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REVIEW article

Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1530985
This article is part of the Research Topic The Impact of GIP/GIPR on Metabolic Diseases: How the Field Is Evolving View all 3 articles

The agony and the efficacy: Central mechanisms of GLP-1 induced adverse events and their mitigation by GIP

Provisionally accepted
Jonathan D Douros Jonathan D Douros 1*Jonathan N Flak Jonathan N Flak 1,2Patrick J Knerr Patrick J Knerr 1
  • 1 Indiana Biosciences Research Institute, Indianapolis, United States
  • 2 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States

The final, formatted version of the article will be published soon.

    Incretin peptides are secreted from the intestine after nutrient ingestion and enhance glucose-stimulated insulin secretion [1]. In healthy individuals glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the primary incretin factors [2; 3]. However, GIP receptor (GIPR) activity is diminished in patients with type 2 diabetes (T2D), while GLP-1 receptor (GLP-1R) function remains intact [4]. This finding, along with the obesogenic physiologic role of GIP [5; 6], motivated the development of GLP-1R agonists over GIPR agonists for the treatment of T2D [7; 8; 9; 10; 11]. Long acting GLP-1 analogues were later approved for obesity based upon early observations that physiologic and pharmacologic GLP-1R agonism reduces food intake in preclinical models [12] and pioneering clinical trials of long acting GLP-1 analogues [13]. Despite the substantial improvements in body weight and glucose control elicited by GLP-1R agonists, patient uptake and compliance are challenged by frequent gastrointestinal adverse events (GI AEs), including nausea and vomiting, that necessitate careful dose titration regimens to achieve efficacious dosing [14]. Emerging preclinical and clinical evidence suggests that GIPR agonism can play a role in reducing the GI AEs of GLP-1R agonism and enable greater therapeutic potential.

    Keywords: GLP-1 - glucagon-like peptide-1, GIP - glucose-dependent insulinotropic peptide, Obesity, Incretin, Pharmacology

    Received: 19 Nov 2024; Accepted: 02 Jan 2025.

    Copyright: © 2025 Douros, Flak and Knerr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jonathan D Douros, Indiana Biosciences Research Institute, Indianapolis, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.