Role of SGLTs in Glucose Homeostasis and Tissue Metabolism

描述(申请人提供)：葡萄糖是身体的主要燃料，必须保持充足的供应，以支持器官和组织的正常功能。从长远来看，过量的葡萄糖摄入会导致体重增加，并增加患糖尿病的风险。血糖被控制在狭窄的范围内，以平衡能量的供需，而这种控制的一个主要因素是将多余的葡萄糖运输到肌肉和脂肪中进行储存。葡萄糖转运蛋白有两类，谷氨酸转运蛋白和谷氨酸甘油三酯，但关于葡萄糖在健康和疾病中的转运的研究主要集中在谷氨酸转运蛋白上。SGLTS基因在全身表达，表明这些转运蛋白在将葡萄糖输送到细胞中的作用比预期的要大。其目的是利用正电子发射断层扫描(PET)来阐明钠/葡萄糖共转运体(SGLTS)在人体葡萄糖稳态和代谢生理学中的重要性。葡萄糖探针2-FDG和PET的引入使人体器官和组织对葡萄糖的摄取和代谢研究发生了革命性的变化。在临床上，这对癌症的检测、分期和治疗产生了巨大的影响。然而，2-FDG不是SGLT的底物，这限制了我们对正常细胞和肿瘤中葡萄糖运输和代谢的了解。这项建议的具体目的是：1)。设计针对SGLT的PET探针；2)合成[F-18]标记的SGLT探针；使用这些新型葡萄糖探针的PET成像来检测SGLT在动物和人类受试者中的生理作用。SGLT1和SGLT2在葡萄糖摄取中的作用将通过将SGLTS基因突变的患者、葡萄糖-半乳糖吸收不良患者和家族性肾性糖尿症患者纳入研究中来测试。同时，我们将使用2-FDG进行研究，以确定谷氨酸和SGLT在感兴趣器官的葡萄糖摄取中的相对重要性。还将使用SGLT和GLUT探针对可用的啮齿动物以及SGLT和GLOT基因敲除小鼠进行研究，以补充对患者的研究。显然，为了充分了解健康和疾病中的能量平衡，需要识别细胞摄取葡萄糖的所有途径。该项目旨在测试钠葡萄糖共转运体在葡萄糖稳态中被严重忽视的作用。相关声明：这项研究旨在确定钠/葡萄糖共转运体(SGLT)在葡萄糖稳态中的作用。SGLT在全身都有表达，但到目前为止，它们在肠道肾脏之外的作用一直被忽视。这项研究的结果可能会为糖尿病和肥胖症提供新的药物靶点，并开发新的PET示踪剂来检测和分期癌症。公共卫生相关性：这项研究旨在确定钠/葡萄糖共转运体(SGLT)在葡萄糖稳态中的作用。SGLT在全身都有表达，但到目前为止，它们在肠道和肾脏之外的作用一直被忽视。这项研究的结果可能会为糖尿病和肥胖症提供新的药物靶点，并开发新的PET示踪剂来检测和分期癌症。

DESCRIPTION (provided by applicant): Glucose is the primary fuel for the body and adequate supplies must be maintained to support the normal function of organs and tissues. Over the long term an excess of glucose intake results in weight gain and added risk for developing diabetes. Blood glucose is held within narrow limits to balance the supply and demand for energy and a major factor in this control is the transport of excess glucose into muscle and fat for storage. There are two classes of glucose transporters, GLUTs and SGLTs, but research on glucose transport in health and disease has focused on the GLUTs. SGLTs genes are expressed throughout the body indicating a larger role of these transporters in the transport of glucose into cells than anticipated. The goal is to elucidate the importance of SGLTs (sodium/glucose cotransporters) in the human physiology of glucose homeostasis and metabolism using Positron Emission Tomography (PET). The Introduction of the glucose probe 2-FDG and PET has revolutionized studies of glucose uptake and metabolism in organs and tissues in the human body. Clinically this has had an enormous impact in cancer detection, staging and therapy. However, 2-FDG is not a substrate for SGLTs and this has limited our understanding of glucose transport and metabolism in normal cells and tumors. The specific aims of this proposal are to: 1). Design PET probes specific for SGLTs; 2). Synthesize [F-18]-labeled probes for SGLTs; and 3). Use PET imaging with these new glucose probes to examine the physiological role of SGLTs in animal and human subjects. The role of SGLT1 and SGLT2 in glucose uptakes will be tested by including in the study patients with mutations in the SGLTs genes, patients with Glucose- Galactose-Malabsorption and Familial Renal Glucosuria. In parallel, we will conduct studies using 2-FDG to determine the relative importance of GLUTs and SGLTs in glucose uptakes in organs of interest. Studies will also be carried out with both SGLT and GLUT probes on available rodents and SGLT and GLUT knockout mice to compliment the studies on patients. Clearly, identification of all the pathways for glucose uptake into cells is required for a full understanding of energy balance in health and disease. This project is designed to test the sorely neglected role of sodium glucose cotransporters in glucose homeostasis.Relevance Statement: This study of designed to determine the role of sodium/glucose cotransporters (SGLTs) in glucose homeostasis. SGLTs are expressed throughout the body but until now their role outside the intestinal kidneys has been neglected. The results of this study may provide new drug targets for diabetes and obesity and develop new PET tracers to detect and stage cancer. PUBLIC HEALTH RELEVANCE: This study is designed to determine the role of sodium/glucose cotransporters (SGLTs) in glucose homeostasis. SGLTs are expressed throughout the body but until now their role outside the intestine and kidneys has been neglected. The results of this study may provide new drug targets for diabetes and obesity and develop new PET tracers to detect and stage cancer.