The Dual Amylin and Calcitonin Receptor Agonist KBP-088 Induces Weight Loss and Improves Insulin Sensitivity Superior to Chronic Amylin Therapy

摘要

KBP-088 (KeyBiosciencePeptide 088) is a potent dual amylin and calcitonin receptor agonist (DACRA). DACRAs are known to elicit potent activity in terms of typical amylin-induced responses, such as reducing food intake and body weight. However, to what extent amylin infusion can mimic the effects of the dual agonist KBP-088 is unknown. We studied the effect of acute dosing with KBP-088 (5 mu g/kg) and rat amylin (100, 300, and 1000 mu g/kg) and subsequently compared the chronic effect of KBP-088 (5 mu g/kg per day) to increasing doses of rat amylin (100, 300, and 1000 mu g/kg per day) delivered by continuous subcutaneous infusion, in high-fat diet (HFD) fed Long-Evans rats. Furthermore, acute amylin sensitivity was investigated. Single dose KBP-088 (5 mu g/kg) potently reduced acute food intake for a prolonged period compared with amylin (100, 300, and 1000 mu g/kg), confirming the difference in potency. Independent of dose, chronic amylin administration (100, 300, and 1000 mu g/kg per day) was less effective than KBP-088 (5 mu g/kg per day) in inducing body weight loss (15% with KBP-088, and 5%, 9%, and 8% with amylin, vehicle corrected) and reducing overall adiposity in HFD rats. Moreover, KBP-088 improved oral glucose tolerance with significantly reduced insulin levels (80% reduction) that were better than all doses of amylin (68%, 53%, and 7% reduction). Acute amylin sensitivity was independent of the chronic treatment. Dual activation of amylin and calcitonin receptors by KBP-088 is superior to amylin in reducing body weight and improving glucose tolerance, indicating a role for the calcitonin receptor.