Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
J Nucl Med. 2019 Nov;60(11):1635-1641. doi: 10.2967/jnumed.118.224881. Epub 2019 May 10.
The diabetes community has long desired an imaging agent to quantify the number of insulin-secreting β-cells, beyond just functional equivalents (insulin secretion), to help diagnose and monitor early stages of both type 1 and type 2 diabetes mellitus. Loss in the number of β-cells can be masked by a compensatory increase in function of the remaining cells. Since β-cells form only about 1% of the pancreas and decrease as the disease progresses, only a few imaging agents, such as exendin, have demonstrated clinical potential to detect a drop in the already scarce signal. However, clinical translation of imaging with exendin has been hampered by pancreatic uptake that is higher than expected in subjects with long-term diabetes who lack β-cells. Exendin binds glucagonlike peptide-1 receptor (GLP-1R), previously thought to be expressed only on β-cells, but recent studies report low levels of GLP-1R on exocrine cells, complicating β-cell mass quantification. Here, we used a GLP-1R knockout mouse model to demonstrate that exocrine binding of exendin is exclusively via GLP-1R (∼1,000/cell) and not any other receptor. We then used lipophilic Cy-7 exendin to selectively preblock exocrine GLP-1R in healthy and streptozotocin-induced diabetic mice. Sufficient receptors remain on β-cells for subsequent labeling with a fluorescent- or In-exendin. Selective GLP-1R blocking, which improves contrast between healthy and diabetic pancreata and provides a potential avenue for achieving the long-standing goal of imaging β-cell mass in the clinic.
糖尿病领域长期以来一直希望有一种成像剂能够定量测量胰岛素分泌β细胞的数量，而不仅仅是功能性等效物（胰岛素分泌），以帮助诊断和监测 1 型和 2 型糖尿病的早期阶段。β细胞数量的减少可能会被剩余细胞功能的代偿性增加所掩盖。由于β细胞仅占胰腺的 1%左右，并且随着疾病的进展而减少，因此只有少数成像剂，如 exendin，已经证明具有临床潜力，可以检测到已经稀缺的信号下降。然而，exendin 成像的临床转化受到以下因素的阻碍：在缺乏β细胞的长期糖尿病患者中，胰腺摄取量高于预期。Exendin 结合胰高血糖素样肽-1 受体 (GLP-1R)，以前认为仅在β细胞上表达，但最近的研究报告称外分泌细胞上存在低水平的 GLP-1R，这使得β细胞质量的定量变得复杂。在这里，我们使用 GLP-1R 敲除小鼠模型证明，外分泌细胞结合 exendin 完全是通过 GLP-1R（∼1,000/细胞），而不是其他受体。然后，我们使用亲脂性 Cy-7 exendin 选择性地预阻断健康和链脲佐菌素诱导的糖尿病小鼠的外分泌 GLP-1R。β细胞上仍然存在足够的受体，可用于随后用荧光或 In-exendin 进行标记。选择性 GLP-1R 阻断可改善健康和糖尿病胰腺之间的对比度，并为实现临床上成像β细胞质量的长期目标提供了潜在途径。
