1993-P: Deconstruction of the Role of the Amylin and Calcitonin Receptors in the Regulation of Body Weight and Glucose Tolerance

Abstract

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity, effects that are superior to those of amylin. However, it is unknown how dual receptor activation by DACRAs compare to activation of either the amylin or the calcitonin receptor in vivo, and to what extent the calcitonin receptor is involved in the beneficial metabolic effects of DACRAs. In this study, we compared the effects of a highly potent DACRA, KBP, rat amylin (rAMY), rat calcitonin (rCT) and the combination of rAMY and rCT on long term efficacy on body weight, food intake and glucose tolerance. High fat fed Sprague Dawley rats were treated 4 weeks with KBP (5 µg/kg/day), rAMY (300 µg/kg/day), rCT, (300 µg/kg/day) and the combination of rAMY and rCT (300+300 µg/kg/day). To compensate for the different activity profiles, peptides were delivered by continuous subcutaneous infusion. Chronic treatment with KBP, rAMY and the combination of rAMY and rCT resulted in a 17%, 11% and 8% vehicle-corrected weight loss, respectively, while rCT alone had no effect. All treatments significantly reduced food intake in the initial phase of the study, while KBP and rAMY resulted in a prolonged reduced food intake. Interestingly, KBP was superior in terms of body weight loss (p<0.001) even though rAMY and KBP reduced the accumulated food intake equally. Moreover, KBP and rAMY improved oral glucose tolerance with significantly reduced insulin levels. Again, KBP was superior to the other treatments (p<0.001). In conclusion, dual activation of amylin and calcitonin receptors by KBP has beneficial effects on body weight and glucose tolerance superior to that of activating either receptor alone. This was despite correcting for the different activity of the peptides. Understanding of the dual or single receptor activation mechanisms is high pharmaceutical interest. Disclosure A.T. Larsen: None. N. Sonne: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience.