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; 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, Bolette Hartmann, Marianne C. Klose, Ulla Feldt-Rasmussen, Alexander H. Sparre-Ulrich^*, Mette M. Rosenkilde^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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.

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.

Originalsprog	Engelsk
Tidsskrift	The Journal of clinical endocrinology and metabolism
ISSN	0021-972X
DOI	https://doi.org/10.1210/clinem/dgae583
Status	E-pub ahead of print - 2024

Bibliografisk note

Adgang til dokumentet

10.1210/clinem/dgae583

Citationsformater

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. (2024). GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly. The Journal of clinical endocrinology and metabolism. 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 ; Jacobsen, Jens C. B.; Poulsen, Steen S.; Zhou, Cuiqi; Jakubauskaite, Ruta; Poulsen, Frantz R.; Bonde, Christian; Albarazi, Mahmoud; Halle, Bo; Christiansen, Charlotte B.; Sanni, Samra J.; Byberg, Sarah; Hoe, Bjørn; Holst, Jens J.; Dela, Flemming; Rasmussen, Aase K.; Knop, Filip K.; Arlien-Søborg, Mai C.; Melmed, Shlomo; Jørgensen, Jens Otto L.; Andersen, Marianne S.; Hartmann, Bolette; Klose, Marianne C.; Feldt-Rasmussen, Ulla; Sparre-Ulrich, Alexander H.; Rosenkilde, Mette M.

I: The Journal of clinical endocrinology and metabolism, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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, Hartmann, B, Klose, MC, Feldt-Rasmussen, U, Sparre-Ulrich, AH & Rosenkilde, MM 2024, 'GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly', The Journal of clinical endocrinology and metabolism. https://doi.org/10.1210/clinem/dgae583

Jensen, Mette H. ; Gasbjerg, Lærke S. ; Skov-Jeppesen, Kirsa ; Jacobsen, Jens C. B. ; Poulsen, Steen S. ; Zhou, Cuiqi ; Jakubauskaite, Ruta ; Poulsen, Frantz R. ; Bonde, Christian ; Albarazi, Mahmoud ; Halle, Bo ; Christiansen, Charlotte B. ; Sanni, Samra J. ; Byberg, Sarah ; Hoe, Bjørn ; Holst, Jens J. ; Dela, Flemming ; Rasmussen, Aase K. ; Knop, Filip K. ; Arlien-Søborg, Mai C. ; Melmed, Shlomo ; Jørgensen, Jens Otto L. ; Andersen, Marianne S. ; Hartmann, Bolette ; Klose, Marianne C. ; Feldt-Rasmussen, Ulla ; Sparre-Ulrich, Alexander H. ; Rosenkilde, Mette M. / GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly. I: The Journal of clinical endocrinology and metabolism. 2024.

@article{a69a82a6e6844fd296cdaddc1282e20c,

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.DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-na{\"i}ve 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.",

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 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 = "2024",

doi = "10.1210/clinem/dgae583",

language = "English",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

}

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 - 2024

Y1 - 2024

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.

U2 - 10.1210/clinem/dgae583

DO - 10.1210/clinem/dgae583

M3 - Journal article

C2 - 39172542

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

ER -