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
PY - 2025/3/1
Y1 - 2025/3/1
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)NH
2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. Methods: A total of 25 treatment-naive patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH
2 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. The main outcome measure was the effect of GIP(3-30)NH
2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. Results: In 4 of 7 patients with paradoxical GH secretion, GIP(3-30)NH
2 infusion completely abolished the paradoxical response (P =. 0003). Somatotrophs were available from 3 of 4 of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. Conclusion: Of 25 patients with acromegaly, 7 had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in 4. 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)NH
2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. Methods: A total of 25 treatment-naive patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH
2 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. The main outcome measure was the effect of GIP(3-30)NH
2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. Results: In 4 of 7 patients with paradoxical GH secretion, GIP(3-30)NH
2 infusion completely abolished the paradoxical response (P =. 0003). Somatotrophs were available from 3 of 4 of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. Conclusion: Of 25 patients with acromegaly, 7 had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in 4. 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 - GIP receptor antagonism
KW - acromegaly
KW - glucose-dependent insulinotropic polypeptide (GIP)
KW - growth hormone (GH)
KW - paradoxical GH secretion
KW - Glucose Tolerance Test
KW - Humans
KW - Middle Aged
KW - Male
KW - Growth Hormone-Secreting Pituitary Adenoma/metabolism
KW - Adenoma/metabolism
KW - Receptors, Gastrointestinal Hormone/metabolism
KW - Acromegaly/drug therapy
KW - Gastric Inhibitory Polypeptide/metabolism
KW - Adult
KW - Female
KW - Aged
KW - Peptide Fragments/metabolism
KW - Human Growth Hormone/metabolism
U2 - 10.1210/clinem/dgae583
DO - 10.1210/clinem/dgae583
M3 - Journal article
C2 - 39172542
SN - 0021-972X
VL - 110
SP - 715
EP - 729
JO - The Journal of clinical endocrinology and metabolism
JF - The Journal of clinical endocrinology and metabolism
IS - 3
ER -