Glucagon-like Peptide-1Protects Against Diabetic Cardiomyopathy By Inactivating The Endoplasmic Reticulum Stress Pathway

Objective:To establish the diabetic cardiomyopathy (DCM) rat model, investigate theprotective effects of GLP-1analog liraglutide (LIRA) on the heart of DCM rats,explain the mechanism between DCM and endoplasmic reticulum stress (ERS), andprovide a new method for the treatment of DCM.Methods:120female Wistar rats were feed with high sugar and fat diet for4weeks, fromthe fifth week, intraperitoneal injection of30mg/kg streptozotocin (STZ) forcontinuous2weeks and maintained high sugar and fat diet for another20weeks. At24weeks,10rats were killed to identify the DCM model. Then100DCM rats wererandomly divided into five groups (n=20): the DCM control group, high dose of LIRAgroup (500μg/kg), medium dose of LIRA group (100μg/kg), low dose of LIRAgroup (50μg/kg) and Insulin group （glargin,3.2IU/kg）, in addition to this,20normal rats were used as the control group.2months after treatment, all animals wereperformed echocardiographic test, then animals were killed and blood was collectedto determine the concentration of fasting blood glucose (FBG), fasting insulin (FINS)and total cholesterol (TC); the heart was removed and stored in liquid nitrogen toperform HE staining, Masson trichrome staining and TUNEL staining; at the sametime, heart tissues were also used to detect the expression of ER related to factors,such as GRP78, CHOP, caspase-12, caspase-3ATF4, TRAF2and XBP1.Results:Combination of high sugar and fat diet and STZ could induce the DCM ratmodel successfully. Intravenous injection of LIRA into rats could improve the diabeticcardiomyopathy through detection of FBG, FINS and TC. Meanwhile, theechocardiography also showed that LIRA could improve the cardiac systolic functionand diastolic function in rats; HE staining, Masson trichrome staining and TUNELstaining also proved that LIRA could improve cardiomyopathy. Compared to DCM group, the expression of GRP78, CHOP, caspase-12, caspase-3ATF4, TRAF2andXBP1were significantly decreased in LIRA group, which suggested that LIRA couldinhibit the ERS to play the role of protecting the heart.Conclusion:The cardiomyocyte apoptosis was mediated by ERS in DCM; GLP-1couldprotect heart from cardiomyocyte apoptosis. Our study provided a new method fortreating DCM, which has great clinical significance.