Lin Cheng-Hsiu, Kuo Yueh-Hsiung, Shih Chun-Ching
Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare Fengyuan District Taichung City 42055 Taiwan
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University Taichung City 40402 Taiwan
RSC Adv. 2018 Jun 5;8(37):20462-20476. doi: 10.1039/c8ra01841c.
The study is designed to examine the potential effects and underlying mechanisms of eburicoic acid (TRR), a compound from , in streptozotocin (STZ)-induced diabetic mice. Diabetic mice were randomly divided into six groups and given TRR orally by gavage (at three dosage rates) or fenofibrate (Feno) (250 mg kg body weight) or metformin (Metf) (300 mg kg body weight) or vehicle for 2 weeks. STZ-induced diabetic mice were found to have increased blood glucose, HbA1, plasma triglyceride (TG) and total cholesterol (TC) levels, but reduced blood insulin, adiponectin, and leptin levels as compared with the CON group. TRR was found to lower blood glucose and HbA1, but increase insulin levels. Plasma TG and TC levels were significantly lowered in TRR, Feno, or Metf-treated STZ-induced diabetic mice as compared with the vehicle-treated STZ group, indicating that TRR, Feno, and Metf ameliorated hyperlipidemia. The islet cells of STZ-induced diabetic mice exhibited a marked reduction from their classic round-shape as compared to the CON mice. The TRR-treated STZ mice revealed restoration of the size of Langerhans islet cells with β-cell repair as compared with the vehicle-treated STZ mice, implying that TRR ameliorated STZ-induced diabetic states within the pancreas. STZ-induction was found to decrease the expressions of membrane glucose transporter 4 (GLUT4), and phosphorylation of Akt in skeletal muscles, and administration of TRR reversed all the decreases. Moreover, administration of TRR increased blood insulin levels and enhanced hepatic expression levels of phospho-Akt and phospho-FoxO1 but decreased the mRNA levels of glucose-6-phosphatase (G6 Pase) and phosphoenolpyruvate carboxykinase (PEPCK) to suppress hepatic glucose production, thus leading to TRR's antidiabetic activity. Additionally, TRR caused an increase in the expression levels of fatty acid oxidation gene peroxisome proliferator-activated receptor α (PPARα), but a decrease in lipogenic fatty acid synthase (FAS) and PPARγ expressions in the liver. TRR treatment suppressed hepatic mRNA levels of sterol regulatory element binding protein (SREBP) 1c and SREBP2, leading to decreased plasma triglyceride and total cholesterol levels. These findings indicate that TRR may effectively enhance therapeutic potential in the treatment of type 1 diabetes mellitus and/or hyperlipidemia.
本研究旨在探讨来源于[具体来源未给出]的化合物麦角硫因（TRR）对链脲佐菌素（STZ）诱导的糖尿病小鼠的潜在作用及潜在机制。将糖尿病小鼠随机分为六组，分别通过灌胃给予TRR（三种剂量率）、非诺贝特（Feno）（250 mg/kg体重）、二甲双胍（Metf）（300 mg/kg体重）或赋形剂，持续2周。与对照组相比，发现STZ诱导的糖尿病小鼠血糖、糖化血红蛋白（HbA1）、血浆甘油三酯（TG）和总胆固醇（TC）水平升高，但血液胰岛素、脂联素和瘦素水平降低。发现TRR可降低血糖和HbA1，但可提高胰岛素水平。与赋形剂处理的STZ组相比，TRR、Feno或Metf处理的STZ诱导的糖尿病小鼠血浆TG和TC水平显著降低，表明TRR、Feno和Metf改善了高脂血症。与对照组小鼠相比，STZ诱导的糖尿病小鼠的胰岛细胞从其经典的圆形明显减少。与赋形剂处理的STZ小鼠相比，TRR处理的STZ小鼠显示朗格汉斯胰岛细胞大小恢复且β细胞修复，这意味着TRR改善了胰腺内STZ诱导的糖尿病状态。发现STZ诱导降低了骨骼肌中膜葡萄糖转运蛋白4（GLUT4）的表达以及Akt的磷酸化，而给予TRR可逆转所有这些降低。此外，给予TRR可提高血液胰岛素水平，增强肝脏中磷酸化Akt和磷酸化FoxO1的表达水平，但降低葡萄糖-6-磷酸酶（G6 Pase）和磷酸烯醇丙酮酸羧激酶（PEPCK）的mRNA水平以抑制肝脏葡萄糖生成，从而导致TRR的抗糖尿病活性。此外，TRR导致肝脏中脂肪酸氧化基因过氧化物酶体增殖物激活受体α（PPARα）的表达水平增加，但脂肪生成脂肪酸合酶（FAS）和PPARγ的表达降低。TRR处理抑制了肝脏中固醇调节元件结合蛋白（SREBP）1c和SREBP2的mRNA水平，导致血浆甘油三酯和总胆固醇水平降低。这些发现表明TRR可能有效增强1型糖尿病和/或高脂血症治疗的潜在疗效。
