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GLUT4
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<h2 id="structure">Structure</h2> <p>Like all proteins, the unique amino acid arrangement in the <a href="/facts/Primary_sequence/VaN6MEYh">primary sequence</a> of GLUT4 is what allows it to transport glucose across the plasma membrane. In addition to the <a href="/facts/Phenylalanine/eyojfW7t">phenylalanine</a> on the N-terminus, two <a href="/facts/Leucine/X7YrkvA5">Leucine</a> residues and acidic motifs on the COOH-terminus are believed to play a key role in the kinetics of <a href="/facts/Endocytosis/NJjChLNj">endocytosis</a> and <a href="/facts/Exocytosis/4P4oQdtA">exocytosis</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p> <h3>Other GLUT proteins</h3> <p>There are 14 total GLUT proteins separated into 3 classes based on <a href="/facts/Protein_primary_structure/QNBoERdu">sequence</a> similarities. Class 1 consists of GLUT 1-4 and 14, class 2 contains GLUT 5, 7, 9 and 11, and class 3 has GLUT 6, 8, 10, 12 and 13. </p><p>Although there are some sequence differences between all GLUT proteins, they all have some basic structural components. For example, both the N and C termini in GLUT proteins are exposed to the <a href="/facts/Cytoplasm/Wa0sE6xf">cytoplasm</a> of the cell, and they all have 12 transmembrane segments.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h2 id="tissue-distribution">Tissue distribution</h2> <h3>Skeletal muscle</h3> <p>In striated <a href="/facts/Skeletal_muscle/en1tVYFN">skeletal muscle</a> cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction. </p><p>During exercise, the body needs to convert glucose to <a href="/facts/Adenosine_triphosphate/nB9bwgcU">ATP</a> to be used as energy. As <a href="/facts/Glucose_6-phosphate/2KybIvaN">G-6-P</a> concentrations decrease, <a href="/facts/Hexokinase/upUIvz6J">hexokinase</a> becomes less inhibited, and the glycolytic and oxidative pathways that make ATP are able to proceed. This also means that muscle cells are able to take in more glucose as its intracellular concentrations decrease. In order to increase glucose levels in the cell, GLUT4 is the primary transporter used in this <a href="/facts/Facilitated_diffusion/CxHhRHKa">facilitated diffusion</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p>Although muscle contractions function in a similar way and also induce the translocation of GLUT4 into the plasma membrane, the two skeletal muscle processes obtain different forms of intracellular GLUT4. The GLUT4 carrier vesicles are either transferrin positive or negative, and are recruited by different stimuli. Transferrin-positive GLUT4 vesicles are utilized during muscle contraction while the transferrin-negative vesicles are activated by insulin stimulation as well as by exercise.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h3>Cardiac muscle</h3> <p><a href="/facts/Cardiac_muscle/oMqU4Sdu">Cardiac muscle</a> is slightly different from skeletal muscle. At rest, they prefer to utilize <a href="/facts/Fatty_acid/JGg3erIu">fatty acids</a> as their main energy source. As activity increases and it begins to pump faster, the cardiac muscles begin to oxidize glucose at a higher rate.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p> An analysis of mRNA levels of <a href="/facts/GLUT1/2sepHEsV">GLUT1</a> and GLUT4 in cardiac muscles show that GLUT1 plays a larger role in cardiac muscles than it does in skeletal muscles.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> GLUT4, however, is still believed to be the primary transporter for glucose.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p><p>Much like in other tissues, GLUT4 also responds to insulin signaling, and is transported into the plasma membrane to facilitate the diffusion of glucose into the cell. <a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h3>Adipose tissue</h3> <p><a href="/facts/Adipose_tissue/PxxedB6e">Adipose tissue</a>, commonly known as fat,<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> is a depository for energy in order to conserve metabolic <a href="/facts/Homeostasis/rloTGAHa">homeostasis</a>. As the body takes in energy in the form of glucose, some is expended, and the rest is stored as <a href="/facts/Glycogen/kWa8fPFE">glycogen</a> (primarily in the liver, muscle cells), or as triglyceride in adipose tissue.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>An imbalance in glucose intake and energy expenditure has been shown to lead to both adipose cell <a href="/facts/Hypertrophy/4JolPfnS">hypertrophy</a> and <a href="/facts/Hyperplasia/gDv6kB4j">hyperplasia</a>, which lead to obesity.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> In addition, mutations in GLUT4 genes in <a href="/facts/Adipocyte/FuM7LlaK">adipocytes</a> can also lead to increased GLUT4 expression in adipose cells, which allows for increased glucose uptake and therefore more fat stored. If GLUT4 is over-expressed, it can actually alter nutrient distribution and send excess glucose into adipose tissue, leading to increased adipose tissue mass.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p> <h2 id="regulation">Regulation</h2> <h3>Insulin</h3> <p>Insulin is released from the pancreas and into the bloodstream in response to increased glucose concentration in the blood.