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

Abstract

Background & Aims Post-prandial glycemia excursions increase after gastric bypass surgery; this effect is even greater among individuals with recurrent hypoglycemia (blood glucose levels <50 mg/dL). These patients also have increased post-prandial levels of insulin and glucagon-like peptide 1 (GLP1). We performed a clinical trial to determine the role of GLP1 in post-prandial glycemia in patients with hyperinsulinemic hypoglycemia syndrome after gastric bypass. Methods Nine patients with recurrent hypoglycemia after gastric bypass (H-GB), 7 asymptomatic individuals with previous gastric bypass (A-GB), and 8 non-diabetic subjects who did not receive surgery (controls) were studied with a mixed-meal tolerance test (350 kcal) using a dual glucose tracer method on 2 days. On 1 day they received continuous infusion of GLP-1 receptor (GLP1R) antagonist, exendin-(9–39) (Ex-9), and on the other day, a saline control. Glucose kinetics and islet and gut hormone responses were measured before and after the meal. Results Infusion of Ex9 corrected hypoglycemia in all H-GB individuals. The reduction of post-prandial insulin secretion by Ex9 was greater in the H-GB group than other groups (H-GB, 50%±8%; A-GB, 13%±10%; and controls, 14%±10%) (P<.05). Meal-derived glucose (RaOral) was significantly greater among subjects who had undergone gastric bypass than controls, and in H-GB patients compared with A-GB subjects. Ex9 shortened the time to peak RaOral in all groups without any significant effect on the overall glucose flux. Post-prandial glucagon levels were higher among patients who had undergone gastric bypass than controls, and increased with Ex9 administration. Conclusions Hypoglycemia following gastric bypass can be corrected by administration of a GLP1R antagonist, which might be used to treat this disorder. These findings are consistent with reports that increased GLP1 activity contributes to hypoglycemia following gastric bypass. ClinicalTrials.gov number, NCT01803451

Discovery, characterization, and clinical development of the glucagon-like peptides

“…jci.org Volume 127 Number 12 December 2017 therapy of bariatric surgery-associated hypoglycemia (98). Whether exendin(9-39) will exhibit sustained efficacy and safety and be similarly useful for treatment of genetic forms of hyperinsulinemic hypoglycemia requires further study.…”

Bariatric surgery and obesity: influence on the incretins

“…To identify the role of endogenous GLP-1 in the amelioration of impaired β-cell function after RYGBP, the specific GLP-1 receptor antagonist exendin 9-39 has been used in four cross sectional [48][49][50][51] studies and one short-term longitudinal 52 study in post-RYGBP patients. Exendin 9-39 completely blunts the recovery of β-cell glucose sensitivity (BCGS) 1 week and 3 months after RYGBP, 52 and worsens post-prandial glucose tolerance, although only minimally.…”

“…Exendin 9-39 completely blunts the recovery of β-cell glucose sensitivity (BCGS) 1 week and 3 months after RYGBP, 52 and worsens post-prandial glucose tolerance, although only minimally. 49 Exendin 9-39 suppresses insulin secretion in response to a meal by 50% 49,50 and corrects the profound reactive hypoglycemia in patients with severe neuroglycopenia. 50 Thus, clearly, the exaggerated GLP-1 response to ingestion of food or glucose has a key role in post-prandial insulin secretion and glycemic control after RYGBP.…”

“…49 Exendin 9-39 suppresses insulin secretion in response to a meal by 50% 49,50 and corrects the profound reactive hypoglycemia in patients with severe neuroglycopenia. 50 Thus, clearly, the exaggerated GLP-1 response to ingestion of food or glucose has a key role in post-prandial insulin secretion and glycemic control after RYGBP. But, whether it is the main factor driving the high rate of diabetes remission after RYGBP is perhaps less clear.…”

Dumpingsyndrom etter kirurgi på magesekken

“…Det er vist forsterket GLP-1-respons av glukosetestmåltid etter reseksjon av spiserør og ventrikkel (11). Hemming av GLP-1-reseptor hos pasienter med gastrisk bypass og postprandial hypoglykemi reduserer forekomsten av hypoglykemi og symptomer på sent dumpingsyndrom (27). Nesidioblastose er en sjelden tilstand med øy-cellehyperplasi i pancreas med økt insulinproduksjon.…”