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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., Competing Interests: Declaration of Interests R.P.D. is a scientific advisory board member and received funds from Balchem Corporation, New Hampton, New York, which were not used in support of these studies. R.P.B. is the named author of a patent pursuant to this work that is owned by Syracuse University. M.R.H. and B.C.D.J. receive funding from Zealand Pharma that was not used in support of these studies. B.C.D.J. receives funding from Pfizer that was not used in support of these studies. M.R.H. receives funding from Novo Nordisk, Eli Lilly & Co. and Boehringer Ingelheim that was not used in support of these studies. All authors declare no other competing financial interests or conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)