Purpose

β cell mass (BCM) and function are essential to the diagnosis and therapy of diabetes. Diabetic patients serve β cell loss is, and damage of β cells leads to severe insulin deficiency. Our understanding of the role of BCM in diabetes progression is extremely limited by lacking efficient methods to evaluate BCM in vivo. In vitro methods of labeling islets, including loading of contrast reagent or integration of exogenous biomarker, require artificial manipulation on islets, of which the clinical application is limited. Imaging methods targeting endogenous biomarkers may solve the above problems. However, traditional reagents targeting GLP-1R and VAMT2 result in a high background of adjacent tissues, complicating the identification of pancreatic signals. Here, we report a non-invasive and quantitative imaging technique by using radiolabeled glycine mimics ([¹⁸F]FBG, a boron-trifluoride derivative of glycine) to assay islet function and monitor BCM changes in living animals.

Methods

Glycine derivatives, FBG, FBSa, 2Me-FBG, 3Me-FBG, were successfully synthesized and labeled with ¹⁸F. Specificity of glycine derivatives were characterized by in vitro experiment. PET imaging and biodistribution studies were performed in animal models carring GLYT over-expressed cells. In vivo evaluation of BCM with [¹⁸F]FBG were performed in STZ (streptozocin) induced T1D (type 1 diabetes) models.

Results

GLYT responds to excess blood glycine levels and transports glycine into islet cells to maintain the activity of the glycine receptor (GLYR). Best PET imaging condition was 80 min after given a total of 240 ~ 250 nmol imaging reagent (a mixture of [¹⁸F]FBG and natural glycine) intravenously. [¹⁸F]FBG can detect both endogenous and exogenous islets clearly in vivo. When applied to STZ induced T1D mouse models, total uptake of [¹⁸F]FBG in the pancreas exhibited a linear correlation with survival BCM.

Conclusion

[¹⁸F]FBG targeting the endogenous glycine transporter (GLYT), which is highly expressed on islet cells, avoiding extra modification on islet cells. Meanwhile the highly restricted expression pattern of GLYT excluded the background in adjacent tissues. This [¹⁸F]FBG-based imaging technique provides a non-invasive method to quantify BCM in vivo, implying a new evaluation index for diabetic assessment.

中文翻译：

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B-甘氨酸作为 β 细胞成像和 β 细胞质量评估的标记物

目的

β细胞质量（BCM）和功能对于糖尿病的诊断和治疗至关重要。糖尿病患者体内β细胞缺失，β细胞受损导致胰岛素严重缺乏。由于缺乏体内评估 BCM 的有效方法，我们对 BCM 在糖尿病进展中的作用的理解极其有限。体外标记胰岛的方法，包括加载造影剂或整合外源生物标志物，需要对胰岛进行人工操作，其临床应用受到限制。针对内源性生物标志物的成像方法可能会解决上述问题。然而，针对 GLP-1R 和 VAMT2 的传统试剂会导致邻近组织的背景较高，从而使胰腺信号的识别变得复杂。在这里，我们报告了一种非侵入性定量成像技术，通过使用放射性标记的甘氨酸模拟物（[ ¹⁸ F]FBG，甘氨酸的三氟化硼衍生物）来测定活体动物的胰岛功能并监测 BCM 变化。

方法

成功合成了甘氨酸衍生物FBG、FBSa、2Me-FBG、3Me-FBG，并用~ ⁽¹⁸⁾ F标记。通过体外实验对甘氨酸衍生物的特异性进行了表征。在携带 GLYT 过表达细胞的动物模型中进行 PET 成像和生物分布研究。在 STZ（链佐星）诱导的 T1D（1 型糖尿病）模型中使用 [ ¹⁸ F]FBG对 BCM 进行体内评估。

结果

GLYT 对血液中过量的甘氨酸水平做出反应，并将甘氨酸转运到胰岛细胞中，以维持甘氨酸受体 (GLYR) 的活性。最佳PET成像条件为静脉注射总计240～250 nmol成像试剂（[ ¹⁸ F]FBG和天然甘氨酸的混合物）后80分钟。 [ ¹⁸ F]FBG 可以在体内清楚地检测内源性和外源性胰岛。当应用于 STZ 诱导的 T1D 小鼠模型时，胰腺中[ ^{18 F]FBG 的总摄取量与存活 BCM 呈线性相关。}

结论

[ ¹⁸ F]FBG 靶向内源性甘氨酸转运蛋白 (GLYT)，该蛋白在胰岛细胞上高度表达，避免了对胰岛细胞的额外修饰。同时，GLYT 的高度受限的表达模式排除了邻近组织中的背景。这种基于[ ¹⁸ F]FBG的成像技术提供了一种体内量化BCM的非侵入性方法，为糖尿病评估提供了新的评估指标。