Objective: Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp-somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load. Design and methods: This study was aimed at linking the GIP/GIPR pathway to GH secretion in 25 somatotropinomasderived 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 celllineSTC-1. Results: Nearly 80% of GIPR-expressing somatotropinomas, all of them negative for gsp mutations, show increased GH secretion upon GIP stimulation, higher sensitivity to Forskolin but not to somatostatin analogs. Besides increased frequency of GH-PI, GIPR 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. Conclusions: We demonstrate that GIPR mediates the GH-PI in a significant proportion of gsp-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. © 2017 European Society of Endocrinology Printed in Great Britain.