2016-P: High Dose DACRA Treatment Improves Glucose Homeostasis, without Additional Weight Loss

Abstract

KBP is a Dual Amylin and Calcitonin Receptor Agonist (DACRA). DACRAs have shown efficacy on weight loss and glucose control in rats. However, it is unclear whether the maximum effect has been reached. High Fat Diet (HFD, 60% fat) fed male Sprague-Dawley rats entered a dose escalation regimen ending at 5 (normal dose), 50 or 500 µg/kg daily KBP (n=10/group). Male ZDF (fa/fa) rats received identical doses without dose escalation in a preventive study setup (n=9-10/group). In HFD rats, KBP treatment resulted in a transient decrease in food intake at each dose escalation step. At study end, KBP treatment resulted in a significant weight loss of 77-94 g (13-16%, P<0.0001) compared to vehicle. Furthermore, KBP reduced the weight of adipose tissues (P<0.05). Surprisingly, there was a trend of 5 µg/kg KBP causing a more pronounced adipose-specific weight loss compared to 500 µg/kg (subcutaneous 1.7 vs. 0.7 g, visceral 4.1 vs. 2.5 g adipose weight loss). During two OGTTs, KBP treatment significantly lowered blood glucose (BG) and insulin levels compared to vehicle indicating improved glucose tolerance. Lastly, 24h fecal energy loss increased by KBP treatment, though this trend was absent when accounting for food intake and total feces output. In ZDF rats, KBP treatment significantly improved fasting BG (endpoint vehicle 29.5, endpoint KBP average 18.3 mmol/L, tAUC P<0.0001) and HbA1c (vehicle 10.2%, KBP average 6.1%, P<0.0001) compared to vehicle, with no significant difference between treatment groups. Importantly, fasting and non-fasting insulin levels of KBP-treated rats were increased compared to vehicle in a dose-dependent manner during an OGTT, resulting in lowered BG levels. Increased insulin levels suggest that KBP protects against the known β-cell degradation in the ZDF model. Taken together, these data suggest that higher doses of KBP than previously investigated may preserve insulin secretion to a greater extent. With respect to weight loss, no additional benefit was observed from the high doses. Disclosure N. Sonne: None. A.T. Larsen: 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.