Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells
Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells
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DOI：
10.2337/diabetes.46.6.1087
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发表时间：
1997-06-01
期刊：
影响因子：
7.7
通讯作者：
Habener, JF
中科院分区：
文献类型：
--
作者：
Kieffer, TJ;Keller, RS;Habener, JF
在遗传突变小鼠模型ob/ob或db/db中，瘦素缺乏或抵抗分别导致严重肥胖和类似NIDDM的综合征的发展。这些突变小鼠中的最早表现之一是高胰岛素血症，表明瘦素通常可直接抑制胰岛素的分泌。在这里，我们表明，胰岛表达长（信号转导）形式的瘦素受体mRNA和β细胞结合的荧光衍生物瘦素（Cy 3-瘦素）。还利用针对受体的细胞外表位产生的抗血清可视化了胰岛素分泌β细胞上的瘦素受体的表达。（100 ng/ml）抑制分离自ob/ob小鼠的胰岛的胰岛素分泌。此外，瘦素使ob/ob β细胞中[Ca 2 +]（i）显著降低，这伴随着细胞超极化和增加的膜电导。ob/ob β细胞贴附膜片钳技术表明，瘦素通过增加ATP敏感性钾通道（K-ATP）的开放概率而激活K-ATP通道，但对平均开放时间无影响。这种作用可被K-ATP特异性抑制剂磺酰脲类药物甲苯磺丁脲逆转。总之，这些观察结果表明瘦素作为胰岛素分泌抑制剂的重要生理作用，并使我们提出瘦素不能抑制ob/ob和db/db小鼠β细胞的胰岛素分泌，这可能部分解释了高胰岛素血症、胰岛素抵抗和NIDDM进展的发生。
In the genetic mutant mouse models ob/ob or db/db, leptin deficiency or resistance, respectively, results in severe obesity and the development of a syndrome resembling NIDDM, One of the earliest manifestations in these mutant mice is hyperinsulinemia, suggesting that leptin may normally directly suppress the secretion of insulin. Here, we show that pancreatic islets express a long (signal-transducing) form of leptin-receptor mRNA and that beta-cells bind a fluorescent derivative of leptin (Cy3-leptin). The expression of leptin receptors on insulin-secreting beta-cells was also visualized utilizing antisera generated against an extracellular epitope of the receptor, A functional role for the beta-cell leptin receptor is indicated by our observation that leptin (100 ng/ml) suppressed the secretion of insulin from islets isolated from ob/ob mice, Furthermore, leptin produced a marked lowering of [Ca2+](i) in ob/ob beta-cells, which was accompanied by cellular hyperpolarization and increased membrane conductance. Cell-attached patch measurements of ob/ob beta-cells demonstrated that leptin activated ATP-sensitive potassium channels (K-ATP) by increasing the open channel probability, while exerting no effect on mean open time, These effects were reversed by the sulfonylurea tolbutamide, a specific inhibitor of K-ATP. Taken together, these observations indicate an important physiological role for leptin as an inhibitor of insulin secretion and lead us to propose that the failure of leptin to inhibit insulin secretion from the beta-cells of ob/ob and db/db mice may explain, in part, the development of hyperinsulinemia, insulin resistance, and the progression to NIDDM.