Few treatments for type 2 diabetes (T2D) and obesity achieve meaningful long-term weight-loss and are often accompanied by nausea and vomiting. Thus, there is a critical need for a new generation of obesity medications that provide glycemic control with enhanced hypophagic response without nausea. Our group has developed and tested two new monomeric chimeric peptides against a novel target for obesity treatment concomitant with T2D in the form of dual agonism of the anorectic neuropeptide Y2-receptor (Y2-R) and the glucoregulatory glucagon-like peptide 1-receptor (GLP-1R). Using rational design and in silico modelling based on the GLP-1R agonist (GLP-1RA) exendin-4 (Ex-4) and the Y2-R agonist PYY(3-36), we developed two novel chimeric peptides, EP44 and GEP44. Both peptides bind and robustly activate the GLP-1R as well as the Y2-R, as assessed by cell-based fluorescence resonance energy transfer assays used to screen designed peptides for dose dependent receptor agonism (GLP-1R agonism EC50: EP44 240 pM, GEP44 300 pM, Ex-4 23 pM; Y2-R agonism EC50: EP44 32 nM, GEP44 10 nM, native PYY3-36 16 nM). We found that EP44 and GEP44 both robustly stimulate the insulin secretion rate in rat islet perfusion in vitro. EP44 potently reduced glucose levels during glucose tolerance tests in rats in vivo (30 min glucose: 269±14 mg/dL pre-treatment, 181±16 mg/dL after five once-daily 10 nmol/kg EP44 doses, P<0.001). Furthermore, we tested effects of daily injections of these chimeric peptides in adult Sprague-Dawley rats on food intake (FI), body weight (BW) changes, blood glucose levels and kaolin intake, the latter as an indicator of nausea. Both peptides reduced FI, with GEP44 producing profound reduction in FI (2-d average EP44 at 30 nmol/kg FI -15%; GEP44 at 20 nmol/kg FI -71%; Ex-4 20 nmol/kg FI -40%). Of note, anorectic doses of EP44 or GEP44 did not trigger kaolin consumption in treated rats, while in Ex-4 treated rats, kaolin consumption accounted for 28% of total daily solid intake, indicating a clear nausea response. During 11 d of treatment with GEP44, FI was consistently reduced resulting in a significantly stronger reduction of BW compared to Ex-4 at the end of treatment (GEP44 -7.6%, Ex-4 -3.7%). In conclusion, utilizing a novel concept of targeting serial anorectic pathways simultaneously with single-small chimeric peptides developed by our group is a new strategy addressing two coexisting conditions, namely obesity and T2D, to safely reduce FI, BW and blood glucose levels.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology