Glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 (Ex4) is one of the most efficacious FDA-approved drug for the treatment of type 2 diabetes. Unfortunately, all GLP-1R-based therapeutics cause nausea, vomiting, and unwanted anorexia that limit applications in humans, especially for oncology patients. Our lab developed a novel GLP-1R agonist conjugated with a precursor of the vitamin B12 (Cbi-Ex4), that showed reduced brain penetrance while maintaining the beneficial peripheral actions on glucose homeostasis.

The objective of this research project is to (1) characterize the effects of chronic, daily doses of Cbi-Ex4 on pica (i.e. kaolin intake, a validated proxy for nausea in rodents), anorexia, and body weight in healthy rats and compared to the effects of equimolar doses of native Ex4, and (2) test the ability of Cbi-Ex4 treatment to ameliorate tumor-induced insulin resistance and improve glucose tolerance without causing malaise and further aggravating anorexia.

Using hepatoma tumor-bearing (TB) rats, a well characterized pre-clinical model for CACS (Fig. 1), I first measured food intake, body weight and kaolin consumption (i.e. a well validated proxy for malaise in rodents) following daily chronic administrations of Cbi-Ex4, Ex4 (positive control), and saline (negative control).

During this project, I gained experience and work with animal models, solidified my skills in various behavioral paradigms, and expanded my set of skills in the wet lab (e.g. cell culture and aseptic techniques).

Further lines of research include investigating Cbi-Ex4’s efficacy in ameliorating glucose metabolism without negative side effects in a tumor-bearing model, including establishing a model that simulates a human model of CACS.