IGFBP-3 IN APOPTOSIS OF B CELLS AND TYPE I DIABETES

儿童面临的最大内分泌疾病是I型糖尿病(T1 DM)，由自身免疫性β细胞死亡和伴随的胰岛素缺乏引起。已有研究表明，在非肥胖糖尿病(NOD)小鼠体内，细胞因子介导的β细胞凋亡(程序性细胞死亡)可导致T1 DM。胰岛素样生长因子(IGF)轴对细胞的生长和死亡过程至关重要。体外研究证实，胰岛素样生长因子结合蛋白-3(IGFBP-3)通过IGF依赖和非IGF两种途径诱导前列腺和乳腺细胞的凋亡。对通常不分泌IGFBP-3的β细胞株的体外研究表明，凋亡诱导细胞因子可诱导IGF结合蛋白-3(IGFBP-3)的产生。我们的中心假设是IGFBP-3是β细胞凋亡(死亡)的重要介质，因此是T1 DM的发病机制。为了验证这一假设，我们将描述NOD小鼠胰岛中IGF-IGFBP轴的特征。我们预期NOD小鼠胰岛过度分泌IGFBP-3可能先于胰岛细胞的凋亡。我们还将使用大鼠胰岛素启动子构建转基因小鼠，该启动子仅在β细胞中表达，以驱动胰岛IGFBP-3的过量生产。我们期待这一新型转基因小鼠发生β细胞凋亡和T1 DM。最后，我们将把NOD小鼠与IGFBP-3基因敲除的小鼠(没有糖尿病)杂交。我们期望在后代中看到胰岛IGFBP-3的分泌与T1 DM之间的直接关系。研究IGF-IGFBP轴和β细胞功能之间的关系将揭示导致糖尿病的重要机制，并可能导致缓解或预防糖尿病及其并发症的新疗法。

The greatest endocrinological disease facing children is type I diabetes mellitus (T1DM), caused by autoimmune beta cell death and attendant insulin deficiency. It has been shown that cytokine-mediated apoptosis (programmed cell death) of beta cells in vivo leads to T1DM in the non-obese diabetic (NOD) mouse. The insulin-like growth factor (IGF) axis is crucial to the processes of cell growth and death. Studies in vitro have confirmed that IGF binding protein-3 (IGFBP-3) induces apoptosis in prostatic and breast cells by both IGF-dependent and IGF-independent pathways. In vitro studies of beta cell lines which do not usually secrete IGFBP-3 have shown that apoptosis-inducing cytokines induce IGF binding protein-3 (IGFBP-3) production. Our central hypothesis is that IGFBP-3 is an important mediator of beta cell apoptosis (death) and therefore the pathogenesis of T1DM. To test this hypothesis we will characterize the IGF-IGFBP axis in pancreatic islets of the NOD mouse. We expect islet over-secretion of IGFBP-3 to precede islet apoptosis in NOD mice. We will also construct a transgenic mouse using the rat insulin promoter, which is expressed exclusively in beta cells, to drive overproduction of islet IGFBP-3. We expect this novel transgenic mouse to develop beta cell apoptosis and T1DM. Finally, we will crossbreed NOD mice with IGFBP-3 knockout mice (which are not diabetic). We expect to see a direct relationship between islet IGFBP-3 secretion and T1DM in the progeny. Studying the relationships between the IGF-IGFBP axis and beta cell function will uncover important mechanisms which cause diabetes and can lead to novel treatments which alleviate or prevent diabetes and its complications.