance; glucagon-like peptide 1 receptor; glucose-dependent insulinotropic peptide; meal tolerance test; area under the curve; recurrent hypoglycemia after gastric bypass; gastrointestinal; endogenous glucose production; glucose disappearance; Ra Oral; insulin secretion rate; Ra TOT; glucose appearance
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2013.11.044

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. 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. 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. 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.