The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp− somatotropinomas

<jats:sec><jats:title>Objective</jats:title><jats:p>Glucose-dependent insulinotropic polypeptide receptor (<jats:italic>GIPR</jats:italic>) overexpression has been recently described in a proportion of<jats:italic>gsp</jats:italic><jats:sup>−</jats:sup>somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load.</jats:p></jats:sec><jats:sec><jats:title>Design and methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Nearly 80% of<jats:italic>GIPR</jats:italic>-expressing somatotropinomas, all of them negative for<jats:italic>gsp</jats:italic>mutations, show increased GH secretion upon GIP stimulation, higher sensitivity to Forskolin but not to somatostatin analogs. Besides increased frequency of GH-PI,<jats:italic>GIPR</jats:italic>overexpression 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>We demonstrate that<jats:italic>GIPR</jats:italic>mediates the GH-PI in a significant proportion of<jats:italic>gsp</jats:italic><jats:sup>−</jats:sup>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.</jats:p></jats:sec>