Vickers Steven P, Cheetham Sharon C, Birmingham Gareth D, Rowley Helen L, Headland Katie R, Dickinson Keith, Grempler Rolf, Hocher Berthold, Mark Michael, Klein Thomas
RenaSci Ltd, BioCity Nottingham, Pennyfoot Street, Nottingham, UK.
Clin Lab. 2012;58(7-8):787-99.
To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats.
Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 microg/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 microg/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 microg/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined.
In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident.
These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.
评估二肽基肽酶-4（DPP-4）抑制剂利那格列汀单独使用、与艾塞那肽联合使用以及在艾塞那肽撤药期间对饮食诱导肥胖（DIO）大鼠的慢性影响。
雌性Wistar大鼠接受自助餐饮食以诱导肥胖。然后动物每天口服一次赋形剂或利那格列汀（3毫克/千克，经口给药），持续28天。在随后的研究中，大鼠通过渗透微型泵接受艾塞那肽（3或30微克/千克/天）或赋形剂，持续28天。此外，在研究期间，将动物分组，分别单独口服利那格列汀或与3微克/千克/天的艾塞那肽剂量联合口服给药。在最后一项研究中，大鼠通过渗透微型泵接受艾塞那肽（30微克/千克/天）或赋形剂，持续11天。随后，接受艾塞那肽治疗的动物转用赋形剂或继续输注艾塞那肽，持续另外10天。从艾塞那肽转用赋形剂的动物也口服赋形剂或利那格列汀。在所有研究中，每天记录体重、食物和水的摄入量，并测定相关的血浆参数和胴体组成。
与艾塞那肽不同，利那格列汀与对照组相比，并未显著降低DIO大鼠的体重或胴体脂肪。联合使用时，利那格列汀增强了艾塞那肽减少体脂的作用，但不影响体重反应。在撤掉艾塞那肽的大鼠中，观察到体重恢复，使得体重与对照组无显著差异。利那格列汀减少了撤掉艾塞那肽后的体重恢复，因此与对照组有明显差异。
这些数据表明，利那格列汀在未治疗或接受艾塞那肽治疗的DIO大鼠中均未显著改变体重，尽管它延迟了撤掉艾塞那肽后的体重增加。这一发现可能提示DPP-4抑制剂在体重增加期间减轻体重方面的效用。
