Journal
CELL REPORTS
Volume 31, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.107768
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Funding
- National Institutes of Health [NIH-DK-097675, DK112812, DK097675, DK115762, DK069575]
- Foundation for Polish Sciences (FNP TEAM) [POIR.04.04.00-00-4232/17-00]
- Swiss National Science Foundation [SNF P2ZHP3-178114, SNF P400PB-186728]
- Xeragenx, St. Louis, Missouri
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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-1 R-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.
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