Xu G G, Gao Z Y, Borge P D, Jegier P A, Young R A, Wolf B A
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Biochemistry. 2000 Dec 5;39(48):14912-9. doi: 10.1021/bi001260w.
The insulin receptor signaling pathway is present in beta-cells and is believed to be important in beta-cell function. We show here that insulin directly regulates beta-cell function in isolated rodent islets. Long-term insulin treatment caused a sustained increase in Ca(2+) and enhanced glucose-stimulated insulin secretion in rat islets, but failed to increase insulin content. Chronic activation of insulin receptor signaling by IRS-1 overexpression in the beta-cell inhibited gene expression of SERCA3, an endoplasmic reticulum Ca(2+)-ATPase. Insulin gene transcription was stimulated by insulin receptor signaling and insulin mimetic compound (L-783 281) in a glucose- and Grb2-dependent manner. Thus, beta-cell SERCA3 is a target for insulin regulation, which implies that beta-cell Ca(2+) homeostasis is regulated in an autocrine feedback loop by insulin. This study identifies a novel regulatory pathway of insulin secretion at the molecular level with two main components: (1) regulation of intracellular Ca(2+) homeostasis via SERCA3 and (2) regulation of insulin gene expression.
胰岛素受体信号通路存在于β细胞中，并且被认为在β细胞功能中起重要作用。我们在此表明，胰岛素直接调节分离的啮齿动物胰岛中的β细胞功能。长期胰岛素治疗导致大鼠胰岛中[Ca(2+)]i持续增加，并增强了葡萄糖刺激的胰岛素分泌，但未能增加胰岛素含量。通过在β细胞中过表达IRS-1来慢性激活胰岛素受体信号传导，抑制了内质网Ca(2+)-ATP酶SERCA3的基因表达。胰岛素受体信号传导和胰岛素模拟化合物（L-783 281）以葡萄糖和Grb2依赖的方式刺激胰岛素基因转录。因此，β细胞SERCA3是胰岛素调节的靶点，这意味着β细胞Ca(2+)稳态通过胰岛素在自分泌反馈回路中受到调节。本研究在分子水平上确定了胰岛素分泌的一条新的调节途径，其有两个主要组成部分：（1）通过SERCA3调节细胞内Ca(2+)稳态，以及（2）调节胰岛素基因表达。
