The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity
The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity
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DOI：
10.1073/pnas.0308450100
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发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Desir, GV
中科院分区：
文献类型：
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作者：
Xu, JC;Wang, PL;Desir, GV
Kv1.3是在许多组织中表达的电压门控钾(K)通道，包括脂肪和骨骼肌。通道抑制改善实验性自身免疫性脑炎，部分是通过降低外周血T淋巴细胞的IL-2和肿瘤坏死因子的产生。基因失活导致暴露在高脂肪饮食中的小鼠（Kv1.3-/-）体重增加较少，肥胖程度低于对照组。有趣的是，尽管高热量饮食的Kv1.3-/-小鼠体重增加，但它们仍处于血糖正常状态，血液胰岛素水平较低。这一观察结果促使我们研究Kv1.3基因失活和抑制对外周葡萄糖稳态和胰岛素敏感性的影响。本研究表明，Kv1.3基因缺失和通道抑制增加了体内外周胰岛素敏感性。Kv1.3-/-小鼠脂肪组织和骨骼肌的基线和胰岛素刺激的葡萄糖摄取增加。抑制Kv1.3活性有助于葡萄糖转运蛋白GLUT4向质膜的易位。抑制脂肪和骨骼肌c-JUN末端激酶活性，降低脂肪组织分泌IL-6和肿瘤坏死因子。我们得出结论，Kv1.3抑制通过增加质膜上GLUT4的量来改善胰岛素敏感性。这些结果确定了K通道调节外周葡萄糖稳态的途径，并确定了Kv1.3作为治疗糖尿病的药理学靶点。
Kv1.3 is a voltage-gated potassium (K) channel expressed in a number of tissues, including fat and skeletal muscle. Channel inhibition improves experimental autoimmune encephalitis, in part by reducing IL-2 and tumor necrosis factor production by peripheral T lymphocytes. Gene inactivation causes mice (Kv1.3-/-) exposed to a high-fat diet to gain less weight and be less obese than littermate control. Interestingly, although Kv1.3-/- mice on the high-calorie diet gain weight, they remain euglycemic, with low blood insulin levels. This observation prompted us to examine the effect of Kv1.3 gene inactivation and inhibition on peripheral glucose homeostasis and insulin sensitivity. Here we show that Kv1.3 gene deletion and channel inhibition increase peripheral insulin sensitivity in vivo. Baseline and insulin-stimulated glucose uptake are increased in adipose tissue and skeletal muscle of Kv1.3-/- mice. Inhibition of Kv1.3 activity facilitates the translocation of the glucose transporter, GLUT4, to the plasma membrane. It also suppresses c-JUN terminal kinase activity in fat and skeletal muscle and decreases IL-6 and tumor necrosis factor secretion by adipose tissue. We conclude that Kv1.3 inhibition improves insulin sensitivity by increasing the amount of GLUT4 at the plasma membrane. These results pinpoint a pathway through which K channels regulate peripheral glucose homeostasis, and identify Kv1.3 as a pharmacologic target for the treatment of diabetes.