Liraglutide透過減少糖尿病心肌病變中脂滴堆積、並緩解心肌纖維化的保護作用

糖尿病心肌病變（Diabetic Cardiomyopathy, DbCM）是一種發生於第二型糖尿病（Type 2 diabetes, T2D）患者的特異性心肌病變，由於胰島素阻抗以及血糖和血脂代謝失衡所致，會引起心肌結構與功能的改變。這種併發症常在心血管疾病的典型症狀出現之前便已潛伏存在，對心臟功能的影響不容忽視。DbCM 的發病機制主要與糖脂毒性引起的胰島素阻抗有關，進一步導致心肌細胞內脂質過度積累，加劇氧化壓力與炎症反應，並促進心肌纖維化的發生，最終可能導致心力衰竭。此外，長期高血糖狀態還會通過糖脂毒性與高血壓的共同作用，引發心肌細胞的鈣離子平衡異常及粒線體功能障礙，進一步加重心臟負荷，形成心肌纖維化並引發心臟衰竭。目前約有五分之一的 T2D 患者最終發展為心力衰竭，這是造成患者失能與死亡的重要原因。雖然左心室射血分率（left ventricular ejection fraction, LVEF）常用於評估心臟功能，但對於保留射血分率的心臟衰竭（heart failure with preserved ejection fraction, HFpEF）患者，LVEF 指標大致正常，容易導致早期診斷不足或延誤，且目前缺乏有效的治療方法。因此，提高 HFpEF 的辨識率以及探索其病理機轉，是臨床診療的重要課題。研究指出，GLP-1受體促效劑（Glucagon-like peptide-1 receptor agonists , GLP-1RA）具有心血管保護作用，包括減少炎症反應與氧化壓力，並可能改善 DbCM。然而，其具體作用機制尚不完全明確，這為未來的研究提供了方向。本研究設計了體內與體外實驗，通過在分化後的 H9c2 心肌細胞中模擬糖脂毒性環境，觀察 Liraglutide 對胰島素訊息傳遞、粒線體功能及抗氧化基因表現的影響。同時，利用高脂飲食誘導的糖尿病小鼠模型，評估 Liraglutide 對心肌纖維化、炎症及脂滴(Lipid Droplets, LDs)堆積的改善效果。此外，我們使用非侵入式血流動力學監測技術（Osypka ICON），分析 T2D 患者的血流動力學參數，發現其心血管狀況與正常人群存在顯著差異，並辨識出可能為糖尿病心肌病變高風險群的患者。本研究結果證實 Liraglutide 在治療 DbCM 上的潛在價值，並為 HFpEF 的早期診斷提供了新的視角，期望未來能為糖尿病相關心臟疾病的臨床診療提供更多依據和創新思路。

Diabetic cardiomyopathy (DbCM) is a specific cardiac complication occurring in patients with type 2 diabetes (T2D), caused by insulin resistance and imbalances in glucose and lipid metabolism. This condition leads to structural and functional changes in the myocardium, often existing silently before the appearance of typical cardiovascular symptoms, yet having significant impacts on cardiac function. The pathogenesis of DbCM is primarily linked to glucolipotoxicity-induced insulin resistance, which results in excessive lipid accumulation in cardiomyocytes, exacerbates oxidative stress and inflammatory responses, and promotes myocardial fibrosis. Over time, these changes impair the heart's systolic and diastolic functions, eventually leading to heart failure. Additionally, chronic hyperglycemia, through the combined effects of glucolipotoxicity and hypertension, causes calcium homeostasis disruption and mitochondrial dysfunction in cardiomyocytes, further increasing cardiac load, inducing fibrosis, and progressing to heart failure.Currently, approximately one-fifth of T2D patients eventually develop heart failure, a major cause of disability and mortality. Although left ventricular ejection fraction (LVEF) is a commonly used parameter for assessing cardiac function, it fails to identify heart failure with preserved ejection fraction (HFpEF), where LVEF remains largely normal. This limitation often leads to underdiagnosis or delayed diagnosis of HFpEF, which lacks effective therapeutic options. Therefore, improving HFpEF identification rates and understanding its pathological mechanisms are critical to advancing clinical management.Studies have suggested that GLP-1 receptor agonists (GLP-1RA) exhibit cardioprotective effects, including reducing inflammation and oxidative stress, and may improve DbCM. However, the precise mechanisms of action remain unclear, presenting an important area for further investigation. This study employed both in vitro and in vivo models to explore these effects. Differentiated H9c2 cardiomyocytes were exposed to a glucolipotoxic environment to evaluate the impact of liraglutide on insulin signaling, mitochondrial function, and the expression of antioxidant genes. Simultaneously, a high-fat diet-induced diabetic mouse model (db/db) was used to assess liraglutide's effects on myocardial fibrosis, inflammation, and lipid droplet accumulation.Additionally, non-invasive hemodynamic monitoring technology (Osypka ICON) was used to analyze the hemodynamic parameters of T2D patients, revealing significant differences in cardiovascular conditions compared to non-T2D controls. A subgroup of patients with suboptimal cardiac output (ICON <30) but largely normal ventricular contractility (as indicated by STR and PEP values) was identified, potentially representing a high-risk group for diabetic cardiomyopathy. The results of this study confirm the potential of liraglutide in treating DbCM and provide new insights into the early diagnosis of HFpEF. These findings hold promise for offering innovative perspectives and clinical approaches to managing diabetes-associated cardiac diseases.