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

Feb 3, 2026Journal of diabetes investigation

Natural GIP signaling is essential for DPP-4 inhibitors to control metabolism in mice

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Abstract

DPP-4 inhibition improved glucose tolerance and reduced body weight in high-fat diet-fed mice by relying on GIP signaling.

GIP signaling is essential for the glucose-lowering and anti-obesity effects of DPP-4 inhibitors in mice.
DPP-4 inhibitors enhanced early-phase insulin secretion and lowered glucose levels under normal diet conditions.
In Giprmice, the benefits of DPP-4 inhibition were abolished, indicating the necessity of GIP for these metabolic effects.
Elevations in circulating biologically intact GIP and GLP-1 were similar in both Giprmice and normal mice.
Dulaglutide administration restored glucose-lowering effects in Giprmice, confirming intact GLP-1 receptor function.

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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 Giprand Giprmice 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 Giprmice, without affecting food intake. These effects were abolished in Giprmice, 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 Giprmice, but not in Giprmice. Importantly, dulaglutide restored glucose-lowering effects in Giprmice, 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.

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

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