GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

Abstract

Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

• Authors: Tito Borner, Caroline E Geisler, Samantha M Fortin, Richard Cosgrove, Jorge Alsina-Fernandez, Mridula Dogra, Sarah Doebley, Marcos J Sanchez-Navarro, Rosa M Leon, Jane Gaisinsky, Arianna White, Ankur Bamezai, Misgana Y Ghidewon, Harvey J Grill, Richard C Crist, Benjamin C Reiner, Minrong Ai, Ricardo J Samms, Bart C De Jonghe, Matthew R Hayes
• Journal: Diabetes (Diabetes) Vol. 70 Issue 11 Pg. 2545-2553 (11 2021) ISSN: 1939-327X [Electronic] United States
• PMID: 34380697 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by the American Diabetes Association.

Chemical References

• Glucagon-Like Peptide-1 Receptor
• Receptors, Gastrointestinal Hormone
• gastric inhibitory polypeptide receptor

Topics

• Animals
• Body Weight (drug effects)
• Feeding Behavior
• Glucagon-Like Peptide-1 Receptor (agonists)
• Male
• Mice
• Mice, Inbred C57BL
• Nausea (chemically induced, drug therapy)
• Rats
• Rats, Sprague-Dawley
• Receptors, Gastrointestinal Hormone (agonists)
• Shrews
• Vomiting