Nordic Bioscience, Herlev, Denmark.
Department of Systems Biology, Technical University of Denmark, Denmark.
Obesity (Silver Spring). 2016 Aug;24(8):1712-22. doi: 10.1002/oby.21563. Epub 2016 Jun 14.
In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 µg/kg-10 µg/kg) compared with saline-treated and pair-fed controls.
Rats with obesity received daily s.c. administrations for 56 days, and glucose tolerance was assessed after one acute injection, 3 weeks of treatment, and again after 7 weeks of treatment. To assess the effect on insulin sensitivity, rats received 5 µg/kg KBP-042 for 21 days before hyperinsulinemic-euglycemic clamp.
KBP-042 induced a sustained weight loss of up to 20% without any significant weight reduction in the pair-fed groups. Decreases in adipose tissues and lipid deposition in the liver were observed, while plasma adiponectin was increased and plasma leptin levels were decreased. Acute administration of KBP-042 led to impaired glucose tolerance and increased plasma lactate, while this diabetogenic effect was reversed by chronic treatment. Finally, assessment of insulin sensitivity using the hyperinsulinemic-euglycemic clamp showed that KBP-042 increased the glucose infusion rate.
The study indicates that KBP-042 combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance.
在这项研究中，KBP-042 是一种双重淀粉样肽和降钙素受体激动剂，与生理盐水处理和配对喂养的对照组相比，我们研究了其在五种不同剂量（0.625μg/kg-10μg/kg）下治疗肥胖和胰岛素抵抗的效果。
肥胖大鼠每天接受皮下给药 56 天，单次急性注射后、治疗 3 周后和治疗 7 周后评估葡萄糖耐量。为了评估对胰岛素敏感性的影响，大鼠在接受 5μg/kg KBP-042 治疗 21 天后接受高胰岛素正常血糖钳夹。
KBP-042 诱导了持续的体重减轻，最高可达 20%，而配对喂养组没有明显的体重减轻。观察到脂肪组织和肝脏脂质沉积减少，而血浆脂联素增加，血浆瘦素水平降低。KBP-042 的急性给药导致葡萄糖耐量受损和血浆乳酸增加，而这种致糖尿病作用在慢性治疗后得到逆转。最后，使用高胰岛素正常血糖钳夹评估胰岛素敏感性表明，KBP-042 增加了葡萄糖输注率。
该研究表明，KBP-042 结合了两种高度相关的特征，即体重减轻和胰岛素敏感性，因此是肥胖和胰岛素抵抗慢性治疗的理想候选药物。
