Functionally probing hSGLT2 in diabetes treatment and glucose homeostasis

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DESCRIPTION (provided by applicant): Diabetes mellitus is one of the great health challenges facing the developed world in the 21st century, with monumental costs levied both to society and the individual. As such, there currently is great interest in finding ways to reduce the morbidity and mortality due to this group of disorders characterized by dysregulated glucose homeostasis. One such direction aims to develop pharmaceutical agents that blunt sugar reabsorption in the kidneys via the human sodium/glucose cotransporter 2 (hSGLT2); and while several dozen drugs are in either research and development or early stage clinical trials, little remains known about hSGLT2. Is it similar to its well-characterized intestinal counterpart hSGLTI ? How does it use a sodium gradient to drive renal reuptake of sugar against a gradient? Which molecules bind to and are transported by hSGLT2 and which toggle between binding and dissociating without being transported? How does global expression (i.e. throughout the entire body) of hSGLT2 play a role in glucose homeostasis? With these, and many more related questions in mind, this study's aims are as follows: Specific Aim 1: Establish a kinetic model for hSGLT2. With novel methods of both steady-state and presteady-state analyses (with patch clamp experiments in HEK293 cells), we will understand key steps and properties of transport by this proposed low-affinity, high-capacity transporter. Specific Aim 2: Identify substrates, agonists, antagonists for hSGLT2. With a working kinetic model, the activity of a variety of molecules - versions of which are the basis of pharmacotherapy aimed at hSGLT2 - will be characterized in this study. As the substrate specificity of hSGLT2 is further refined, I anticipate this research leading to the design and testing of hSGLT2-specific probes for imagining with positron emission tomography (PET). Through this, we will understand the global impact of blocking hSGLT2 transport, and we will be able to functionally image both regulated and dysregulated glucose homeostasis. *A disease of epidemic proportions, diabetes mellitus poses unique challenges to both the scientists who research and physicians who treat it. Recent therapeutic development aims to target the kidneys' reabsorption of glucose through the human sodium glucose cotransporter 2 (hSGLT2) which, if blocked, helps to control blood glucose levels. This work focuses on characterizing this transporter in order to better define efficacy and side effects of drugs targeting hSGLT2, as well as defining hSGLT2's true impact on blood glucose levels through future studies in functional imaging.