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

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posted on 11.08.2021, 14:16 by 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
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 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. Utilizing single-nuclei RNA-sequencing, we identified the cellular phenotypes of AP/NTS GIPR- and GLP-1R-expressing cells on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in GABAergic 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.

Funding

This work was supported by NIH-DK 021397 (MRH; HJG), NIH-DK112812 (BCDJ), by the Swiss National Science Foundation (Grant SNF P400PB_186728) (TB) and an investigator initiated sponsored agreement from Eli Lilly & Co. (MRH; BCDJ). BCR is supported, in part, by a 2017 NARSAD Young Investigator Grant (#26634) from the Brain and Behavior Research Foundation as the Patrick A. Coffer Investigator, funding for which was generously provided by Ronald and Kathy Chandonais.

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