艾塞那肽治疗对高脂饮食和低剂量链脲佐菌素诱导的糖尿病大鼠骨骼肌胰岛素抵抗的影响。
Effects of exenatide therapy on insulin resistance in the skeletal muscles of high-fat diet and low-dose streptozotocin-induced diabetic rats.
作者信息
Wu Hui, Sui Chunhua, Xia Fangzhen, Zhai Hualing, Zhang Huixin, Xu Hui, Weng Pan, Lu Yingli
机构信息
a Department of Endocrinology , Zhejiang Provincial People's Hospital , Hangzhou , P.R. China and.
b Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital Affiliated Shanghai Jiaotong University School of Medicine , Shanghai , P.R. China.
出版信息
Endocr Res. 2016;41(1):1-7. doi: 10.3109/07435800.2015.1015726. Epub 2015 Sep 11.
PURPOSE
The glucagon-like peptide (GLP)-1 agonist exenatide shows the same multiple effects on glucose homeostasis as native GLP-1, which can reduce blood glucose levels in individuals with type-2 diabetes mellitus (T2DM). However, its underlying action mechanism on glucose metabolism in the skeletal muscle of T2DM cases is unknown. We investigated the effects and action mechanisms of exenatide on insulin resistance (IR) in the skeletal muscle of high-fat diet and low-dose streptozotocin-induced T2DM rats.
METHODS
Four groups of Sprague-Dawley rats were studied: non-T2DM (control, C); non-T2DM + exenatide (C + E); T2DM (D); and T2DM + exenatide (D + E). After eight weeks, isotope-tracer methodology was applied to measure the total rate of appearance (Ra) of glucose and glucose infusion rate (GIR) using a hyperinsulinemic-euglycemic clamp with 3-(3)H-glucose infusion. Glucose uptake in gastrocnemius muscles was determined by measuring 2-deoxy-D-(14)C-glucose radioactivity. Simultaneously, ultrastructural changes in the cells of gastrocnemius muscles were studied.
RESULTS
In the D + E group, body weight and levels of fasting plasma glucose, triglyceride, total cholesterol, low-density lipoprotein and insulin were decreased significantly (p < 0.01) compared with the D group. The Ra of glucose (94.70 ± 13.46 versus 121.07 ± 16.55 μmol/kg/min) was decreased (p < 0.01), whereas the exogenous GIR (144.68 ± 11.03 versus 114.50 ± 9.40 μmol/kg/min) and glucose uptake in muscle (0.24 ± 0.02 versus 0.17 ± 0.02 μmol/g/min) were increased markedly (p < 0.01). Ultrastructural observations revealed that exenatide attenuated the effect of swollen mitochondrial and endoplasmic reticulum within the cells of the skeletal muscle of T2DM rats.
CONCLUSIONS
These data suggest that exenatide can significantly improve insulin sensitivity in skeletal muscle by increasing glucose uptake in T2DM rats.
目的
胰高血糖素样肽（GLP）-1激动剂艾塞那肽对葡萄糖稳态具有与天然GLP-1相同的多种作用，可降低2型糖尿病（T2DM）患者的血糖水平。然而，其对T2DM患者骨骼肌葡萄糖代谢的潜在作用机制尚不清楚。我们研究了艾塞那肽对高脂饮食和低剂量链脲佐菌素诱导的T2DM大鼠骨骼肌胰岛素抵抗（IR）的影响及作用机制。
方法
研究了四组Sprague-Dawley大鼠：非T2DM（对照组，C）；非T2DM + 艾塞那肽（C + E）；T2DM（D）；以及T2DM + 艾塞那肽（D + E）。八周后，采用同位素示踪法，通过用3-(3)H-葡萄糖输注的高胰岛素-正常血糖钳夹技术测量葡萄糖的总出现率（Ra）和葡萄糖输注率（GIR）。通过测量2-脱氧-D-(14)C-葡萄糖放射性来测定腓肠肌中的葡萄糖摄取。同时，研究了腓肠肌细胞的超微结构变化。
结果
与D组相比，D + E组的体重、空腹血糖、甘油三酯、总胆固醇、低密度脂蛋白和胰岛素水平均显著降低（p < 0.01）。葡萄糖的Ra（94.70 ± 13.46对121.07 ± 16.55 μmol/kg/min）降低（p < 0.01），而外源性GIR（144.68 ± 11.03对114.50 ± 9.40 μmol/kg/min）和肌肉中的葡萄糖摄取（0.24 ± 0.02对0.17 ± 0.02 μmol/g/min）显著增加（p < 0.01）。超微结构观察显示艾塞那肽减弱了T2DM大鼠骨骼肌细胞内线粒体和内质网肿胀的影响。
结论
这些数据表明，艾塞那肽可通过增加T2DM大鼠的葡萄糖摄取来显著改善骨骼肌的胰岛素敏感性。
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