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

Cell Rep. 2020 Jun 16;31(11):107768. doi: 10.1016/j.celrep.2020.107768.

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.

Keywords: B12; GLP-1 agonist; anorexia; brain permeability; cobinamide; diabetes; emesis; hypophagia; musk shrew; reduced side effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / drug therapy
  • Blood Glucose / drug effects
  • Glucagon-Like Peptide 1 / drug effects*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glycemic Control / methods
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Peptides / metabolism
  • Receptors, Glucagon / drug effects
  • Receptors, Glucagon / metabolism*

Substances

  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptides
  • Receptors, Glucagon
  • Glucagon-Like Peptide 1