Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus (T2DM) often produce nausea, vomiting (emesis), and in some patients, undesired anorexia. Notably, these side effects are caused by direct central GLP-1R activation.Our group developed a conjugate of vitamin B12 bound to the GLP-1R agonist exendin-4 (Ex4) which shows reduced hindbrain penetrance.


We evaluated the efficacy of the B12-Ex4 conjugate to improve glucose tolerance without inducing anorexia in Goto Kakizaki (GK) rats, a lean T2DM model. We also utilized the musk shrew (Suncus murinus), a mammalian model capable of emesis, to characterize B12-Ex4 versus native Ex4 on glycemic profile, feeding behavior, and vomiting.


In both species, native Ex4 and B12-Ex4 equivalently blunted blood glucose rises followinga glucose tolerance test. Remarkably, while Ex4 led to the expected stress-mediated hyperglycemia in GK rats prior to glucose delivery, no change in blood glucose was observed after B12-Ex4 administration. In both GK rats and shrews, acute Ex4 administration significantly reduced 24h food intake and body weight; in contrast, equimolar administration of B12-Ex4 had no effect on either variable. Importantly, the number of shrews experiencing emesis after systemic B12-Ex4 was greatly diminished compared to native Ex4. However, when administered centrally, both induced profound emesis; functionally validating the reduced hindbrain permeability of B12-Ex4.


Collectively, these findings highlight the potential therapeutic value of B12-Ex4 as a novel treatment for T2DM superior to Ex4, especially in a non-obese population, with robust improvement in appearance of adverse effects alongside comparable glucoregulation to the native compound.Support: DK112812, DK096139, DK097675,DK115762, SNF P2ZHP3_178114