GLUT4

File:PDB 2al3 EBI.jpg. These are ubiquitin-regulatory regions that can assist with cell signaling.{{cite journal | vauthors = Buchberger A, Howard MJ, Proctor M, Bycroft M | title = The UBX domain: a widespread ubiquitin-like module | journal = Journal of Molecular Biology | volume = 307 | issue = 1 | pages = 17–24 | date = March 2001 | pmid = 11243799 | doi = 10.1006/jmbi.2000.4462 }} ]]

Like all proteins, the unique amino acid arrangement in the primary sequence of GLUT4 is what allows it to transport glucose across the plasma membrane. In addition to the phenylalanine on the N-terminus, two Leucine residues and acidic motifs on the COOH-terminus are believed to play a key role in the kinetics of endocytosis and exocytosis.{{cite journal | vauthors = Huang S, Czech MP | title = The GLUT4 glucose transporter | journal = Cell Metabolism | volume = 5 | issue = 4 | pages = 237–252 | date = April 2007 | pmid = 17403369 | doi = 10.1016/j.cmet.2007.03.006 | doi-access = free }}

There are 14 total GLUT proteins separated into 3 classes based on sequence 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.

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 cytoplasm of the cell, and they all have 12 transmembrane segments.{{cite journal | vauthors = Mueckler M, Thorens B | title = The SLC2 (GLUT) family of membrane transporters | journal = Molecular Aspects of Medicine | volume = 34 | issue = 2–3 | pages = 121–138 | date = 2013 | pmid = 23506862 | pmc = 4104978 | doi = 10.1016/j.mam.2012.07.001 }}

File:1008 Skeletal Muscle Contraction.jpg

In striated skeletal muscle cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction.

During exercise, the body needs to convert glucose to ATP to be used as energy. As G-6-P concentrations decrease, hexokinase 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 facilitated diffusion.{{cite journal | vauthors = Richter EA, Hargreaves M | title = Exercise, GLUT4, and skeletal muscle glucose uptake | journal = Physiological Reviews | volume = 93 | issue = 3 | pages = 993–1017 | date = July 2013 | pmid = 23899560 | doi = 10.1152/physrev.00038.2012 }}

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.{{cite journal | vauthors = Ploug T, van Deurs B, Ai H, Cushman SW, Ralston E | title = Analysis of GLUT4 distribution in whole skeletal muscle fibers: identification of distinct storage compartments that are recruited by insulin and muscle contractions | journal = The Journal of Cell Biology | volume = 142 | issue = 6 | pages = 1429–1446 | date = September 1998 | pmid = 9744875 | pmc = 2141761 | doi = 10.1083/jcb.142.6.1429 }}{{cite journal | vauthors = Lauritzen HP | title = Insulin- and contraction-induced glucose transporter 4 traffic in muscle: insights from a novel imaging approach | journal = Exercise and Sport Sciences Reviews | volume = 41 | issue = 2 | pages = 77–86 | date = April 2013 | pmid = 23072821 | pmc = 3602324 | doi = 10.1097/JES.0b013e318275574c }}

Cardiac muscle is slightly different from skeletal muscle. At rest, they prefer to utilize fatty acids 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.{{cite journal | vauthors = Morgan HE, Henderson MJ, Regen DM, Park CR | title = Regulation of glucose uptake in heart muscle from normal and alloxan-diabetic rats: the effects of insulin, growth hormone, cortisone, and anoxia | journal = Annals of the New York Academy of Sciences | volume = 82 | issue = 2 | pages = 387–402 | date = September 1959 | pmid = 14424107 | doi = 10.1111/j.1749-6632.1959.tb44920.x | s2cid = 32458568 | bibcode = 1959NYASA..82..387M }}

 An analysis of mRNA levels of GLUT1 and GLUT4 in cardiac muscles show that GLUT1 plays a larger role in cardiac muscles than it does in skeletal muscles.{{cite journal | vauthors = Laybutt DR, Thompson AL, Cooney GJ, Kraegen EW | title = Selective chronic regulation of GLUT1 and GLUT4 content by insulin, glucose, and lipid in rat cardiac muscle in vivo | journal = The American Journal of Physiology | volume = 273 | issue = 3 Pt 2 | pages = H1309–H1316 | date = September 1997 | pmid = 9321820 | doi = 10.1152/ajpheart.1997.273.3.H1309 }} GLUT4, however, is still believed to be the primary transporter for glucose.{{cite journal | vauthors = Rett K, Wicklmayr M, Dietze GJ, Häring HU | title = Insulin-induced glucose transporter (GLUT1 and GLUT4) translocation in cardiac muscle tissue is mimicked by bradykinin | journal = Diabetes | volume = 45 Suppl 1 | issue = Supplement 1 | pages = S66–S69 | date = January 1996 | pmid = 8529803 | doi = 10.2337/diab.45.1.S66 | s2cid = 7766813 }}

