Characterization of cellular plasticity in the pancreatic islet of Na+-D-glucose cotransporter 1 (SGLT1) knockout mice

钠-葡萄糖共转运蛋白1 （SGLT1）主要在小肠中表达，调节膳食葡萄糖的吸收，从而直接影响血糖稳态。此外，SGLT1位于肾脏，有助于过滤后的肝葡萄糖的重吸收。鉴于这些经典的生理作用，抑制SGLT1是目前糖尿病患者预防餐后血糖水平升高和增加尿糖排泄的一种很有前景的治疗策略。最近的数据表明，SGLT1在包括心脏、脑、肺、肝和胰腺在内的多种器官中表达；然而，对器官特异性功能的了解才刚刚开始。先前发表的数据证明SGLT1对维持胰岛完整性很重要。SGLT1基因敲除小鼠的胰岛显示结构和功能特征的改变。此外，细胞形态受到干扰，分泌胰岛素的β-细胞减少，分泌胰高血糖素的α-细胞增加。初步数据表明，去分化和/或转分化事件，特别是β细胞，可能是这些发现的潜在原因，可能抵消了胰岛微环境中α细胞特异性SGLT1活性的丧失。该项目的目的是表征和追踪SGLT1基因敲除胰岛的去分化和/或转分化过程。此外，研究了胰腺谱系鉴定过程中发育程序的改变。转录组分析应该揭示潜在的分子程序。鉴于其对血糖稳态的重要性，其作为抗高血糖策略靶点的有趣作用及其与β细胞身份丧失的关系，拟议的项目将显著充实对胰腺SGLT1生物学的理解。此外，该项目将允许识别潜在的分子机制，调节蛋白和/或信号通路。此外，所获得的发现将有助于更详细地了解β细胞身份的变化，这是高度相关的，因为胰岛是血糖稳态的中心。在这种情况下，细胞身份的保存是微调体内循环糖的生理水平的基础。有趣的是，越来越多的证据表明，糖尿病相关的改变可以诱导胰岛细胞组成的变化，类似于SGLT1敲除胰岛的变化。在这种情况下，成熟β细胞的去分化和/或转分化最近被认为是导致糖尿病胰岛中功能β细胞团丧失的原因。因此，确定β细胞可塑性的关键触发因素和调控过程对于通过逆转或药物阻断病变胰岛的去分化和/或转分化来解决β细胞再生的新概念具有重要意义。

The sodium-glucose cotransporter 1 (SGLT1) is predominantly expressed in the small intestine regulating dietary glucose absorption, thereby directly affecting blood glucose homeostasis. Furthermore, SGLT1 is located in the kidney contributing to the reabsorption of filtered hepatic glucose. In view of these classical physiological roles, inhibition of SGLT1 is currently a promising therapeutic strategy in diabetic patients to prevent the increase in blood glucose levels after meal and to increase urinary glucose excretion. Recent data demonstrate that SGLT1 is expressed in a variety of organs comprising the heart, brain, lung, liver and the pancreas; however, organ-specific functions are only at the beginning to be understood. Own previously published data provide evidence that SGLT1 is important to maintain pancreatic islet integrity. Pancreatic islets of SGLT1 knockout mice display altered structural and functional characteristics. In addition, the cellular cytomorphology is disturbed with a decrease in insulin-secreting β- and increase in glucagon-secreting α-cells. Preliminary data suggest de- and/or transdifferentiation events, especially of β-cells, as underlying reasons that may account for these findings possibly to counteract the loss of α-cell-specific SGLT1 activity in the islet microenvironment. The aim of the proposed project is to characterize and trace de- and/or transdifferentiation processes in the SGLT1 knockout islet. Further, alterations in developmental programs during pancreatic lineage specification are studied. Transcriptome analyses should reveal underlying molecular programs. In view of its importance for blood glucose homeostasis, its interesting role as target for anti-hyperglycemic strategies and its relation to the loss of β-cell identity, the proposed project will significantly substantiate the understanding of pancreatic SGLT1 biology. Furthermore, the project will allow the identification of underlying molecular mechanisms, regulatory proteins and/or signaling pathways. In addition, the obtained findings will contribute to a more detailed understanding of β-cell identity changes, which is of high relevance, as the pancreatic islet is at the center of blood glucose homeostasis. In this context, preservation of cellular identities is fundamental to fine-tune the physiological level of circulating sugar in the body. Interestingly, there is increasing evidence that diabetes-associated alterations can inducevariations in islet cell compositions similar to those suggested for SGLT1 knockout islets. In this context, de- and/or transdifferentiation of mature β-cells were recently proposed to contribute to the loss of functional β-cell mass in the diabetic islet. Therefore, identifying key triggers and regulatory processes of β-cell plasticity is of great interest for new concepts addressing β-cell regeneration by reversing or pharmacologically blocking de- and/or transdifferentiation in the diseased islet.