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Insulin is stored in <a href="/facts/Beta_cells/MXcTmlDL">beta cells</a> in the pancreas. When glucose in the blood binds to glucose receptors on the beta cell membrane, a <a href="/facts/Biochemical_cascade/bCsA7XXG">signal cascade</a> is initiated inside the cell that results in insulin stored in <a href="/facts/Vesicle_(biology_and_chemistry)/1KjHpjMM">vesicles</a> in these cells being released into the blood stream.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> Increased insulin levels cause the uptake of glucose into the cells. GLUT4 is stored in the cell in <a href="/facts/Transport_vesicles/1KjHpjMM">transport vesicles</a>, and is quickly incorporated into the plasma membrane of the cell when insulin binds to <a href="/facts/Membrane_receptors/0YGSjDdL">membrane receptors</a>.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p><p>Under conditions of low insulin, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> The genetically engineered muscle insulin receptor knock‐out (MIRKO) mouse was designed to be insensitive to glucose uptake caused by insulin, meaning that GLUT4 is absent. Mice with diabetes or fasting hyperglycemia, however, were found to be immune to the negative effects of the insensitivity.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <p>The mechanism for GLUT4 is an example of a <a href="/facts/Signal_transduction/1bs0Me6w">cascade</a> effect, where binding of a <a href="/facts/Ligand/6etB3qeW">ligand</a> to a membrane receptor amplifies the signal and causes a cellular response. In this case, insulin binds to the <a href="/facts/Insulin_receptor/PCEbQj6k">insulin receptor</a> in its <a href="/facts/Protein_dimer/c8LwFJPG">dimeric</a> form and activates the receptor's tyrosine-kinase domain. The receptor then recruits Insulin Receptor Substrate, or <a href="/facts/IRS1/10dcP6Qy">IRS-1</a>, which binds the enzyme PI-3 kinase. PI-3 kinase converts the membrane lipid <a href="/facts/PIP2/Sq6VS4vk">PIP2</a> to <a href="/facts/PIP3/KII7ugLk">PIP3</a>. PIP3 is specifically recognized by PKB (<a href="/facts/Protein_kinase_B/odL6duk1">protein kinase B</a>) and by PDK1, which can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates <a href="/facts/TBC1D4/n2s8lIdo">TBC1D4</a>, which inhibits the <a href="/facts/GTPase-activating_protein/cYrksJYC">GTPase-activating domain</a> associated with TBC1D4, allowing for Rab protein to change from its GDP to GTP bound state. Inhibition of the GTPase-activating domain leaves proteins next in the cascade in their active form, and stimulates GLUT4 to be expressed on the plasma membrane.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p><p><a href="/facts/RAC1/4tNQpMVA">RAC1</a> is a <a href="/facts/GTPase/74gpHwWI">GTPase</a> also activated by insulin. Rac1 stimulates reorganization of the cortical <a href="/facts/Actin_cytoskeleton/TR7qU9Jv">Actin cytoskeleton</a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> which allows for the GLUT4 vesicles to be inserted into the plasma membrane.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> A <a href="/facts/RAC1/4tNQpMVA">RAC1</a> <a href="/facts/Knockout_mouse/Aw50cobf">Knockout mouse</a> has reduced glucose uptake in muscle tissue.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p><p><a href="/facts/Knockout_mouse/Aw50cobf">Knockout mice</a> that are heterozygous for GLUT4 develop <a href="/facts/Insulin_resistance/cz6oFqke">insulin resistance</a> in their muscles as well as <a href="/facts/Diabetes/2xeHXbsI">diabetes</a>.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p> <h3>Muscle contraction</h3> <p>Muscle contraction stimulates muscle cells to translocate GLUT4 receptors to their surfaces. This is especially true in cardiac muscle, where continuous contraction increases the rate of GLUT4 translocation; but is observed to a lesser extent in increased skeletal muscle contraction.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> In skeletal muscle, muscle contractions substantially increase GLUT4 translocation,<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> which is regulated by <a href="/facts/RAC1/4tNQpMVA">RAC1</a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> and <a href="/facts/AMP-activated_protein_kinase/Uka4mXB7">AMP-activated protein kinase (AMPK)</a>.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> Contraction-induced glucose uptake involves the phosphorylation of <a href="/facts/Rab_(G-protein)/fYkGrtGA">RabGaps</a>, <a href="/facts/TBC1D1/GxBVNzRg">TBC1D1</a> and <a href="/facts/TBC1D4/n2s8lIdo">TBC1D4</a>, by AMPK and other kinases such as SNARK.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> This mechanism remains functional in insulin-resistant states, establishing the muscle-contraction pathway's independence from insulin stimulation.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> The figure to the right demonstrates how insulin- and contraction-stimulated GLUT4 translocation differ but ultimately converge on TBC1D1/4. Phosphorylation of TBC1D1/4 inactivates it, allowing Rab proteins to load GTP and directly participate in the trafficking of GLUT4 to the membrane.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> </p><p>AMPK plays a crucial role in the contraction pathway.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> ATP is known as an energy-sensing enzyme, as it's highly responsive to an increase in the AMP to ATP ratio.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> ATP is hydrolyzed to ADP during muscle contraction by <a href="/facts/Actomyosin/uGRRhxms">actomyosin ATPase</a>.