Gastric inhibitory polypeptide (GIP) is an incretin that potentiates insulin secretion from pancreatic -cells by binding to GIP receptor (GIPR) and subsequently increasing the level of intracellular adenosine 3',5'-monophosphate (cAMP). We have identified a novel GIPR splice variant in mouse -cells that retains intron 8, resulting in a C-terminal truncated form (truncated GIPR). This isoform was co-expressed with full-length GIPR (wild-type GIPR) in normal GIPR-expressing tissues. In an experiment using cells transfected with both GIPRs, truncated GIPR didn’t lead to cAMP production induced by GIP but inhibited GIP-induced cAMP production through wild-type GIPR (n=3-4)(P < 0.05). Wild-type GIPR was located normally on the cell surface but its expression was decreased in the presence of truncated GIPR, suggesting a dominant negative effect of truncated GIPR against wild-type GIPR. The functional relevance of truncated GIPR in vivo was investigated. In high fat diet-fed obese mice (HFD mice), blood glucose levels were maintained by compensatory increased insulin secretion (n=8) (P < 0.05), and cAMP production (n=6) (P < 0.01) and insulin secretion (n=10) (P < 0.05) induced by GIP were significantly increased in isolated islets, suggesting hypersensitivity of the GIPR. Total GIPR mRNA expression was not increased in the islets of HFD mice, but the expression ratio of truncated GIPR to total GIPR was reduced by 32% compared to that of control mice (n=6)(P < 0.05). These results indicate that a relative reduction of truncated GIPR expression may be involved in hypersensitivity of GIPR and hyperinsulinemia in diet-induced obese mice.