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. {{cite journal | vauthors = Slot JW, Geuze HJ, Gigengack S, James DE, Lienhard GE | title = Translocation of the glucose transporter GLUT4 in cardiac myocytes of the rat | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 17 | pages = 7815–7819 | date = September 1991 | pmid = 1881917 | pmc = 52394 | doi = 10.1073/pnas.88.17.7815 | doi-access = free | bibcode = 1991PNAS...88.7815S }}{{cite journal | vauthors = Luiken JJ, Glatz JF, Neumann D | title = Cardiac contraction-induced GLUT4 translocation requires dual signaling input | journal = Trends in Endocrinology and Metabolism | volume = 26 | issue = 8 | pages = 404–410 | date = August 2015 | pmid = 26138758 | doi = 10.1016/j.tem.2015.06.002 | s2cid = 171571 | url = https://cris.maastrichtuniversity.nl/en/publications/b8b4950b-f9f7-452f-b1f2-8d2cdd4f8b2f }}

Adipose tissue, commonly known as fat,{{cite news|url=https://www.sciencedaily.com/terms/adipose_tissue.htm|title=Adipose tissue|work=ScienceDaily|access-date=2017-05-24}} is a depository for energy in order to conserve metabolic homeostasis. As the body takes in energy in the form of glucose, some is expended, and the rest is stored as glycogen (primarily in the liver, muscle cells), or as triglyceride in adipose tissue.{{cite journal | vauthors = Favaretto F, Milan G, Collin GB, Marshall JD, Stasi F, Maffei P, Vettor R, Naggert JK | title = GLUT4 defects in adipose tissue are early signs of metabolic alterations in Alms1GT/GT, a mouse model for obesity and insulin resistance | journal = PLOS ONE | volume = 9 | issue = 10 | pages = e109540 | date = 2014-10-09 | pmid = 25299671 | pmc = 4192353 | doi = 10.1371/journal.pone.0109540 | doi-access = free | bibcode = 2014PLoSO...9j9540F }}

An imbalance in glucose intake and energy expenditure has been shown to lead to both adipose cell hypertrophy and hyperplasia, which lead to obesity.{{cite journal | vauthors = Shepherd PR, Gnudi L, Tozzo E, Yang H, Leach F, Kahn BB | title = Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue | journal = The Journal of Biological Chemistry | volume = 268 | issue = 30 | pages = 22243–22246 | date = October 1993 | pmid = 8226728 | doi = 10.1016/S0021-9258(18)41516-5 | doi-access = free }} In addition, mutations in GLUT4 genes in adipocytes 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. 

Insulin is released from the pancreas and into the bloodstream in response to increased glucose concentration in the blood.{{cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html|title=Insulin Synthesis and Secretion|website=www.vivo.colostate.edu|access-date=2017-05-24}} Insulin is stored in beta cells in the pancreas. When glucose in the blood binds to glucose receptors on the beta cell membrane, a signal cascade is initiated inside the cell that results in insulin stored in vesicles in these cells being released into the blood stream.{{cite journal | vauthors = Fu Z, Gilbert ER, Liu D | title = Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes | journal = Current Diabetes Reviews | volume = 9 | issue = 1 | pages = 25–53 | date = January 2013 | pmid = 22974359 | pmc = 3934755 | doi = 10.2174/1573399811309010025 }} Increased insulin levels cause the uptake of glucose into the cells. GLUT4 is stored in the cell in transport vesicles, and is quickly incorporated into the plasma membrane of the cell when insulin binds to membrane receptors.

