TY - JOUR
T1 - GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly
AU - Jensen, Mette H
AU - Gasbjerg, Lærke S
AU - Skov-Jeppesen, Kirsa
AU - Jacobsen, Jens C B
AU - Poulsen, Steen S
AU - Zhou, Cuiqi
AU - Jakubauskaite, Ruta
AU - Poulsen, Frantz R
AU - Bonde, Christian
AU - Albarazi, Mahmoud
AU - Halle, Bo
AU - Christiansen, Charlotte B
AU - Sanni, Samra J
AU - Byberg, Sarah
AU - Hoe, Bjørn
AU - Holst, Jens J
AU - Dela, Flemming
AU - Rasmussen, Aase K
AU - Knop, Filip K
AU - Arlien-Søborg, Mai C
AU - Melmed, Shlomo
AU - Jørgensen, Jens Otto L
AU - Andersen, Marianne S
AU - Hartmann, Bolette
AU - Klose, Marianne C
AU - Feldt-Rasmussen, Ulla
AU - Sparre-Ulrich, Alexander H
AU - Rosenkilde, Mette M
N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2024/8/22
Y1 - 2024/8/22
N2 - 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.
AB - 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.
KW - glucose-dependent insulinotropic polypeptide (GIP
KW - GIP receptor antagonism
KW - acromegaly
KW - growth hormone (GH)
KW - paradoxical GH secretion
UR - https://www-webofscience-com.db.rsu.lv/wos/alldb/full-record/WOS:001327198700001
U2 - 10.1210/clinem/dgae583
DO - 10.1210/clinem/dgae583
M3 - Article
C2 - 39172542
SN - 0021-972X
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
ER -