GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel

Abstract

Infants with congenital hyperinsulinism owing to inactivating mutations in the K(ATP) channel (K(ATP)HI) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia. In preclinical studies, we showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in SUR-1(-/-) mice. The aim of this study was to examine the effects of exendin-(9-39) on fasting blood glucose in subjects with K(ATP)HI. This was a randomized, open-label, two-period crossover pilot clinical study. Nine subjects with K(ATP)HI received either exendin-(9-39) or vehicle on two different days. The primary outcome was blood glucose; secondary outcomes were insulin, glucagon, and GLP-1. In all subjects, mean nadir blood glucose and glucose area under the curve were significantly increased by exendin-(9-39). Insulin-to-glucose ratios were significantly lower during exendin-(9-39) infusion compared with vehicle. Fasting glucagon and intact GLP-1 were not affected by treatment. In addition, exendin-(9-39) significantly inhibited amino acid-stimulated insulin secretion in pancreatic islets isolated from neonates with K(ATP)HI. Our findings have two important implications: 1) GLP-1 and its receptor play a role in the regulation of fasting glycemia in K(ATP)HI; and 2) the GLP-1 receptor may be a therapeutic target for the treatment of children with K(ATP)HI.

Trial registration: ClinicalTrials.gov NCT00571324.

Figures

FIG. 1.

Effect of exendin-(9-39) on fasting blood glucose. Mean blood glucose ± SEM during vehicle and exendin-(9-39). Subjects received vehicle from time −60 to 0 min, followed by vehicle or exendin-(9-39) for 6 h. Exendin-(9-39) was infused at a dose of 100 pmol/kg/min from 0 to 120 min, 300 pmol/kg/min from 120 to 240 min, and 500 pmol/kg/min from 240 to 360 min.

FIG. 2.

Effect of exendin-(9-39) on fasting plasma insulin. Mean plasma insulin ± SEM during vehicle and exendin-(9-39). Subjects received vehicle from time −60 to 0 min, followed by vehicle or exendin-(9-39) for 6 h. Exendin-(9-39) was infused at a dose of 100 pmol/kg/min from 0 to 120 min, 300 pmol/kg/min from 120 to 240 min, and 500 pmol/kg/min from 240 to 360 min.

FIG. 3.

Effect of exendin-(9-39) on insulin-to-glucose ratio. Mean insulin-to-glucose ratio ± SEM during vehicle and exendin-(9-39). Subjects received vehicle from time −60 to 0 min, followed by vehicle or exendin-(9-39) for 6 h. Exendin-(9-39) was infused at a dose of 100 pmol/kg/min from 0 to 120 min, 300 pmol/kg/min from 120 to 240 min, and 500 pmol/kg/min from 240 to 360 min.

FIG. 4.

Effect of exendin-(9-39) on glucagon and intact GLP-1. A: Mean plasma glucagon ± SEM during vehicle and exendin-(9-39). B: Mean plasma intact GLP-1 ± SEM during vehicle and exendin-(9-39). Subjects received vehicle from time −60 to 0 min, followed by vehicle or exendin-(9-39) for 6 h. Exendin-(9-39) was infused at a dose of 100 pmol/kg/min from 0 to 120 min, 300 pmol/kg/min from 120 to 240 min, and 500 pmol/kg/min from 240 to 360 min.

FIG. 5.

Effect of exendin-(9-39) on amino acid–stimulated insulin secretion in human KATPHI islets. Insulin secretion ± SEM at baseline, 0 mmol/L glucose after stimulation with 10 mmol/L glucose, 4 mmol/L amino acids, and 4 mmol/L amino acids in the presence of 100 nmol/L exendin-(9-39). N = 3; ANOVA, P = 0.001; post hoc Bonferroni, 10 mmol/L glucose vs. AAM P = 0.001, AAM vs. AAM plus exendin-(9-39) P = 0.003.