Glucose transporters are classified into two families: facilitative glucose transporters (GLUTs) and sodium‐dependent glucose transporters (SGLTs), through which glucose is transported by facilitated diffusion, and Na+/glucose are co-transported by an electrochemical gradient across the membrane, respectively. Six isoforms of the SGLT gene belong to the SLC5 gene family and they consist of 15 exons. All SGLT proteins have 14 transmembrane helices in topology. SGLT1 and SGLT2 function as a glucose/galactose transporter and a glucose transporter across the membrane, respectively. SGLT3 is not a transporter in some species.

Glucose is the main metabolic substrate that fuels the brain under normal physiological conditions. To maintain a constant supply of glucose to brain tissue, a complicated network consisting of various kinds of glucose transporters is responsible for the delivery of glucose from plasma to neurons. There are two glucose transporter families found in the brain. The first are the non-energy-dependent glucose transporters (GLUTs) which facilitate glucose transport down its concentration gradient. It is the main pathway of glucose uptake under normal physiological conditions. Among the many isoforms of GLUTs, GLUTl and GLUT3 are most dominantly distributed in the brain. GLUTl is the major transporter found in the most glial cells and blood brain barrier (BBB) consisting of tightly-joint capillary vessel cells; GLUT3 is the predominant glucose transporter in neurons and it is the one with the highest affinity among the GLUT family.

The second glucose transporter family is the secondary active sodium dependent glucose transporters (SGLTs) which were first identified in intestine and kidney. In the kidney, glucose filtered in glomeruli is reabsorbed in proximal renal tubules, and is not usually secreted in the urine. However, when the blood glucose level is over 160~180mg/dL, glucose reabsorption exceeds reabsorption capacity and glucose does appear in the urine. SGLT1 is expressed mainly in the S2 and S3 segments of the proximal renal tubules, and reabsorbs one glucose molecule coupled with two sodium ions. SGLT2 has 60% homology with SGLT1 and is highly expressed in the brush border membrane (BBM) of the S1 segment of the proximal renal tubules. SGLT2 has a low affinity to glucose and reabsorbs one glucose molecule coupled with one sodium ion. It is thought that SGLT1 and SGLT2 reabsorb 10 and 90% of filtered glucose, respectively, in the kidney. Considering that SGLT2 is largely involved in glucose reabsorption and that SGLT2 expression is upregulated in the diabetic rat, inhibition of SGLT2 might well be a new therapeutic approach to excrete glucose into the urine and manage blood glucose levels in type 2 diabetes mellitus patients. To date, various SGLT2 inhibitors have been developed for treatment of type 2 diabetes mellitus.

The presence of SGLT1 protein was determined most recently in the brain. The distribution of SGLT1 in the brain was identified by in situ hybridization of SGLT1 mRNA and immunostaining of SGLT1 protein. SGLT1 was found either on the cell membrane of neurons, like the granular cells in dentate gyrus of hippocampus, or located intracellularly in small vesicles in the pyramidal cells in cerebral cortex and Purkinje cells in cerebellum. SGLTs pump glucose into cells, and the intracellular concentration can be potentially an order of magnitude higher than the external mileu. When glucose concentration in blood decreases (e.g., during metabolic stress) or the need of glucose increases (e.g., during energy-demanding brain activities such as epilepsy), the extracellular glucose concentration would fall significantly. Under these conditions, the efficiency of glucose transport via GLUTs might become limited. Therefore, it was hypothesized that in this situation the active glucose transporters, SGLTs, could become especially important to maintain glucose utilization in cells since it can work against the glucose concentration gradient. In addition to being a glucose transporter, SGLT1 has also been characterized as a glucose "sensor" in some glucose-excited neurons in hypothalamus. The SGLTl-dependent activity of these neurons was showed to be related to the control of feeding behavior and glucose homeostasis. These findings imply that SGLTs express in brain and may be functional for certain purpose.

Reference:Shu-Jung Yu. Functional Cerebral Sodium Dependent Glucose Transporters In Vivo

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