TY - JOUR T1 - The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, induces an equally potent weight loss across a broad dose range while higher doses may further improve insulin action JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.263723 SP - jpet.119.263723 AU - Nina Sonne AU - Anna Thorsø Larsen AU - Kim Vietz Andreassen AU - Morten Asser Karsdal AU - Kim Henriksen Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/01/29/jpet.119.263723.abstract N2 - Pharmacological treatment with Dual Amylin and Calcitonin Receptor Agonists (DACRAs) cause a significant weight loss and improvement of glucose homeostasis. In this study, the maximally efficacious dose of the novel DACRA, KBP-066, was investigated. Two different rat models were used: High Fat Diet (HFD) fed male Sprague-Dawley rats and male Zucker Diabetic Fatty (ZDF, fa/fa) rats to determine the maximum weight loss and glucose homeostatic effect, respectively. One acute study and one chronic study was performed in HFD rats. Two chronic studies were performed in ZDF rats: a preventive and an interventive. All studies covered a dose range of 5, 50 and 500 μg/kg KBP-066 delivered by s.c. injection. Treatment with KBP-066 resulted in a significant weight reduction of 13-16% and improved glucose tolerance in HFD rats which was independent of dose concentration. Dosing with 50 and 500 μg/kg led to a transient but significant increase in blood glucose, both in the acute and the chronic study in HFD rats. All doses of KBP-066 significantly improvement glucose homeostasis in ZDF rats, both in the preventive and interventive study. Moreover, dosing with 50 and 500 μg/kg preserved insulin secretion to a greater extent than 5 μg/kg when compared to ZDF vehicle rats. Taken together, these results show that maximum weight loss is achieved with 5 μg/kg which is within the range of previously reported DACRA dosing, while increasing dosing concentration to 50 and 500 μg/kg may further improve preservation of insulin secretion compared to 5 μg/kg in diabetic ZDF rats.SIGNIFICANCE STATEMENT Here we show that KBP-066 induces an equally potent body weight loss across a broad dose-range in obese rats. However, KBP-066 dose-dependently improves insulin action in diabetic rats both as preventive and interventive treatment. This suggests that the pharmacological treatment dose of KBP-066 may need to be flexible in order to obtain the best results. ER -