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

Na-D-葡萄糖协同转运蛋白 1 (SGLT1) 敲除小鼠胰岛细胞可塑性的表征

• 批准号: 458690406
• 负责人: Dr. Daniela Zdzieblo, Ph.D.
• 金额: --
• 依托单位: Lehrstuhl für Tissue Engineering und Regenerative Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/458690406?language=en
• 关键词: Characterization; cellular; plasticity; pancreatic; islet

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.

钠-葡萄糖协同转运蛋白1（SGLT 1）主要在小肠中表达，调节饮食葡萄糖吸收，从而直接影响血糖稳态。此外，SGLT 1位于肾脏中，有助于滤过的肝葡萄糖的重吸收。鉴于这些经典的生理作用，抑制SGLT 1目前是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有前景的治疗策略。最近的数据表明，SGLT 1在包括心脏、脑、肺、肝脏和胰腺在内的多种器官中表达;然而，器官特异性功能仅在开始时才被了解。先前发表的数据提供了SGLT 1对维持胰岛完整性很重要的证据。SGLT 1基因敲除小鼠的胰岛显示出改变的结构和功能特征。此外，细胞形态学受到干扰，胰岛素分泌β细胞减少，胰高血糖素分泌α细胞增加。初步数据表明，去分化和/或转分化事件（尤其是β细胞）是可能解释这些结果的根本原因，可能抵消胰岛微环境中α细胞特异性SGLT 1活性的丧失。拟议项目的目的是表征和跟踪SGLT 1敲除胰岛中的去分化和/或转分化过程。此外，研究了胰腺谱系特化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，拟议项目将显著证实对胰腺SGLT 1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细胞身份变化，这具有高度相关性，因为胰岛处于血糖稳态的中心。在这种情况下，细胞特性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SGLT 1敲除胰岛的变化。在这种情况下，最近提出成熟β细胞的去分化和/或转分化会导致糖尿病胰岛中功能性β细胞质量的丧失。因此，鉴定β-细胞可塑性的关键触发和调节过程对于通过逆转或阻断患病胰岛中的去分化和/或转分化来解决β-细胞再生的新概念是非常有意义的。