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

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.