Endogenous GIP signaling is indispensable for DPP ‐4 inhibitor‐mediated metabolic control in mice

ABSTRACT Aims/Introduction Dipeptidyl peptidase‐4 (DPP‐4) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose‐dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon‐like peptide‐1 (GLP‐1) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose‐lowering and anti‐obesity effects of DPP‐4 inhibition. Materials and Methods Male Gipr +/+ and Gipr −/− mice were treated with anagliptin or linagliptin under normal diet or high‐fat diet (HFD) conditions. Glucose tolerance, insulin secretion, incretin levels, body weight, and adiposity were assessed. To confirm GLP‐1 pathway integrity, dulaglutide was administered to a subset of animals. Results DPP‐4 inhibition significantly improved glucose tolerance and attenuated body‐weight gain in HFD‐fed Gipr +/+ mice, without affecting food intake. These effects were abolished in Gipr −/− mice, despite similar elevations in circulating biologically intact GIP and GLP‐1. Under normal diet, DPP‐4 inhibitors enhanced early‐phase insulin secretion and lowered glucose levels in Gipr +/+ mice, but not in Gipr −/− mice. Importantly, dulaglutide restored glucose‐lowering effects in Gipr −/− mice, confirming preserved GLP‐1 receptor function. Conclusions Endogenous GIP signaling is essential for both glucose‐lowering and anti‐obesity actions of DPP‐4 inhibitors in mice. GLP‐1 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP‐4 inhibitors, highlighted the physiological importance of GIP, and suggested context‐dependent metabolic actions of incretins.