Unbound MEDLINE

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.

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  • Publisher Full Text

    • Authors

    Calabria AC, Li C, Gallagher PR, Stanley CA, De León DD

    Institution

    Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    Source

    Diabetes 61:10 2012 Oct pg 2585-91

    MeSH

    Adolescent
    Adult
    Blood Glucose
    Congenital Hyperinsulinism
    Cross-Over Studies
    Female
    Glucagon
    Glucagon-Like Peptide 1
    Humans
    Infant, Newborn
    Insulin
    Islets of Langerhans
    KATP Channels
    Male
    Mutation
    Peptide Fragments
    Pilot Projects
    Receptors, Glucagon

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22855730