目的:糖尿病(DM)是世界上主要的疾病之一。核医学成像可以检测体内胰腺β细胞的功能状态,这可能会阐明糖尿病的病理机制并制定个性化的治疗计划。在这项研究中,我们评估了[125I]ADAM的能力,血清素转运蛋白(SERT)显像剂,作为检测胰腺β细胞团(BCM)的探针。
方法:在INS-1细胞(大鼠胰岛β细胞系)中评价体外细胞研究。在雄性正常Sprague-Dawley大鼠和四氧嘧啶诱导的1型糖尿病(T1DM)大鼠中进行了生物分布研究。免疫荧光染色和Westernblot检测SERT蛋白在大鼠胰腺中的分布和表达。
结果:体外细胞研究表明,与INS-1细胞相关的[125I]ADAM的浓度随孵育时间逐渐增加,和SERT特异性抑制剂,艾司西酞普兰,对这种相互作用表现出抑制作用。生物分布研究还表明,在艾司西酞普兰的存在下,正常大鼠胰腺中[125I]ADAM的摄取降低。然而,在具有显著β细胞减少的T1DM大鼠模型中,与对照组相比,胰腺的摄取增加。通过免疫荧光染色和Westernblot,发现正常胰腺的内分泌和外分泌细胞都表达SERT蛋白,外分泌细胞中SERT蛋白的水平高于胰岛。在糖尿病状态下,SERT在外分泌细胞中的表达进一步增加。
结论:SERT显像剂,[125I]ADAM,在目前的形式将不适合成像β细胞,特别是因为胰腺外分泌细胞有非常高的非特异性信号。此外,我们注意到SERT表达水平在糖尿病状态异常升高,这可能为研究糖尿病的病理机制提供了一个意想不到的目标。
Diabetes mellitus (DM) is one of the major diseases in the world. Nuclear medicine imaging may be able to detect functional status of pancreatic β cells in vivo, which might elucidate the pathological mechanisms of diabetes and develop individualized treatment plans. In this study, we evaluated the ability of [125I]ADAM, a serotonin transporter (
SERT) imaging agent, as a probe for detecting pancreatic β-cell mass (BCM).
In vitro cell studies were evaluated in INS-1 cells (rat islet β cell line). Biodistribution studies were performed in male normal Sprague-Dawley rats and alloxan-induced type 1 diabetes mellitus (T1DM) rats. Distribution and expression of
SERT protein in pancreas of rats were also measured by immunofluorescence staining and Western blot.
In vitro cell studies showed that the concentration of [125I]ADAM associated with the INS-1 cells was increased gradually with incubation time, and the SERT specific inhibitor, escitalopram, exhibited the inhibitory effect on this interaction. Biodistribution studies also showed that the uptake of [125I]ADAM in the pancreas of normal rats was decreased in the presence of escitalopram. However, in the T1DM rat model with a significant β cells reduction, the uptake of pancreas was increased when compared with the control. Through immunofluorescence staining and Western blot, it was found that both the endocrine and exocrine cells of the normal pancreas expressed SERT protein, and the level of
SERT protein in the exocrine cells was higher than islets. In the diabetic state, the expression of
SERT in the exocrine cells was further increased.
The
SERT imaging agent, [125I]ADAM, at the present form will not be suitable for imaging β cells, specifically because there were extraordinarily high non-specific signals contributing from the exocrine cells of pancreas. In addition, we noticed that the level of SERT expression was abnormally elevated in the diabetic state, which might provide an unexpected target for studying the pathological mechanisms of diabetes.