Gydesen Sofie, Andreassen Kim Vietz, Hjuler Sara Toftegaard, Hellgren Lars I, Karsdal Morten Asser, Henriksen Kim
Nordic Bioscience, Herlev, Denmark;
Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark; and.
Am J Physiol Endocrinol Metab. 2017 Nov 1;313(5):E598-E607. doi: 10.1152/ajpendo.00419.2016. Epub 2017 Mar 14.
Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance ( < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance ( < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.
在开始给药时，胰淀素和胰高血糖素样肽-1（GLP-1）激动剂会产生众所周知的厌食效应，可通过剂量递增来控制。在本研究中，我们调查了如何在维持新型高效双靶点胰淀素和降钙素受体激动剂（DACRA）KBP-089疗效的同时优化其耐受性。此外，我们还测试了KBP-089在高脂饮食（HFD）喂养大鼠中的GLP-1附加潜力。KBP-089在体外能有效激活胰淀素和降钙素受体，显示出延长的受体激活以及对急性食物摄入量的有效降低。每天或隔天给药的HFD大鼠在研究结束时体重减轻程度相同，尽管隔天给药的大鼠食物摄入量和体重的减少不均衡。在4倍剂量递增过程中，KBP-089在每个递增步骤都会引起食物摄入量的短暂减少，且减少幅度随时间逐渐减小，随后给予2.5、10和40μg/kg的剂量，导致体重减轻约15%（相对于溶媒对照），脂肪组织（AT）相应减少，并且在所有治疗组中，口服葡萄糖耐量均得到改善（<0.01）。两倍和线性递增均能均匀抑制体重，在任何递增步骤中食物摄入量均无显著减少。与溶媒对照相比，KBP-089（1.25μg/kg）和利拉鲁肽（50μg/kg）分别使24小时食物摄入量减少29%和37%；然而，当它们联合使用时，24小时食物摄入量减少了87%。长期来看，KBP-089（1.25μg/kg）和利拉鲁肽（50μg/kg）分别使HFD大鼠体重降低8%和2%，而联合使用则使体重降低了12%。此外，联合使用还改善了葡萄糖耐量（<0.05）。总之，DACRAs在食物摄入量和体重方面与GLP-1具有互补作用。此外，在递增给药时，KBP-089耐受性良好，在瘦型和HFD大鼠中均能诱导并维持显著的体重减轻和AT减少，突出了KBP-089作为抗肥胖药物的潜力。
