SUN-660 Appetite Suppressing Effects of Glucoregulatory Chimeric Peptides Devoid of Nausea

Abstract

Current treatments for type 2 diabetes (T2D) and obesity do not reliably achieve long-term weight-loss and up to 50% of patients experience nausea and vomiting. Thus, there is a critical need for obesity medications that provide glycemic control with enhanced hypophagic response without nausea. Based on rational design and in silico modelling of the glucagon-like peptide 1-receptor agonist (GLP1RA) exendin-4 (Ex4) and the neuropeptide Y2 receptor (Y2R) agonist peptide YY (PYY) 3-36, our group has developed and tested several new monomeric chimeric peptides that display dual agonism of the anorectic Y2R and the glucoregulatory GLP1R. In addition, we explored a third agonistic behavior at the neuropeptide Y1 receptor (Y1R), which potentially relates to pancreatic beta-cell protection. Our current lead, GEP44, binds and robustly activates the Y2R, Y1R, and GLP1R. In our experiments, half maximal effective concentration (EC50) values for GEP44 were 10 nM at Y2R, 24 nM at Y1R, and 330 pM at GLP1R for dose responses of cell-based fluorescence resonance energy transfer assays. For the control substrates PYY3-36, PYY1-36, and Ex4, EC50 values were 16 nM, 12 nM, and 16 pM at the Y2R, Y1R, and GLP1R, respectively. 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 an indicator of nausea (kaolin intake). GEP44 produced profound reduction in FI (2-d average GEP44 at 20 nmol/kg FI -71%; Ex-4 20 nmol/kg FI -40%). Anorectic doses of GEP44 did not trigger a pica response assessed by 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 Ex4 at the end of treatment (GEP44 -7.6%, Ex4 -3.7%, p<0.05). Furthermore, 5-day injections of GEP44 showed greater reduction of glucose levels than for Ex4 in diet induced obese rats receiving intraperitoneal glucose. These results were supported by results generated using a customized perifusion system that demonstrated acute stimulation of insulin secretion by exposure of isolated rodent and human islets to GEP44 and Ex4 (both p<0.01 vs. vehicle). In conclusion, simultaneously targeting serial anorectic pathways with single molecule chimeric peptides developed by our group can address multiple coexisting conditions, namely obesity and T2D, to more efficaciously reduce FI, BW and blood glucose levels thereby reducing off target effects.