1. GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.
- Author
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Borner T, Geisler CE, Fortin SM, Cosgrove R, Alsina-Fernandez J, Dogra M, Doebley S, Sanchez-Navarro MJ, Leon RM, Gaisinsky J, White A, Bamezai A, Ghidewon MY, Grill HJ, Crist RC, Reiner BC, Ai M, Samms RJ, De Jonghe BC, and Hayes MR
- Subjects
- Animals, Body Weight drug effects, Feeding Behavior, Male, Mice, Mice, Inbred C57BL, Rats, Rats, Sprague-Dawley, Shrews, Vomiting, Glucagon-Like Peptide-1 Receptor agonists, Nausea chemically induced, Nausea drug therapy, Receptors, Gastrointestinal Hormone agonists
- 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., (© 2021 by the American Diabetes Association.)
- Published
- 2021
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