IMPE Abstracts

Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery involves changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). Designing dual or triple agonists based on glucagon-like peptide (GLP)-1 with glucagon, and/or glucose-dependent insulinotropic polypeptide (GIP) are promising novel approaches for anti-obesity drugs tackling different weight-regulatory pathways, albeit such developments continue to suffer from significant gastrointestinal illnesses. Our own studies have focused instead on the development of monomeric molecules combining the effects of GLP-1 receptor agonists (GLP-1RAs) with neuropeptide Y1- and Y2-receptor (Y1-R/Y2-R) agonists based on peptide YY (PYY). We have evaluated effects of two peptide agonists (GEP44, GEP12) of the GLP-1R, Y1-R, and Y2-R on glucose-stimulated insulin secretion rate (ISR) on rat and human pancreatic islets in vitro. GEP44, GEP12, and GLP-1RA exendin-4 (Ex-4), but not PYY_1-36 or PYY_3-36, significantly increased ISR. We identified that GEP44 and GEP12 elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of ISR in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. While GEP12 elicited stronger increases than GEP44 in ISR in vitro using pancreatic islets and in vivo in diet-induced obese (DIO) rats, it was weaker in reducing food intake and body weight compared to GEP44. We also tested glucose uptake in response to these peptides in skeletal muscle cells. GEP44 and PYY_1-36, but not Ex-4, increased glucose uptake into muscle. GEP44 showed potent anorectic effects in lean and diet-induced obese (DIO) rats with up to 80 % reduction of food intake and stronger reductions of body weight than known GLP-1RAs, including Ex-4 and liraglutide (LIRA), and without triggering nausea as assessed by kaolin intake and behavioral scoring. We tested the responses in a long-term study with increasing doses from 5 to 50 nmol/kg/day of GEP44 vs. LIRA. At the end of the 27-day treatment, the reductions in body weight compared to the vehicle were -15% and -9% for rats treated with GEP44 and LIRA, respectively. Similarly, the cumulative reduction in food intake reduction was -39% vs. -20%, GEP44 vs. LIRA, respectively. In conclusion, our lead GEP44 is a strong anorectic peptide which leads to strong reduction of body weight devoid of nausea. In addition, it has glucoregulatory properties as evidenced by increased islet ISR and muscle glucose uptake. GEP44 is a promising chimeric peptide which may become suitable for treatment of obesity and type 2 diabetes.