GIPR in GH-PitNETs: molecular and functional insights.

Acromegaly, primarily caused by GH-secreting pituitary neuroendocrine tumors (GH-PitNETs), in about half of cases exhibits resistance to somatostatin receptor ligands (SRLs), making surgery the primary treatment. Recent evidence suggests that glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression in a subset of GH-PitNETs contributes to disease heterogeneity, particularly in tumors showing a paradoxical GH rise after glucose load, which are associated with a less aggressive phenotype and better first-generation SRLs response. This study investigated the functional role of GIPR in somatotroph cells by generating stable human GIPR-expressing GH3 cells (GH3hGIPR) and comparing them with empty vector controls. Functional assays demonstrated that GIPR activation induces cAMP/PKA and MAPK/ERK signaling, enhances GH and prolactin secretion, and increases intracellular calcium oscillations, dependent on extracellular calcium influx. Transcriptomic analysis revealed differential gene expression patterns linked to cell motility, neuronal development, and extracellular matrix remodeling in GH3hGIPR cells, aligning with clinical observations in GIPR+ tumors. However, GIPR overexpression did not alter cell proliferation or viability, suggesting that its role in tumor behavior may depend on additional molecular or epigenetic factors. These findings highlight the importance of GIPR signaling in somatotroph cell function and its potential influence on therapeutic responses, though further studies are needed to clarify its contribution to tumorigenesis and SRL sensitivity.