Andreassen, Kim V2; Feigh, Michael3; Hjuler, Sara T2; Gydesen, Sofie2; Henriksen, Jan Erik5; Beck-Nielsen, Henning5; Christiansen, Claus2; Karsdal, Morten Asser6; Henriksen, Kim5
1 Endocrinology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 Nordic Bioscience A/S3 Nordic Bioscience, Herlev, Denmark; and Diabetes Research Centre, Department of Endocrinology, University of Southern Denmark, Odense, Denmark.4 Department of Cancer and Inflammation Research, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU5 Endocrinology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU6 Department of Cancer and Inflammation Research, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU
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.
American Journal of Physiology: Endocrinology and Metabolism, 2014, Vol 307, Issue 1