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

Mette H Jensen; Lærke S Gasbjerg; Kirsa Skov-Jeppesen; Jens C B Jacobsen; Steen S Poulsen; Cuiqi Zhou; Ruta Jakubauskaite; Frantz R Poulsen; Christian Bonde; Mahmoud Albarazi; Bo Halle; Charlotte B Christiansen; Samra J Sanni; Sarah Byberg; Bjørn Hoe; Jens J Holst; Flemming Dela; Aase K Rasmussen; Filip K Knop; Mai C Arlien-Søborg; Shlomo Melmed; Jens Otto L Jørgensen; Marianne S Andersen; Jens Otto Lunde Jørgensen; Bolette Hartmann; Marianne C Klose; Ulla Feldt-Rasmussen; Alexander H Sparre-Ulrich; Mette M Rosenkilde

doi:10.1210/clinem/dgae583

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

Mette H Jensen, Lærke S Gasbjerg, Kirsa Skov-Jeppesen, Jens C B Jacobsen, Steen S Poulsen, Cuiqi Zhou, Ruta Jakubauskaite, Frantz R Poulsen, Christian Bonde, Mahmoud Albarazi, Bo Halle, Charlotte B Christiansen, Samra J Sanni, Sarah Byberg, Bjørn Hoe, Jens J Holst, Flemming Dela, Aase K Rasmussen, Filip K Knop, Mai C Arlien-SøborgShlomo Melmed, Jens Otto L Jørgensen, Marianne S Andersen, Jens Otto Lunde Jørgensen, Bolette Hartmann, Marianne C Klose, Ulla Feldt-Rasmussen, Alexander H Sparre-Ulrich, Mette M Rosenkilde

Department of Clinical Medicine - Department of Endocrinology and Internal Medicine

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Abstract

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. 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)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. The main outcome measure was the effect of GIP(3-30)NH₂ 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)NH₂ 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.

Original language	English
Journal	The Journal of clinical endocrinology and metabolism
Volume	110
Issue	3
Pages (from-to)	715-729
Number of pages	15
ISSN	0021-972X
DOIs	https://doi.org/10.1210/clinem/dgae583
Publication status	Published - 1 Mar 2025

Keywords

GIP receptor antagonism
acromegaly
glucose-dependent insulinotropic polypeptide (GIP)
growth hormone (GH)
paradoxical GH secretion

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10.1210/clinem/dgae583

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Jensen, M. H., Gasbjerg, L. S., Skov-Jeppesen, K., Jacobsen, J. C. B., Poulsen, S. S., Zhou, C., Jakubauskaite, R., Poulsen, F. R., Bonde, C., Albarazi, M., Halle, B., Christiansen, C. B., Sanni, S. J., Byberg, S., Hoe, B., Holst, J. J., Dela, F., Rasmussen, A. K., Knop, F. K., ... Rosenkilde, M. M. (2025). GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly. The Journal of clinical endocrinology and metabolism, 110(3), 715-729. https://doi.org/10.1210/clinem/dgae583

@article{a6651425eda5490fad7be79c199ab5c6,

title = "GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly",

abstract = "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. 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)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. The main outcome measure was the effect of GIP(3-30)NH2 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)NH2 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.",

keywords = "GIP receptor antagonism, acromegaly, glucose-dependent insulinotropic polypeptide (GIP), growth hormone (GH), paradoxical GH secretion",

author = "Jensen, {Mette H} and Gasbjerg, {L{\ae}rke S} and Kirsa Skov-Jeppesen and Jacobsen, {Jens C B} and Poulsen, {Steen S} and Cuiqi Zhou and Ruta Jakubauskaite and Poulsen, {Frantz R} and Christian Bonde and Mahmoud Albarazi and Bo Halle and Christiansen, {Charlotte B} and Sanni, {Samra J} and Sarah Byberg and Bj{\o}rn Hoe and Holst, {Jens J} and Flemming Dela and Rasmussen, {Aase K} and Knop, {Filip K} and Arlien-S{\o}borg, {Mai C} and Shlomo Melmed and J{\o}rgensen, {Jens Otto L} and Andersen, {Marianne S} and J{\o}rgensen, {Jens Otto Lunde} and Bolette Hartmann and Klose, {Marianne C} and Ulla Feldt-Rasmussen and Sparre-Ulrich, {Alexander H} and Rosenkilde, {Mette M}",

note = "{\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.",

year = "2025",

month = mar,

day = "1",

doi = "10.1210/clinem/dgae583",

language = "English",

volume = "110",

pages = "715--729",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "3",

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Jensen, MH, Gasbjerg, LS, Skov-Jeppesen, K, Jacobsen, JCB, Poulsen, SS, Zhou, C, Jakubauskaite, R, Poulsen, FR, Bonde, C, Albarazi, M, Halle, B, Christiansen, CB, Sanni, SJ, Byberg, S, Hoe, B, Holst, JJ, Dela, F, Rasmussen, AK, Knop, FK, Arlien-Søborg, MC, Melmed, S, Jørgensen, JOL, Andersen, MS, Jørgensen, JOL, Hartmann, B, Klose, MC, Feldt-Rasmussen, U, Sparre-Ulrich, AH & Rosenkilde, MM 2025, 'GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly', The Journal of clinical endocrinology and metabolism, vol. 110, no. 3, pp. 715-729. https://doi.org/10.1210/clinem/dgae583

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly. / Jensen, Mette H; Gasbjerg, Lærke S; Skov-Jeppesen, Kirsa et al.
In: The Journal of clinical endocrinology and metabolism, Vol. 110, No. 3, 01.03.2025, p. 715-729.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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 - Jørgensen, Jens Otto Lunde

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)NH2 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)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. The main outcome measure was the effect of GIP(3-30)NH2 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)NH2 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)NH2 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)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. The main outcome measure was the effect of GIP(3-30)NH2 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)NH2 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

UR - http://www.scopus.com/inward/record.url?scp=85213692573&partnerID=8YFLogxK

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 -

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

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