Imaging Insulin Secretion from Mouse Pancreas by MRI Is Improved by Use of a Zinc-Responsive MRI Sensor with Lower Affinity for Zn2+ Ions
Imaging Insulin Secretion from Mouse Pancreas by MRI Is Improved by Use of a Zinc-Responsive MRI Sensor with Lower Affinity for Zn2+ Ions
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DOI：
10.1021/jacs.8b07607
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发表时间：
2018-12-19
影响因子：
15
通讯作者：
Sherry, A. Dean
中科院分区：
文献类型：
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作者：
Martins, Andre F.;Jordan, Veronica Clavijo;Sherry, A. Dean
已经证明，在葡萄糖刺激的胰岛素分泌过程中，使用基于钆的 Zn2+ 敏感剂，可以通过 MRI 检测到与胰岛素一起包装在 β 细胞颗粒中的二价锌离子。本研究旨在评估具有单一 Zn2+ 传感部分但具有可变 Zn2+ 结合亲和力的更简单的试剂设计是否也可以检测胰腺的胰岛素分泌。使用旨在将胰腺固定在固定位置进行成像的植入式 MR 兼容窗口，我们现在证明，在施用葡萄糖刺激胰岛素分泌后，可以使用这些药物在胰腺尾部检测到局灶性强烈的“热点”。对同一组织进行组织学染色，证实通过成像识别的热点对应于胰岛簇，这可能反映了对葡萄糖突然增加最敏感的第一反应者胰岛。使用高亲和力 Zn2+ 传感器与低亲和力传感器获得的图像的比较表明，低亲和力传感器产生最佳的图像对比度。考虑 Zn2+、GdL 传感器和 HSA 之间形成的所有可能复合物的平衡模型预测，对 Zn2+ 亲和力较低的 GdL 传感器在葡萄糖刺激的胰岛素分泌 (GSIS) 之前从内源性 Zn2+ 产生较低的背景信号，并且较弱的结合亲和力试剂对 GSIS 后 β 细胞附近 Zn2+ 浓度的进一步增加更敏感。这些模型预测与体内成像观察结果一致。
It has been demonstrated that divalent zinc ions packaged with insulin in beta-cell granules can be detected by MRI during glucose-stimulated insulin secretion using a gadolinium-based Zn2+-sensitive agent. This study was designed to evaluate whether a simpler agent design having single Zn2+-sensing moieties but with variable Zn2+ binding affinities might also detect insulin secretion from the pancreas. Using an implanted MR-compatible window designed to hold the pancreas in a fixed position for imaging, we now demonstrate that focally intense "hot spots" can be detected in the tail of the pancreas using these agents after administration of glucose to stimulate insulin secretion. Histological staining of the same tissue, verified that the hot spots identified by imaging correspond to clusters of islets, perhaps reflecting first-responder islets that are most responsive to a sudden increase in glucose. A comparison of images obtained when using a high-affinity Zn2+ sensor versus a lower-affinity sensor showed that the lower-affinity sensors produced the best image contrast. An equilibrium model that considers all possible complexes formed between Zn2+, the GdL sensor, and HSA predicts that a GdL sensor with lower affinity for Zn2+ generates a lower background signal from endogenous Zn2+ prior to glucose-stimulated insulin secretion (GSIS) and that the weaker binding affinity agent is more responsive to a further increase in Zn2+ concentration near beta-cells after GSIS. These model predictions are consistent with the in vivo imaging observations.