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首页> 外文期刊>Endocrinology, Diabetes & Metabolism >Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor
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Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor

机译：肝素通过抑制胰岛素与胰岛素受体的结合而损害骨骼肌葡萄糖摄取

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Aim Heparin, a widely used antithrombotic drug has many other anticoagulant-independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an approach for developing heparin-targeted therapies for diabetes. Methods For serum heparin levels and correlation analysis, 122 volunteer’s plasma, DIO (4?weeks HFD) and db/db mice serums were collected and used for spectrophotometric determination. OGTT, ITT, 2-NBDG uptake and muscle GLUT4 immunofluorescence were detected in chronic intraperitoneal injection of heparin or heparinase (16?days) and muscle-specific loss-of-function mice. In 293T cells, the binding of insulin to its receptor was detected by fluorescence resonance energy transfer (FRET), Myc-GLUT4-mCherry plasmid was used in GLUT4 translocation. In vitro, C2C12 cells as mouse myoblast cells were further verified the effects of heparin on glucose homeostasis through 2-NBDG uptake, Western blot and co-immunoprecipitation. Results Serum concentrations of heparin are positively associated with blood glucose levels in humans and are significantly increased in diet-induced and db/db obesity mouse models. Consistently, a chronic intraperitoneal injection of heparin results in hyperglycaemia, glucose intolerance and insulin resistance. These effects are independent of heparin’s anticoagulant function and associated with decreases in glucose uptake and translocation of glucose transporter type 4 (GLUT4) in skeletal muscle. By using a muscle-specific loss-of-function mouse model, we further demonstrated that muscle GLUT4 is required for the detrimental effects of heparin on glucose homeostasis. Conclusions Heparin reduced insulin binding to its receptor by interacting with insulin and inhibited insulin-mediated activation of the PI3K/Akt signalling pathway in skeletal muscle, which leads to impaired glucose uptake and hyperglycaemia.
机译：AIM肝素，一种广泛使用的抗血栓形成药物具有许多其他抗凝血性无关的生理功能。在这里，我们阐明肝素在葡萄糖稳态中的新作用，这表明一种用于患肝素针对糖尿病患者的方法。收集血清肝素水平和相关分析，122型志愿者等离子体，DIO（4？TOPE HFD）和DB / DB小鼠血清，用于分光光度法测定。在慢性腹膜内注射肝素或肝素酶（16？天）和肌肉特异性失去功能小鼠中，检测到OGTT，ITT，2-NBDG摄取和肌肉无荧光。在293T的细胞中，通过荧光共振能量转移（FRET）检测胰岛素对其受体的结合，MyC-Glut4-MCHerry质粒用于Glut4易位。在体外，作为小鼠肌细胞细胞的C2C12细胞进一步验证了肝素对葡萄糖稳态的影响通过2-NBDG吸收，Western印迹和共免疫沉淀。结果肝素的血清浓度与人体血糖水平正相关，饮食诱导和DB / DB肥胖小鼠模型中显着增加。一致地，慢性腹膜内注射肝素，导致高血糖，葡萄糖不耐受和胰岛素抵抗力。这些效果与肝素的抗凝血功能无关，并且随着葡萄糖输送剂4（Glut4）的葡萄糖摄取和易位的降低相关。通过使用肌肉特异性函数鼠标模型，我们进一步证明了肝素对肝素对葡萄糖稳态的不利影响所必需的。结论肝素通过与胰岛素相互作用和抑制胰岛素介导的骨骼肌抑制胰岛素介导的激活，肝素对其受体结合的胰岛素结合，导致葡萄糖摄取和高血糖受损。

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