GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

Autor:	Jensen MH; Antag Therapeutics Aps, Copenhagen, Denmark.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Gasbjerg LS; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Skov-Jeppesen K; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jacobsen JCB; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Poulsen SS; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Zhou C; Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Jakubauskaite R; Department of Radiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark., Poulsen FR; Department of Neurosurgery, Odense University Hospital, Odense, Denmark., Bonde C; Department of Neurosurgery, Odense University Hospital, Odense, Denmark., Albarazi M; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark., Halle B; Department of Neurosurgery, Odense University Hospital, Odense, Denmark., Christiansen CB; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Sanni SJ; Antag Therapeutics Aps, Copenhagen, Denmark., Byberg S; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Hoe B; Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark., Holst JJ; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Dela F; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Human Physiology and Biochemistry, Riga Stradiņš University, Riga, Latvia., Rasmussen AK; Department of Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark., Knop FK; Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Arlien-Søborg MC; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark., Melmed S; Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Jørgensen JOL; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark., Andersen MS; Department of Endocrinology, Odense University Hospital, Odense, Denmark., Hartmann B; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Klose MC; Department of Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark., Feldt-Rasmussen U; Department of Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Sparre-Ulrich AH; Antag Therapeutics Aps, Copenhagen, Denmark., Rosenkilde MM; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2024 Aug 22. Date of Electronic Publication: 2024 Aug 22.
DOI:	10.1210/clinem/dgae583
Abstrakt:	Context: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. Objective: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. Design, Patients, Setting, Interventions: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. Main Outcome Measure: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. Results: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. Conclusions: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
Databáze:	MEDLINE
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