Borge Prabakhar D, Moibi Jacob, Greene Scott R, Trucco Matteo, Young Robert A, Gao Zhiyong, Wolf Bryan A
Department of Pathology and Laboratory Medicine, the Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4399, USA.
Diabetes. 2002 Dec;51 Suppl 3:S427-33. doi: 10.2337/diabetes.51.2007.s427.
Glucose is the main physiological secretagogue for insulin secretion by pancreatic beta-cells, and the major biochemical mechanisms involved have been elucidated. In particular, an increase in intracellular calcium is important for insulin exocytosis. More recently, it has become apparent that the beta-cell also has many of the elements of the insulin receptor signal transduction pathway, including the insulin receptor and insulin receptor substrate (IRS) proteins 1 and 2. Studies with transgenic models have shown that the beta-cell-selective insulin receptor knockout and the IRS-1 knockout lead to reduced glucose-induced insulin secretion. Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). We have thus postulated the existence of a novel autocrine-positive feedback loop of insulin on its own secretion involving interaction with the insulin receptor signal transduction pathway and regulation of intracellular calcium homeostasis. Our current working hypothesis is that this glucose-dependent interaction occurs at the level of IRS-1 and the sarco(endo)plasmic reticulum calcium ATPase, the calcium pump of the endoplasmic reticulum.
葡萄糖是胰腺β细胞分泌胰岛素的主要生理促分泌剂，且所涉及的主要生化机制已得到阐明。特别是，细胞内钙的增加对胰岛素胞吐作用很重要。最近，越来越明显的是，β细胞也具有胰岛素受体信号转导途径的许多元件，包括胰岛素受体和胰岛素受体底物（IRS）蛋白1和2。转基因模型研究表明，β细胞选择性胰岛素受体敲除和IRS-1敲除会导致葡萄糖诱导的胰岛素分泌减少。β细胞中胰岛素受体和IRS-1的过表达导致胰岛素分泌增加和胞质Ca(2+)增加。因此，我们推测存在一种新型的胰岛素自身分泌自分泌正反馈回路，涉及与胰岛素受体信号转导途径的相互作用以及细胞内钙稳态的调节。我们目前的工作假设是，这种葡萄糖依赖性相互作用发生在IRS-1和肌浆（内质）网钙ATP酶（内质网的钙泵）水平。
