GLUCOSE SENSING IN PANCREATIC-ISLET BETA-CELLS - THE KEY ROLE OF GLUCOKINASE AND THE GLYCOLYTIC-INTERMEDIATES
GLUCOSE SENSING IN PANCREATIC-ISLET BETA-CELLS - THE KEY ROLE OF GLUCOKINASE AND THE GLYCOLYTIC-INTERMEDIATES
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DOI：
10.1073/pnas.90.5.1781
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发表时间：
1993-03-01
影响因子：
11.1
通讯作者：
GERMAN, MS
中科院分区：
文献类型：
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作者：
GERMAN, MS
胰岛的β细胞通过改变胰岛素合成和分泌的速率来响应葡萄糖浓度的变化。β细胞通过葡萄糖代谢产物的水平来感知葡萄糖浓度。独特的β细胞蛋白葡萄糖转运蛋白2和葡萄糖激酶催化β细胞葡萄糖催化剂的前两个步骤。为了测试任一种蛋白质是否通过控制葡萄糖催化剂的速率来控制β细胞对葡萄糖的敏感性，我们使用基因转移技术在β细胞中表达同工酶葡萄糖转运蛋白1和己糖激酶I，并测量胰岛素基因启动子对葡萄糖的反应。表达葡萄糖转运蛋白1的细胞与对照细胞没有显著差异，但在表达己糖激酶I的细胞中，胰岛素启动子活性增加，在1 mM葡萄糖时达到最大值，并且在生理范围内对葡萄糖浓度的变化没有反应。我们的结论是，葡萄糖激酶催化β细胞中葡萄糖催化剂的限速步骤，因此，作为葡萄糖传感器。丙酮酸是无氧糖酵解的终产物，在正常β细胞中很容易被线粒体氧化，但不能代替葡萄糖作为胰岛素合成和分泌的刺激物。我们发现，丙酮酸可以刺激细胞中的胰岛素启动子表达细菌的促细胞生成酶磷酸烯醇丙酮酸羧激酶，这使得丙酮酸转化为磷酸烯醇丙酮酸和糖酵解的早期中间体。我们得出结论，果糖1，6-二磷酸和磷酸烯醇丙酮酸之间的厌氧糖酵解的中间产物是必不可少的β细胞葡萄糖传感。
The beta cells of the pancreatic islets of Langerhans respond to changes in glucose concentration by varying the rate of insulin synthesis and secretion. Beta cells sense glucose concentration by the levels of the products of glucose catabolism. Distinctive beta-cell proteins glucose transporter 2 and glucokinase catalyze the first two steps in beta-cell glucose catabolism. To test whether either protein controls the sensitivity of the beta cell to glucose by controlling the rate of glucose catabolism, we used gene-transfer techniques to express the isoenzymes glucose transporter 1 and hexokinase I in beta cells and measured the response to glucose of the insulin gene promoter. Cells expressing glucose transporter 1 do not differ significantly from control cells, but in cells expressing hexokinase I, insulin promoter activity increases, reaches a maximum by 1 mM glucose, and does not respond to changes in glucose concentration within the physiologic range. We conclude that glucokinase catalyzes the rate-limiting step of glucose catabolism in beta cells and, therefore, acts as the glucose sensor. Pyruvate, the end product of anaerobic glycolysis, is readily oxidized by mitochondria in normal beta cells but cannot substitute for glucose as a stimulator of insulin synthesis and secretion. We found that pyruvate can stimulate the insulin promoter in cells expressing the bacterial gluconeogenic enzyme phosphoenolpyruvate carboxykinase, which allows the conversion of pyruvate to phosphoenolpyruvate and the earlier intermediates of glycolysis. We conclude that the intermediates of anaerobic glycolysis between fructose 1,6-diphosphate and phosphoenolpyruvate are essential for beta-cell glucose sensing.