Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction
Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction
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DOI：
10.1093/eurheartj/ehp396
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发表时间：
2010-01-01
影响因子：
39.3
通讯作者：
Camici, Paolo G.
中科院分区：
文献类型：
--
作者：
Cook, Stuart A.;Varela-Carver, Anabel;Camici, Paolo G.
目的 全身和心肌胰岛素抵抗是非胰岛素依赖型糖尿病 (NIDDM) 和左心室功能障碍 (LVD) 的特征。我们确定了胰岛素受体底物 1 (IRS1)、IRS1 相关 PI3K (IRS1-PI3K) 和葡萄糖转运蛋白 4 (GLUT4) 的异常是否会导致组织特异性胰岛素抵抗。 方法和结果 我们从对照患者 (n = 7)、NIDDM 患者 (n = 9) 和 LVD 患者 (n = 9) 中收集了骨骼肌 (n = 27) 和心肌活检 (n = 24)。 8），通过正常血糖-高胰岛素钳夹和正电子发射断层扫描来表征。在三种小鼠模型中进行了比较研究。我们证明了 LVD 患者骨骼肌中 IRS1 的降低未被识别，而 NIDDM 和 LVD 患者心脏 IRS1-PI3K 活性意外增加。在 NIDDM 中，肌膜 GLUT4 随之减少，而在 LVD 患者中，肌膜 GLUT4 增加。我们证实了胰岛素抵抗 ob/ob 小鼠心脏中 IRS1-PI3K 的激活和肌膜 GLUT4 的减少，同时我们还证明了 GLUT4 对接和融合的扰动。在心脏中表达激活的 PI3K 的小鼠中证明了 PI3K 和 GLUT4 之间的直接关系，并且在 LVD 小鼠模型中证实了肌膜处 GLUT4 的增加。结论我们的数据表明 NIDDM 和 LVD 之间的心肌胰岛素抵抗机制不同。
Aims Whole body and myocardial insulin resistance are features of non-insulin-dependent diabetes mellitus (NIDDM) and left-ventricular dysfunction (LVD). We determined whether abnormalities of insulin receptor substrate-1 (IRS1), IRS1-associated PI3K (IRS1-PI3K), and glucose transporter 4 (GLUT4) contribute to tissue-specific insulin resistance.Methods and results We collected skeletal muscle (n = 27) and myocardial biopsies (n = 24) from control patients (n = 7), patients with NIDDM (n = 9) and patients with LVD (n = 8), who were characterized by euglycaemic-hyperinsulinaemic clamp and positron emission tomography. Comparative studies were carried out in three mouse models. We demonstrate an unrecognized reduction of IRS1 in skeletal muscle of LVD patients and an unexpected increase in cardiac IRS1-PI3K activity in NIDDM and LVD patients. In NIDDM, there was a concomitant reduction in sarcolemmal GLUT4, whereas in patients with LVD sarcolemmal GLUT4 was increased. We confirm activation of IRS1-PI3K and reduction in sarcolemmal GLUT4 in the insulin resistant ob/ob mouse heart where we also demonstrate perturbation of GLUT4 docking and fusion. A direct relationship between PI3K and GLUT4 was demonstrated in mice expressing activated PI3K in the heart and increased GLUT4 at the sarcolemma was confirmed in a mouse model of LVD.Conclusion Our data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.