Imaging Beta Cell Function in Vivo with Zinc Responsive MRI Contrast Agents

II型糖尿病是一种慢性疾病，其特征是β细胞功能的暂时丧失和渐进性 胰岛素缺乏症。尽管多年来对β细胞功能的机制进行了深入的研究 随着糖尿病发病率的下降，对糖尿病发病机制的理解一直受到我们的阻碍 在疾病进展或治疗过程中无法监测β细胞的命运 恢复。尽管在体外已经证明了各种分子成像方法， 体内β细胞质量和功能的非侵入性成像仍然难以实现。在过去的5年半里 多年来，我们的实验室改进了最初设计的响应性磁共振造影剂 对分泌组织中锌离子的释放做出反应，并证明了 胰岛素和锌离子来自胰腺β-细胞的葡萄糖团注启动可以成像 啮齿动物和猕猴中的非人类灵长类。猴子的成像研究表明 在整个胰腺中，锌离子和胰岛素的分泌并不均匀，这与已知数据一致。 胰岛在整个胰腺的不均匀分布。试剂中锌离子的还原 结合亲和力(~103)导致检测的灵敏度显著提高 体内胰腺分泌的锌离子。此外，我们已经证明，一个人可以 用核磁共振检查胰腺尾部的“第一反应者胰岛”作为“热点” 低或高亲和力锌离子传感器。在这个续集项目中，我们将监控第一响应者 两种成熟的T2 DM模型中的胰岛：Zucker糖尿病脂肪(ZDF)大鼠(肥胖模型) 和Goto-Kakizaki(GK)大鼠(非肥胖模型)。动物将每两周进行一次成像 在疾病发展过程中，当他们对临床批准的T2 DM药物有反应时。这个 成像方法将通过胰岛素含量(荧光)的独立测量来验证。 SR-XRF测定锌离子含量。我们的目标是证明β细胞的功能是可以监测的 在胰腺的头部和尾部区域可以通过MRI重现，这项技术将 提供对β细胞功能的新见解，将催化新药的开发 T2 DM。

Type II diabetes is chronic disease characterized by temporal loss of β-cell function and gradual insulin deficiency. Despite years of intensive research into the mechanisms of β-cell functional decline, progress in understanding the pathogenesis of diabetes has been hampered by our inability to monitor the fate of β-cells during progression of the disease or during therapeutic recovery. Although various molecular imaging approaches have been demonstrated in vitro, non-invasive imaging of β-cell mass and function in vivo remains elusive. Over the past 5½ years, our lab has improved upon the original design of a responsive MRI contrast agent that responds to release of Zn2+ ions from secretory tissues and demonstrated that release of insulin and Zn2+ from pancreatic β-cells initiated by a bolus of glucose bolus can be imaged in rodents and in the macaque non-human primate. The monkey imaging studies showed that Zn2+ and insulin secretion is not uniform throughout the pancreas, consistent with known data on the non-uniform distribution of islets throughout the pancreas. A reduction in agent Zn2+ binding affinity (by ~103) resulted in a dramatic improvement in the sensitivity for detection of Zn2+ secretion from the pancreas in vivo. Furthermore, we have demonstrated that one can detect “first responder islets” as “hot spots” in the tail of the pancreas by MRI using either a low or high affinity Zn2+ sensor. In this continuation project, we will monitor first responder islets in two well-established T2DM model, the Zucker Diabetic Fatty (ZDF) rat (obese model) and the Goto-Kakizaki (GK) rat (non-obese model). Animals will be imaged every 2 weeks during progression of the disease and as they respond to clinically approved T2DM drugs. The imaging methods will be validated by independent measures of insulin content (fluorescence) and Zn2+ content by SR-XRF. Our goal is to demonstrate that β-cell function can be monitored in the head and tail regions of the pancrease reproducibly by MRI and that this technology will provide new insights into β-cell function that will catalyze development of new drugs for T2DM.