The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion ofgsp-somatotropinomas.
OBJECTIVE
Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion ofgsp-somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load.


METHODS
This study was aimed at linking the GIP/GIPR pathway to GH secretion in 25 somatotropinomas-derived primary cultures and correlating molecular with clinical features in acromegalic patients. Given the impairment of the GIP/GIPR axis in acromegaly, an additional aim was to assess the effect of GH/IGF-1 stimulation on GIP expression in the enteroendocrine cell line STC-1.


RESULTS
Nearly 80% ofGIPR-expressing somatotropinomas, all of them negative forgspmutations, show increased GH secretion upon GIP stimulation, higher sensitivity to Forskolin but not to somatostatin analogs. Besides increased frequency of GH-PI,GIPRoverexpression does not appear to affect acromegalic patients' clinical features. In STC-1 cells transfected with GIP promoter-driven luciferase vector, IGF-1 but not GH induced dose-dependent increase in luciferase activity.


CONCLUSIONS
We demonstrate thatGIPRmediates the GH-PI in a significant proportion ofgsp-acromegalic patients. In these cases, the stimulatory effect of IGF-1 on GIP promoter support the hypothesis of a functional GH/IGF-1/GIP axis. Further studies based on larger cohorts and the development of a stable transgenic model with inducible GIPR overexpression targeted to pituitary somatotroph lineage will be mandatory to establish the real role of GIPR in the pathogenesis of somatotropinomas.
Endocrinology DivisionDepartment of Medicine, Hospital/University of Padova, Padova, Italy.
D
D
Regazzo
Pituitary UnitDepartment of Neurosurgery.
M
M
Losa
Endocrinology DivisionDepartment of Medicine, Hospital/University of Padova, Padova, Italy.
N M
NM
Albiger
Pathology UnitIstituto Scientifico San Raffaele, Università Vita-Salute, Milano, Italy.
M R
MR
Terreni
Department of BiologyUniversity of Padova, Padova, Italy.
G
G
Vazza
Endocrinology DivisionDepartment of Medicine, Hospital/University of Padova, Padova, Italy.
F
F
Ceccato
Otolaryngology and Otosurgery Unit.
E
E
Emanuelli
Department of NeuroscienceHospital/University of Padova, Padova, Italy.
L
L
Denaro
Endocrinology DivisionDepartment of Medicine, Hospital/University of Padova, Padova, Italy.
C
C
Scaroni
Department of BiologyUniversity of Padova, Padova, Italy.
G
G
Occhi
D000172:Acromegaly / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics* / Q000378:metabolism*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
D011964:Receptors, Gastrointestinal Hormone; D019382:Human Growth Hormone; D005576:Colforsin; D005749:Gastric Inhibitory Polypeptide; D007334:Insulin-Like Growth Factor I; D004247:DNA; C041086:gastric inhibitory polypeptide receptor