Targeting metabolic dysregulations as a therapeutic strategy in diabetic cardiomyopathy

TMUIR > College of Biomedical Engineering > International Ph.D. Program in Biomedical Engineering > Thesis > Item 987654321/61332

Please use this identifier to cite or link to this item: http://libir.tmu.edu.tw/handle/987654321/61332

Title:	Targeting metabolic dysregulations as a therapeutic strategy in diabetic cardiomyopathy
Authors:	TRANG, NGUYEN NGOC
Contributors:	國際醫學研究博士學位學程陳亦仁
Keywords:	diabetic cardiomyopathy
Date:	2021-06-29
Issue Date:	2022-01-24 18:30:51 (UTC+8)
Abstract:	Diabetic cardiomyopathy, a major complication in diabetes mellitus (DM) patients, is defined as abnormal myocardial dysfunction without evidence of hypertension, myocardial ischemia, or valvular heart disease, and is associated with an increased incidence of heart failure (HF). However, the mechanism and functional consequences underlying the pathological effect of diabetic cardiomyopathy have yet to be completely elucidated. Altered cardiac metabolism, oxidative stress, inflammation, myocardial fibrosis, impaired calcium (Ca2+) handling, increased myocardial cell death, mitochondrial dysfunction were proposed to contribute to the pathogenesis of diabetic cardiomyopathy. In a diabetic heart, the amount of fatty acids taken up by the cardiomyocyte exceeds the metabolic demand that caused myocardial lipotoxicity, and increased stress on the endoplasmic reticulum (ER), mitochondrial dysfunction, and altered gene expression ultimately leading to an increased amount of reactive oxygen species causing cellular dysfunction and apoptosis. However, the optimal therapeutic strategy through medications and/or diet for diabetic cardiomyopathy remains limited. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new classes of anti-hyperglycemic medications that have significant cardiac impacts in clinical practice but the mechanisms by which SGLT2is and GLP-1RAs improve cardiovascular outcomes are not fully understood. The ketogenic diet (KD) is a special type of high-fat and low-carbohydrate diet that has beneficial effects on patients with DM and metabolic syndrome. However, it is not clear whether KD may modulate diabetic cardiomyopathy. Aims I. To investigate the effects of SGLT2is and/or GLP1-RAs on myocardial energy metabolism, cardiac function, inflammatory and apoptosis signaling in diabetic cardiomyopathy. II. To investigate the impacts of KD on cardiac protection and its underlying mechanism in diabetic hearts. Methods I. Biochemistry and echocardiograms were studied before and after treatment with empagliflozin (10 mg/kg/day, oral gavage), and/or liraglutide (200 μg/kg every 12 h, subcutaneously) for 4 weeks in male Wistar rats with streptozotocin (65 mg/kg intraperitoneally)-induced diabetes. Cardiac fibrosis, apoptosis, and protein expression of metabolic and inflammatory signaling molecules were evaluated by histopathology and Western blotting in ventricular cardiomyocytes of different groups. II. Echocardiograms, biochemistry, and micro-positron emission tomography were performed to evaluate cardiac function and glucose uptake in healthy control, or streptozotocin (65 mg/kg intraperitoneally)-induced DM with normal diet (ND) or ketogenic diet (KD) for 6 weeks in vivo. Histopathology, ATP measurement, and Western blot were used for in vitro analysis of myocardial fatty acid, ketone bodies, and glucose in ventricular preparations. Results and conclusions Empagliflozin modulated fatty acid and glucose metabolism, while liraglutide regulated inflammation and apoptosis in diabetic cardiomyopathy. The better effects of combined treatment may lead to a potential strategy in targeting diabetic cardiomyopathy. KD might improve cardiac function by decreasing fatty acid oxidation, downregulating ER stress, and inflammation in the DM heart. These findings suggested that targeting cardiac metabolic dysregulations in DM via SLGT2i, GLP-1RAs or KD may be a potential therapeutic strategy in diabetic cardiomyopathy.
Description:	博士指導教授：陳亦仁委員：陳耀昌委員：張世霖委員：林永國委員：李亭儀
Data Type:	thesis
Appears in Collections:	[International Ph.D. Program in Biomedical Engineering] Thesis

Files in This Item:

File	Description	Size	Format
index.html		0Kb	HTML	122	View/Open

View Licence

Loading...