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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Borner T,Workinger JL,Tinsley IC,Fortin SM,Stein LM,Chepurny OG,Holz GG,Wierzba AJ,Gryko D,Nexø E,Shaulson ED,Bamezai A,Da Silva VAR,De Jonghe BC,Hayes MR,Doyle RPdoi
10.1016/j.celrep.2020.107768subject
Has Abstractpub_date
2020-06-16 00:00:00pages
107768issue
11issn
2211-1247pii
S2211-1247(20)30748-8journal_volume
31pub_type
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