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> <a href="/facts/Adenylate_kinase/XVLmsCUa">Adenylate kinase</a> subsequently converts ADP through the following reaction: 2ADP→ATP+AMP.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> This ensures rapid replenishment of ATP, while increasing AMP concentration.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> ATP competes with AMP for coupling to the AMPK binding domain and thus inhibits AMPK activity, particularly when the muscle is at rest and ATP concentration is high.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> AMP has a much stronger affinity for the binding domain (known as the Bateman domain) of AMPK, and will thus out-compete ATP as AMP concentration increases.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> This ultimately results in the phosphorylation and activation of AMPK by LKB1<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> and triggers a cascade of signaling events driven by AMPK, leading to the translocation of GLUT4.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> </p><p>Muscle stretching also stimulates GLUT4 translocation and glucose uptake in rodent muscle via <a href="/facts/RAC1/4tNQpMVA">RAC1</a>.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>GLUT4 has been shown to interact with <a href="/facts/Death_associated_protein_6/fwlmBARX">death-associated protein 6</a>, also known as Daxx. Daxx, which is used to regulate <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a>, has been shown to associate with GLUT4 in the cytoplasm. UBX-domains, such as the one found in GLUT4, have been shown to associate with apoptotic signaling.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> So this interaction aids in the translocation of Daxx within the cell.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> </p><p>In addition, recent reports demonstrated the presence of GLUT4 gene in central nervous system such as the <a href="/facts/Hippocampus/X7CqbP8X">hippocampus</a>. Moreover, impairment in insulin-stimulated trafficking of GLUT4 in the hippocampus result in decreased metabolic activities and plasticity of hippocampal neurons, which leads to depressive like behaviour and cognitive dysfunction.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a><a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a><a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> </p> <h2 id="interactive-pathway-map">Interactive pathway map</h2> <p><i>Click on genes, proteins and metabolites below to link to respective articles.</i><a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=GLUT4+Protein">GLUT4+Protein</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li><a href="https://web.archive.org/web/20110927134141/http://www.signaling-gateway.org/molecule/query?afcsid=A001046"><i>USCD—Nature molecule pages: The signaling pathway", "GLUT4"</i></a><i>; contains a high-resolution network map. Accessed 25 December 2009.</i></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Watson RT, Pessin JE (2001). "9" (PDF). Written at 51 Newton Road, Iowa City, Iowa 52242. Intracellular Organization of Insulin Signaling and GLUT4 Translocation. Department of Physiology & Biophysics. Vol. 56. The University of Iowa. pp. 175–193. doi:10.1210/rp.56.1.175. PMID 11237212. {{cite book}}: |journal= ignored (help)CS1 maint: location (link) CS1 maint: location missing publisher (link) <a href="https://www.endocrine.org/~/media/endosociety/files/ep/rphr/56/rphr_vol_56_ch_09_intracellular_organization.pdf" target="_blank">https://www.endocrine.org/~/media/endosociety/files/ep/rphr/56/rphr_vol_56_ch_09_intracellular_organization.pdf</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>James DE, Brown R, Navarro J, Pilch PF (May 1988). "Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein". Nature. 333 (6169): 183–185. Bibcode:1988Natur.333..183J. doi:10.1038/333183a0. PMID 3285221. S2CID 4237493. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>James DE, Strube M, Mueckler M (March 1989). "Molecular cloning and characterization of an insulin-regulatable glucose transporter". Nature. 338 (6210): 83–87. Bibcode:1989Natur.338...83J. doi:10.1038/338083a0. PMID 2645527. S2CID 4285627. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Birnbaum MJ (April 1989). "Identification of a novel gene encoding an insulin-responsive glucose transporter protein". Cell. 57 (2): 305–315. doi:10.1016/0092-8674(89)90968-9. PMID 2649253. 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"The GLUT4 glucose transporter". Cell Metabolism. 5 (4): 237–252. doi:10.1016/j.cmet.2007.03.006. PMID 17403369. <a href="https://doi.org/10.1016%2Fj.cmet.2007.03.006" target="_blank">https://doi.org/10.1016%2Fj.cmet.2007.03.006</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Mueckler M, Thorens B (2013). "The SLC2 (GLUT) family of membrane transporters". Molecular Aspects of Medicine. 34 (2–3): 121–138. doi:10.1016/j.mam.2012.07.001. PMC 4104978. PMID 23506862. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104978" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104978</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Richter EA, Hargreaves M (July 2013). "Exercise, GLUT4, and skeletal muscle glucose uptake". Physiological Reviews. 93 (3): 993–1017. doi:10.1152/physrev.00038.2012. 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