褪黑激素對第二型糖尿病合併非酒精性脂肪肝之作用機轉

非酒精性脂肪肝病（nonalcoholic fatty liver disease, NAFLD）是現今最常見的慢性肝病形式之一，全球盛行率持續攀升，已成為代謝性疾病領域的關注焦點。第二型糖尿病（type 2 diabetes mellitus, T2DM）同樣為全球性流行的代謝異常疾病，與NAFLD在病理及生理機轉上具有高度重疊性，尤其在胰島素阻抗、脂質毒性與慢性低度發炎反應方面。當T2DM與NAFLD合併存在時，兩者之間會形成惡性循環，導致代謝失衡更加嚴重，加速肝臟病變進程，並增加心血管疾病、肝纖維化與肝癌等併發症的發生風險。 近年研究發現，褪黑激素（melatonin, MT）除了其調節晝夜節律的傳統角色外，亦具有抗氧化、抗發炎、調控脂質與葡萄糖代謝等多重生理功能，在代謝性疾病之防治上展現潛在的應用價值。本研究即以探討MT對T2DM合併NAFLD之病理狀態的調節機轉為核心目標，並結合細胞與動物雙模式實驗設計，進行全方位的機轉驗證與效應評估。 動物實驗部分，本研究使用C57BL/6-Apoeem1Narl/Narl基因剔除小鼠，透過鏈脲佐菌素（streptozotocin, STZ）腹腔注射與高脂飲食（high-fat diet, HFD）聯合誘導，建立T2DM與NAFLD共病動物模型，並每日以管餵方式給予MT連續8週，後續進行血液生化檢測、肝組織病理評估與免疫組織化學分析。細胞實驗部分，則以Hep G2人類肝癌細胞為模型，使用高濃度葡萄糖（high glucose）與油酸（oleic acid）共同刺激誘導糖脂毒性環境，進行MT處理後，評估其對細胞活性、脂質堆積、粒線體膜電位與脂質/發炎相關蛋白表現的調節效應。 結果顯示，MT處理能有效改善實驗小鼠之體重與血糖狀態，降低血清總膽固醇與肝酵素指標（如GPT），同時明顯緩解肝臟脂肪堆積、發炎細胞浸潤程度。細胞實驗中亦觀察到，MT可減少脂肪油滴堆積，恢復粒線體功能，並減少脂肪生成與發炎反應相關蛋白（如SREBP-1、SREBP-2、FASN、HMGCR、NF-κB、NLRP3）之表現，同時促進脂肪酸氧化與能量代謝相關蛋白（如AMPK、PPARα、CPT1A）之活化。綜上所述，本研究證實MT可透過多重路徑機制，包括調節脂質代謝、抑制發炎反應及改善胰島素敏感性，有效緩解T2DM與NAFLD共病所造成之代謝異常，並具明確的肝臟保護效果。未來若能進一步結合臨床試驗驗證其療效，MT有望發展為代謝性共病症候群的潛在治療選項之一。

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, with a continuously increasing prevalence that has brought it to the forefront of metabolic disease research. Type 2 diabetes mellitus (T2DM), another widespread metabolic disorder, shares substantial pathophysiological overlap with NAFLD, particularly in terms of insulin resistance, lipotoxicity, and chronic low-grade inflammation. When these two diseases coexist, they interact in a deleterious cycle, exacerbating metabolic disturbances, accelerating liver damage, and elevating the risk of cardiovascular complications, hepatic fibrosis, and hepatocellular carcinoma. Melatonin (MT), traditionally known for regulating circadian rhythms, has recently been recognized for its antioxidant, anti-inflammatory, and metabolic regulatory roles, highlighting its potential in managing metabolic diseases. This study investigates the regulatory mechanisms by which MT mitigates the pathological features of T2DM with concurrent NAFLD, employing both in vivo and in vitro models. In vivo study demonstrated that C57BL/6-Apoeem1Narl/Narl mice were induced with T2DM-NAFLD using streptozotocin (STZ) and a high-fat diet (HFD), followed by daily oral administration of MT for eight weeks. In vitro study, HepG2 cells were subjected to high glucose and oleic acid to simulate a lipotoxic environment. Experimental evaluations revealed that MT improved hyperglycemia and body weight, reduced serum cholesterol and hepatic enzyme levels, and alleviated hepatic steatosis and inflammation. Furthermore, MT suppressed lipogenesis- and inflammation-related protein expression while promoting fatty acid oxidation and mitochondrial function. These results suggest that MT exerts protective effects against T2DM and NAFLD comorbidity by regulating lipid metabolism, suppressing inflammation, and enhancing insulin sensitivity through multiple molecular pathways. These findings support the potential of melatonin as a therapeutic candidate for metabolic comorbidities, pending further clinical validation.