Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
Department of Burns and Orthopedics, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China.
Mol Med Rep. 2018 Aug;18(2):2449-2457. doi: 10.3892/mmr.2018.9180. Epub 2018 Jun 18.
Liraglutide is a type of glucagon‑like‑peptide 1 receptor agonist, which has been reported as a novel type of antidiabetic agent with numerous benefits, including cardiovascular and neuroprotective effects. To the best of our knowledge, few studies to date have reported the potential mechanism underlying the neuroprotective effects of liraglutide on rats with type 2 diabetes mellitus (T2DM). The present study aimed to investigate the neuroprotective actions of liraglutide in diabetic rats and to determine the mechanisms underlying these effects. A total of 30 male T2DM Goto‑Kakizaki (GK) rats (age, 32 weeks; weight, 300‑350 g) and 10 male Wistar rats (age, 32 weeks; weight, 300‑350 g) were used in the present study. Wistar rats received vehicle treatment, and GK rats randomly received treatment with vehicle, low dose of liraglutide (75 µg/kg) or high dose of liraglutide (200 µg/kg) for 28 days. Cognitive deficits were evaluated using the Morris water maze test. The expression levels of phosphoinositide 3‑kinase (PI3K), protein kinase B (Akt), phosphorylated (p)‑Akt, AMP‑activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Beclin‑1, microtubule‑associated protein light chain 3 (LC)‑3 II, caspase‑3, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein and Bcl‑2 were assessed by western blot analysis. The results demonstrated that diabetic GK rats exhibited cognitive dysfunction, whereas treatment with liraglutide alleviated the learning and memory deficits, particularly in the high‑dose liraglutide group. The expression levels of Beclin‑1 and LC‑3 II were decreased in GK rats; however, this decrease was alleviated in the presence of liraglutide. Liraglutide also reversed T2DM model‑induced increases in mTOR, and decreases in p‑AMPK, PI3K and p‑Akt expression, and modulated the expression of apoptosis‑associated proteins. Furthermore, the administration of liraglutide inhibited apoptosis and exerted a protective effect against cognitive deficits via the activation of autophagy. In conclusion, the protective effects of liraglutide may be associated with increased mTOR expression via activation of the AMPK and PI3K/Akt signaling pathways.
利拉鲁肽是一种胰高血糖素样肽-1 受体激动剂，已被报道为一种新型的抗糖尿病药物，具有许多益处，包括心血管和神经保护作用。据我们所知，目前为止，很少有研究报道利拉鲁肽对 2 型糖尿病大鼠的神经保护作用的潜在机制。本研究旨在探讨利拉鲁肽对糖尿病大鼠的神经保护作用，并确定其作用机制。本研究共使用 30 只雄性 2 型糖尿病 Goto-Kakizaki（GK）大鼠（年龄 32 周；体重 300-350g）和 10 只雄性 Wistar 大鼠（年龄 32 周；体重 300-350g）。Wistar 大鼠给予载体处理，GK 大鼠随机给予载体、低剂量利拉鲁肽（75μg/kg）或高剂量利拉鲁肽（200μg/kg）治疗 28 天。采用 Morris 水迷宫试验评估认知功能障碍。通过 Western blot 分析评估磷酸肌醇 3-激酶（PI3K）、蛋白激酶 B（Akt）、磷酸化（p）-Akt、AMP 激活的蛋白激酶（AMPK）、哺乳动物雷帕霉素靶蛋白（mTOR）、Beclin-1、微管相关蛋白轻链 3（LC）-3 II、半胱天冬酶-3、B 细胞淋巴瘤 2（Bcl-2）相关 X 蛋白和 Bcl-2 的表达水平。结果表明，糖尿病 GK 大鼠表现出认知功能障碍，而利拉鲁肽治疗可减轻学习和记忆障碍，特别是在高剂量利拉鲁肽组。GK 大鼠 Beclin-1 和 LC-3 II 的表达水平降低，但利拉鲁肽的存在减轻了这种降低。利拉鲁肽还逆转了 T2DM 模型诱导的 mTOR 增加以及 p-AMPK、PI3K 和 p-Akt 表达的降低，并调节了凋亡相关蛋白的表达。此外，利拉鲁肽通过激活自噬抑制细胞凋亡并发挥对认知功能障碍的保护作用。综上所述，利拉鲁肽的保护作用可能与通过激活 AMPK 和 PI3K/Akt 信号通路增加 mTOR 表达有关。
