Diet-induced glucose intolerance in mice with decreased β-cell ATP-sensitive K+ channels
Diet-induced glucose intolerance in mice with decreased β-cell ATP-sensitive K+ channels
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DOI：
10.2337/diabetes.53.12.3159
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发表时间：
2004-12-01
期刊：
影响因子：
7.7
通讯作者：
Nichols, CG
中科院分区：
文献类型：
--
作者：
Remedi, MS;Koster, JC;Nichols, CG
ATP敏感性K+通道（K-ATP通道）控制β细胞中的电活动，因此是兴奋-分泌偶联的关键参与者。在转基因（AAA）小鼠中β-细胞K-ATP通道的部分抑制导致胰岛素分泌过多和葡萄糖耐受性增强，而在Kir6.2敲除（KO）小鼠中这些通道的完全抑制导致过度兴奋，但轻度葡萄糖耐受不良。为了测试过度兴奋和饮食应激的相互作用，我们将AAA和KO小鼠置于高脂肪饮食中。在饮食3个月后，AAA和KO小鼠都转化为分泌不足和明显的葡萄糖不耐受表型。尽管Kir6.2在多种组织中表达，但其在AAA和KO小鼠中的主要功能结果是增强的β细胞电活性。我们的研究结果提供了证据，当与饮食压力相结合时，这种过度兴奋是糖尿病的一个致病因素。我们提出了一个“倒U”模型的反应增强β细胞的兴奋性：预期的初始分泌过多可以进展到分泌不足。和葡萄糖不耐受，无论是自发的还是对饮食压力的反应。
ATP-sensitive K+ channels (K-ATP channels) control electrical activity in beta-cells and therefore are key players in excitation-secretion coupling. Partial suppression of beta-cell K-ATP channels in transgenic (AAA) mice causes hypersecretion of insulin and enhanced glucose tolerance, whereas complete suppression of these channels in Kir6.2 knockout (KO) mice leads to hyperexcitability, but mild glucose intolerance. To test the interplay of hyperexcitability and dietary stress, we subjected AAA and KO mice to a high-fat diet. After 3 months on the diet, both AAA and KO mice converted to an under-secreting and markedly glucose-intolerant phenotype. Although Kir6.2 is expressed in multiple tissues, its primary functional consequence in both AAA and KO mice is enhanced beta-cell electrical activity. The results of our study provide evidence that, when combined with dietary stress, this hyperexcitability is a causal diabetic factor. We propose an "inverse U" model for the response to enhanced beta-cell excitability: the expected initial hypersecretion can progress to undersecretion. and glucose-intolerance, either spontaneously or in response to dietary stress.