Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark.
J Pharmacol Exp Ther. 2020 Jul;374(1):74-83. doi: 10.1124/jpet.119.263392. Epub 2020 Apr 21.
Amylin treatment improves body weight and glucose control, although it is limited by a short action and need for high doses. Dual amylin and calcitonin receptor agonists (DACRAs) are dual amylin and calcitonin receptor agonists with beneficial effects beyond those of amylin. However, to what extent the additional benefits reside in their higher potency or their targeting of the calcitonin receptor remains unclear. Here we deconstruct the receptors involved in the effects of a DACRA, KBP-088, by comparing it to rat amylin (rAMY), rat calcitonin (rCT), and their combination in obese high-fat diet (HFD) and diabetic Zucker diabetic fatty (ZDF) rats. HFD-fed Sprague-Dawley rats and ZDF rats were treated for 4 weeks with KBP-088 (5 µg/kg per day), rAMY (300 µg/kg per day), rCT (300 µg/kg per day), and the combination of rAMY and rCT (300+300 µg/kg per day) using infusion pumps. Body weight, food intake, fasting glycemia, glycated hemoglobin type A1c levels, and glucose tolerance were assessed. In obese HFD-fed rats, KBP-088, rAMY, and the combination of rAMY and rCT significantly reduced body weight and improved glucose tolerance, whereas rCT alone had no effect. In diabetic ZDF rats, rCT was efficient in lowering fasting glycemia similar to rAMY, whereas dual activation by KBP-088 and the combination of rAMY and rCT were superior to activating either receptor alone. In conclusion, calcitonin therapy regulates fasting blood glucose in a diabetic rat model, thereby underscoring the importance of calcitonin receptor activation as well as the known role of amylin receptor agonism in the potent metabolic benefits of this group of peptides. SIGNIFICANCE STATEMENT: We deconstruct the receptors activated by dual amylin and calcitonin receptor agonist (DACRA) therapy to elucidate through which receptor the beneficial metabolic effects of the DACRAs are mediated. We show that calcitonin receptor activation is important for blood glucose regulation in diabetes. This is in addition to the known metabolic beneficial role of amylin receptor activation. These data help in understanding the potent metabolic benefits of the DACRAs and underline the potential of DACRAs as treatment for diabetes and obesity.
阿莫林治疗可改善体重和血糖控制，但作用时间短，需要高剂量。双重淀粉样肽和降钙素受体激动剂（DACRAs）是双重淀粉样肽和降钙素受体激动剂，其益处超出了淀粉样肽。然而，额外的益处是由于其更高的效力还是由于其针对降钙素受体尚不清楚。在这里，我们通过比较 KBP-088 与大鼠淀粉样肽（rAMY）、大鼠降钙素（rCT）及其组合在肥胖高脂肪饮食（HFD）和糖尿病 Zucker 肥胖型糖尿病（ZDF）大鼠中的作用，来解构参与 DACRA 作用的受体。用输注泵对 HFD 喂养的 Sprague-Dawley 大鼠和 ZDF 大鼠进行为期 4 周的 KBP-088（5μg/kg/天）、rAMY（300μg/kg/天）、rCT（300μg/kg/天）和 rAMY 和 rCT 组合（300+300μg/kg/天）治疗。评估体重、食物摄入量、空腹血糖、糖化血红蛋白 A1c 水平和葡萄糖耐量。在肥胖的 HFD 喂养大鼠中，KBP-088、rAMY 和 rAMY 和 rCT 的组合显著降低体重并改善葡萄糖耐量，而 rCT 单独则没有作用。在糖尿病 ZDF 大鼠中，rCT 降低空腹血糖的效果类似于 rAMY，而 KBP-088 和 rAMY 和 rCT 组合的双重激活优于单独激活任一受体。总之，降钙素治疗可调节糖尿病大鼠模型的空腹血糖，从而强调降钙素受体激活的重要性以及淀粉样肽组的这种代谢益处已知的淀粉样肽受体激动剂作用。意义声明：我们解构了双重淀粉样肽和降钙素受体激动剂（DACRA）治疗激活的受体，以阐明通过哪种受体介导 DACRA 的有益代谢作用。我们表明，降钙素受体激活对于糖尿病中的血糖调节很重要。这除了已知的代谢有益作用的淀粉样肽受体激活。这些数据有助于理解 DACRA 的强大代谢益处，并强调 DACRA 作为糖尿病和肥胖症治疗的潜力。
