A second generation GLP-1 receptor agonist mitigates vomiting and anorexia while retaining glucoregulatory potency in lean diabetic and emetic mammalian models.

AIMS: FDA approved glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus (T2DM) often produce nausea, vomiting, and in some patients, undesired anorexia. These side effects are caused by direct central GLP-1R activation. We developed a conjugate of vitamin B12 bound to the GLP-1R agonist exendin-4 (Ex4), which shows reduced penetrance into the central nervous system (CNS), while maintaining peripheral glucoregulatory function. METHODS: We evaluated whether B12-Ex4 improves glucose tolerance without inducing anorexia in Goto-Kakizaki (GK) rats, a lean T2DM model of an understudied but medically compromised population of patients requiring the glucoregulatory effects of GLP-1R agonists without anorexia. We also utilized the musk shrew (Suncus murinus), a mammalian model capable of emesis, to test B12-Ex4 on glycemic profile, feeding, and emesis. RESULTS: In both models, native Ex4 and B12-Ex4 equivalently blunted the rise in blood glucose levels during a glucose tolerance test. In both GK rats and shrews, acute Ex4 administration decreased food intake, leading to weight loss; in contrast, equimolar administration of B12-Ex4 had no effect on feeding and body weight. There was a near absence of emesis in shrews given systemic B12-Ex4, in contrast to reliable emesis produced by Ex4. When administered centrally, both B12-Ex4 and Ex4 induced similar potency of emesis, suggesting that brain penetrance of B12-Ex4 is required for induction of emesis. CONCLUSIONS: These findings highlight the potential therapeutic value of B12-Ex4 as a novel treatment for T2DM devoid of weight-loss and with reduced adverse effects and better tolerance, but similar glucoregulation to current GLP-1R agonists. This article is protected by copyright. All rights reserved.