Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt.
Life Sci. 2022 Oct 15;307:120865. doi: 10.1016/j.lfs.2022.120865. Epub 2022 Aug 5.
Montelukast (MNK), a leukotriene receptor antagonist, has proven its antioxidant/anti-inflammatory capacity to guard against diabetes-induced complications and to enhance metformin antidiabetic effect. Nevertheless, here we evaluated the involvement of endoplasmic reticulum (ER) stress and insulin signaling cascade in the effect of MNK and/or dapagliflozin (DAPA) using the soleus muscle of type 2 diabetic (T2D)/insulin resistant (IR) rats.
To induce T2D/IR, rats were fed a westernized diet (WD) for 8 weeks followed by a sub-diabetogenic dose of streptozotocin (STZ). Animals were divided into control (receiving normal diet; ND), diabetic untreated, and diabetic treated for 4 weeks with DAPA, MNK, or their combination (DAPA+MNK). Blood glucose and serum lipid profile were determined, and the soleus muscle was tested for ER stress-induced IR, besides histopathological examination.
Treatment with DAPA, MNK, and especially their combination decreased the fasting plasma levels of glucose and insulin while improving insulin sensitivity and lipid profile. This was achieved via the activation of insulin signaling IRS-1/AKT/GLUT4 pathway in the soleus muscle consequent to the deactivation of the ER stress response elements, namely IRE1α, ATF6, and PERK to suppress p-JNK and p-eIF2α.
Improved insulin signaling along with the deactivation of the ER stress response by MNK comparable to the DAPA are partly responsible for the enhanced soleus muscle insulin sensitivity, effects that nominate MNK as an add-on to DAPA to enhance its antidiabetic efficacy.
孟鲁司特（MNK）是一种白三烯受体拮抗剂，已被证明具有抗氧化/抗炎能力，可预防糖尿病引起的并发症，并增强二甲双胍的降血糖作用。然而，在这里，我们使用 2 型糖尿病（T2D）/胰岛素抵抗（IR）大鼠的比目鱼肌来评估 ER 应激和胰岛素信号级联在 MNK 和/或达格列净（DAPA）作用中的参与。
为了诱导 T2D/IR，大鼠用西式饮食（WD）喂养 8 周，然后用亚致糖尿病剂量的链脲佐菌素（STZ）处理。动物分为对照组（接受正常饮食；ND）、糖尿病未治疗组和糖尿病治疗组，分别用 DAPA、MNK 或两者联合（DAPA+MNK）治疗 4 周。测定血糖和血清脂质谱，检测比目鱼肌 ER 应激诱导的胰岛素抵抗，同时进行组织病理学检查。
DAPA、MNK 治疗，尤其是两者联合治疗，降低了空腹血浆葡萄糖和胰岛素水平，同时改善了胰岛素敏感性和脂质谱。这是通过在比目鱼肌中激活胰岛素信号 IRS-1/AKT/GLUT4 途径来实现的，该途径导致 ER 应激反应元件，即 IRE1α、ATF6 和 PERK 的失活，从而抑制 p-JNK 和 p-eIF2α。
MNK 可与 DAPA 一样，通过激活胰岛素信号和失活 ER 应激反应，改善胰岛素敏感性，这部分解释了 MNK 增强比目鱼肌胰岛素敏感性的作用，这些作用使 MNK 成为 DAPA 的附加物，以增强其抗糖尿病疗效。
