| Literature DB >> 32553160 |
Tito Borner1, Jayme L Workinger2, Ian C Tinsley2, Samantha M Fortin3, Lauren M Stein3, Oleg G Chepurny4, George G Holz4, Aleksandra J Wierzba5, Dorota Gryko5, Ebba Nexø6, Evan D Shaulson1, Ankur Bamezai3, Valentina A Rodriguez Da Silva7, Bart C De Jonghe1, Matthew R Hayes7, Robert P Doyle8.
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a "corrinated" Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.Entities:
Keywords: B12; GLP-1 agonist; anorexia; brain permeability; cobinamide; diabetes; emesis; hypophagia; musk shrew; reduced side effects
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Year: 2020 PMID： 32553160 PMCID： PMC7376604 DOI： 10.1016/j.celrep.2020.107768
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423