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.
Original language | English (US) |
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Article number | 107768 |
Journal | Cell Reports |
Volume | 31 |
Issue number | 11 |
DOIs | |
State | Published - Jun 16 2020 |
Keywords
- B12
- GLP-1 agonist
- anorexia
- brain permeability
- cobinamide
- diabetes
- emesis
- hypophagia
- musk shrew
- reduced side effects
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)