ESPE2022 Henning Andersen Award Winners Development of Anorexigenic and Glucoregulatory Chimeric Peptides (1 abstracts)
Designing monomeric 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 combination of GLP-1 receptor agonists (GLP-1RAs) with neuropeptide Y1- and Y2-receptor (Y1-R/Y2-R) agonists based on peptide YY (PYY). Our current lead is the first triagonist of GLP-1R, Y1-R and Y2-R (GEP44), which is a chimeric peptide, comprised of amino acid residues from both the GLP-1RA exendin-4 (Ex-4) and peptide YY (PYY). 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. Recent experiments in DIO male rats (n=4-6 rats/group) demonstrate a more robust reduction of body weight, food intake, and conjunct reduction in blood glucose in response to GEP44 vs. equimolar LIRA (10 nmol/kg for 9 days, followed by 25 nmol/kg for 7 days). At the 25 nmol/kg/d dose, food intake was reduced by 62% (GEP44) vs. 25% (LIRA). At the end of the 16-d treatment, body weight reduction was -12.1% (GEP44) vs. 3.2% (LIRA) and mean fasting glucose levels were 86 (GEP44) vs. 109 (LIRA) vs. 110 mg/dL (vehicle), P<0.01 GEP44 vs. LIRA. Body weight changes in GEP44 treated animals were similar to pair-fed vehicle treated animals, suggesting that the strong reduction of body weight in response to GEP44 is related to reduction in food intake and not to changes in energy expenditure. We have also evaluated glucose-stimulated insulin secretion rate (ISR) by rat and human pancreatic islets in response to GEP44 in vitro. ISR was significantly increased in response to GEP44 and Ex-4, but not to PYY1-36 or PYY3-36. We also tested glucose uptake in response to these peptides in skeletal muscle cells. GEP44 and PYY1-36, but not Ex-4, increased glucose uptake into muscle. In conclusion, 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.
15 Sep 2022 - 17 Sep 2022