Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans
Open accessAbstract
The gastrointestinal hormone, glucagon-like peptide-1(7-36)amide (GLP-1) is released after a meal. The potency of synthetic GLP-1 in stimulating insulin secretion and in inhibiting glucagon secretion indicates the putative physiological function of GLP-1. In vitro, the nonmammalian peptide, exendin(9-39)amide [ex(9-39)NH2], is a specific and competitive antagonist of GLP-1. This in vivo study examined the efficacy of ex(9-39)NH2 as an antagonist of exogenous GLP-1 and the physiological role of endogenous GLP-1. Six healthy volunteers underwent 10 experiments in random order. In each experiment, a 30-min period of euglycemia was followed by an intravenous infusion of glucose for 150 min that established a stable hyperglycemia of 8 mmol/liter. There was a concomitant intravenous infusion of one of the following: (1) saline, (2) GLP-1 (for 60 min at 0.3 pmol . kg-1 . min-1 that established physiological postprandial plasma levels, and for another 60 min at 0.9 pmol . kg-1 . min-1 to induce supraphysiological plasma levels), (3-5) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + GLP-1, (6-8) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + saline, (9 and 10) GIP (glucose-dependent insulinotropic peptide; for 60 min at 0.8 pmol . kg-1 . min-1, with saline or ex(9-39)NH2 at 300 pmol . kg-1 . min-1). Each volunteer received each of these concomitant infusions on separate days. ex(9-39)NH2 dose-dependently reduced the insulinotropic action of GLP-1 with the inhibitory effect declining with increasing doses of GLP-1. ex(9-39)NH2 at 300 pmol . kg-1 . min-1 blocked the insulinotropic effect of physiological doses of GLP-1 and completely antagonized the glucagonostatic effect at both doses of GLP-1. Given alone, this load of ex(9-39)NH2 increased plasma glucagon levels during euglycemia and hyperglycemia. It had no effect on plasma levels of insulin during euglycemia but decreased plasma insulin during hyperglycemia. ex(9-39)NH2 did not alter GIP-stimulated insulin secretion. These data indicate that in humans, ex(9-39)NH2 is a potent GLP-1 antagonist without any agonistic properties. The pancreatic A cell is under a tonic inhibitory control of GLP-1. At hyperglycemia, the B cell is under a tonic stimulatory control of GLP-1.
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- Authors
- Schirra, J., Sturm, K., Leicht, P., Arnold, R., Göke, B., & Katschinski, M.
- Affiliations
- Philipps University of Marburg (DE)
- ORCID
- Schirra, J
- Venue
- Journal of Clinical Investigation
- Published
- 1998-04-01
- Volume
- 101
- Issue
- 7
- Pages
- 1421-1430
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508720
- OpenAlex
- W2111242088
- Cited by
- 265
- References
- 42
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 10 · 2023: 5 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 17 · 2018: 13 · 2017: 10 · 2016: 14 · 2015: 8 · 2014: 11 · 2013: 12 · 2012: 9
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- glucagon-like peptide-1(7-36)amide, glucose-dependent insulinotropic polypeptide, insulin secretion, glucagon secretion, postprandial hyperglycemia, hyperinsulinemic-euglycemic clamp, incretins
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Adult, C-Peptide, Glucagon, Glucose, Humans, Insulin, Male, Peptide Fragments, Protein Precursors, Time Factors, Receptors, Glucagon, Glucagon-Like Peptide 1
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