Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis

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. In a collaboration with Dr. Robert Doyle at Syracuse University, our labs created a conjugated GLP-1R agonist (Cbi-Ex4) with reduced brain penetrance. Cbi-Ex4 enhances glycemic control without inducing emesis or anorexia. Our preclinical findings highlight its potential therapeutic use for patients seeking improved glycemic control without the loss of appetite and emesis characteristic of current GLP-1 therapeutics. 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.