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Review
. 2025 Jul 1;72(7):751-764.
doi: 10.1507/endocrj.EJ25-0087. Epub 2025 Apr 3.

Physiology and clinical applications of GIP

Shunsuke Yamane  1 , Norio Harada  1   2 , Nobuya Inagaki  1   3
Affiliations
Review

Physiology and clinical applications of GIP

Shunsuke Yamane et al. Endocr J. .

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, primarily located in the upper small intestine, in response to food intake and plays a significant role in the postprandial regulation of nutrient metabolism. Although the importance of GIP in metabolic regulation has long been recognized, progress in developing GIP as a therapeutic target has been limited. However, the GIP/GIP receptor (GIPR) axis has garnered increasing attention in recent years. Emerging evidence suggests that dual GIP/GLP-1 receptor agonists and triple GIP/GLP-1/glucagon receptor agonists provide beneficial metabolic effects in individuals with type 2 diabetes and obesity. In this review, we outline the physiological roles of GIP, detailing the mechanisms of GIP secretion from K cells in response to macronutrients, its actions on key target organs involved in metabolic regulation, and ongoing developments in its therapeutic applications.

Keywords: Diabetes; Glucose-dependent insulinotropic polypeptide (GIP); Incretin; Obesity.

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Conflict of interest statement

N.I. received clinical commissioned/joint research grant from asken, scholarship grant from Sumitomo Pharma, Mitsubishi Tanabe Pharma and Nippon Boehringer Ingelheim, and honoraria for lectures from Novo Nordisk Pharma, Sumitomo Pharma, Eli Lilly Japan and Mitsubishi Tanabe Pharma. N.H. received honoraria for lectures from Novo Nordisk Pharma, Mitsubishi Tanabe Pharma. S.Y. has no conflict of interest.

Figures

Fig. 1
Fig. 1. Schematic representation illustrating potential mechanisms of fat-induced GIP secretion via GPR40 and GPR120, showing involvement of CCK and bile. GPR, G protein-coupled receptor; CCK, cholecystokinin; GIP, glucose-dependent insulinotropic polypeptide
Fig. 2
Fig. 2. Potential mechanisms by which GIP hypersecretion under HFD conditions induces insulin resistance and hepatic steatosis. IL-6, interleukin-6; GIP, glucose-dependent insulinotropic polypeptide; GIPR, GIP receptor; IR, insulin receptor; LPL, lipoprotein lipase.
Graphical Abstract
Graphical Abstract. Effects of physiological and pharmacological GIP blood concentrations on systemic metabolism regulation. GIP, glucose-dependent insulinotropic polypeptide; GIPR, GIP receptor.
See this image and copyright information in PMC

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