title: A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats.
abstract: The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and β-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes.
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Kim V
authors.initials: KV
authors.lastname: Andreassen
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and Diabetes Research Centre, Department of Endocrinology, University of Southern Denmark, Odense, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Feigh
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Sara T
authors.initials: ST
authors.lastname: Hjuler
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Sofie
authors.initials: S
authors.lastname: Gydesen
authors.affiliation: Diabetes Research Centre, Department of Endocrinology, University of Southern Denmark, Odense, Denmark.
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Henriksen
authors.affiliation: Diabetes Research Centre, Department of Endocrinology, University of Southern Denmark, Odense, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Beck-Nielsen
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and kh@nordicbioscience.com.
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D001786:Blood Glucose / Q000187:drug effects; D002116:Calcitonin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007333:Insulin Resistance; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018003:Receptors, Calcitonin / Q000037:antagonists & inhibitors*; D058287:Receptors, Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; C000607802:KBP-042; D018003:Receptors, Calcitonin; D058287:Receptors, Islet Amyloid Polypeptide; D002116:Calcitonin
keywords: amylin receptor; blood glucose; calcitonin receptor; dual amylin and calcitonin receptor agonist; insulin sensitivity; type 2 diabetes; weight loss