Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目标：孟鲁司特（MNK），白三烯受体拮抗剂，已证明其抗氧化/抗炎能力，可预防糖尿病引起的并发症并增强二甲双胍的抗糖尿病作用。然而，在此,我们利用2型糖尿病(T2D)/胰岛素抵抗(IR)大鼠的比目鱼肌,评估了内质网(ER)应激和胰岛素信号级联在MNK和/或达格列净(DAPA)作用中的作用.
方法：诱导T2D/IR，给大鼠喂食西化饮食（WD）8周，然后用亚糖尿病剂量的链脲佐菌素（STZ）。动物分为对照组（接受正常饮食；ND），糖尿病未经治疗，糖尿病患者用DAPA治疗4周，MNK,或其组合（DAPA+MNK）。测定血糖和血脂，对比目鱼肌进行内质网应激诱导的IR测试,除了组织病理学检查.
结果：DAPA治疗，MNK,尤其是它们的组合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血脂状况。这是通过激活胰岛素信号IRS-1/AKT/GLUT4途径在比目鱼肌中，由于内质网应激反应元件的失活，即IRE1α，ATF6和PERK抑制p-JNK和p-eIF2α。
结论：与DAPA相比，改善的胰岛素信号以及MNK引起的内质网应激反应的失活是比目鱼肌胰岛素敏感性增强的部分原因。提名MNK作为DAPA的附加剂，以增强其抗糖尿病功效。
方法：诱导T2D/IR，给大鼠喂食西化饮食（WD）8周，然后用亚糖尿病剂量的链脲佐菌素（STZ）。动物分为对照组（接受正常饮食；ND），糖尿病未经治疗，糖尿病患者用DAPA治疗4周，MNK,或其组合（DAPA+MNK）。测定血糖和血脂，对比目鱼肌进行内质网应激诱导的IR测试,除了组织病理学检查.
结果：DAPA治疗，MNK,尤其是它们的组合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血脂状况。这是通过激活胰岛素信号IRS-1/AKT/GLUT4途径在比目鱼肌中，由于内质网应激反应元件的失活，即IRE1α，ATF6和PERK抑制p-JNK和p-eIF2α。
结论：与DAPA相比，改善的胰岛素信号以及MNK引起的内质网应激反应的失活是比目鱼肌胰岛素敏感性增强的部分原因。提名MNK作为DAPA的附加剂，以增强其抗糖尿病功效。
