Preferential effect of Montelukast on Dapagliflozin: Modulation of IRS-1/AKT/GLUT4 and ER stress response elements improves insulin sensitivity in soleus muscle of a type-2 diabetic rat model

Abstract

AimsMontelukast (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. Main methodsTo 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. Key findingsTreatment 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. SignificanceImproved 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.