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.{{cite journal | vauthors = Cushman SW, Wardzala LJ | title = Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane | journal = The Journal of Biological Chemistry | volume = 255 | issue = 10 | pages = 4758–4762 | date = May 1980 | pmid = 6989818 | doi = 10.1016/S0021-9258(19)85561-8 | doi-access = free }}

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.{{cite journal | vauthors = Sonksen P, Sonksen J | title = Insulin: understanding its action in health and disease | journal = British Journal of Anaesthesia | volume = 85 | issue = 1 | pages = 69–79 | date = July 2000 | pmid = 10927996 | doi = 10.1093/bja/85.1.69 | doi-access = free }}

File:Signal_Transduction_Diagram-_Insulin.svg

The mechanism for GLUT4 is an example of a cascade effect, where binding of a ligand to a membrane receptor amplifies the signal and causes a cellular response. In this case, insulin binds to the insulin receptor in its dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then recruits Insulin Receptor Substrate, or IRS-1, which binds the enzyme PI-3 kinase. PI-3 kinase converts the membrane lipid PIP2 to PIP3. PIP3 is specifically recognized by PKB (protein kinase B) and by PDK1, which can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates TBC1D4, which inhibits the GTPase-activating domain 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.{{cite journal | vauthors = Leto D, Saltiel AR | title = Regulation of glucose transport by insulin: traffic control of GLUT4 | language = En | journal = Nature Reviews. Molecular Cell Biology | volume = 13 | issue = 6 | pages = 383–396 | date = May 2012 | pmid = 22617471 | doi = 10.1038/nrm3351 | s2cid = 39756994 }}

RAC1 is a GTPase also activated by insulin. Rac1 stimulates reorganization of the cortical Actin cytoskeleton{{cite journal | vauthors = JeBailey L, Wanono O, Niu W, Roessler J, Rudich A, Klip A | title = Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells | journal = Diabetes | volume = 56 | issue = 2 | pages = 394–403 | date = February 2007 | pmid = 17259384 | doi = 10.2337/db06-0823 | doi-access = free }} which allows for the GLUT4 vesicles to be inserted into the plasma membrane.{{cite journal | vauthors = Sylow L, Kleinert M, Pehmøller C, Prats C, Chiu TT, Klip A, Richter EA, Jensen TE | title = Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance | journal = Cellular Signalling | volume = 26 | issue = 2 | pages = 323–331 | date = February 2014 | pmid = 24216610 | doi = 10.1016/j.cellsig.2013.11.007 }}{{cite journal | vauthors = Sylow L, Jensen TE, Kleinert M, Højlund K, Kiens B, Wojtaszewski J, Prats C, Schjerling P, Richter EA | title = Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle | journal = Diabetes | volume = 62 | issue = 6 | pages = 1865–1875 | date = June 2013 | pmid = 23423567 | pmc = 3661612 | doi = 10.2337/db12-1148 }} A RAC1 Knockout mouse has reduced glucose uptake in muscle tissue.

Knockout mice that are heterozygous for GLUT4 develop insulin resistance in their muscles as well as diabetes.{{cite journal | vauthors = Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM, Houseknecht K, Katz EB, Charron MJ | title = GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes | journal = Nature Medicine | volume = 3 | issue = 10 | pages = 1096–1101 | date = October 1997 | pmid = 9334720 | doi = 10.1038/nm1097-1096 | s2cid = 8643507 }}

File:GLUT4signalingpathway.png

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.{{cite journal | vauthors = Lund S, Holman GD, Schmitz O, Pedersen O | title = Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 13 | pages = 5817–5821 | date = June 1995 | pmid = 7597034 | pmc = 41592 | doi = 10.1073/pnas.92.13.5817 | doi-access = free | bibcode = 1995PNAS...92.5817L }} In skeletal muscle, muscle contractions substantially increase GLUT4 translocation,{{cite journal | vauthors = Jensen TE, Sylow L, Rose AJ, Madsen AB, Angin Y, Maarbjerg SJ, Richter EA | title = Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca(2+) release | journal = Molecular Metabolism | volume = 3 | issue = 7 | pages = 742–753 | date = October 2014 | pmid = 25353002 | pmc = 4209358 | doi = 10.1016/j.molmet.2014.07.005 }} which is regulated by RAC1{{cite journal | vauthors = Sylow L, Møller LL, Kleinert M, Richter EA, Jensen TE | title = Rac1--a novel regulator of contraction-stimulated glucose uptake in skeletal muscle | journal = Experimental Physiology | volume = 99 | issue = 12 | pages = 1574–1580 | date = December 2014 | pmid = 25239922 | doi = 10.1113/expphysiol.2014.079194 | doi-access = free }}{{cite journal | vauthors = Sylow L, Jensen TE, Kleinert M, Mouatt JR, Maarbjerg SJ, Jeppesen J, Prats C, Chiu TT, Boguslavsky S, Klip A, Schjerling P, Richter EA | title = Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle | journal = Diabetes | volume = 62 | issue = 4 | pages = 1139–1151 | date = April 2013 | pmid = 23274900 | pmc = 3609592 | doi = 10.2337/db12-0491 }} and AMP-activated protein kinase (AMPK).{{cite journal | vauthors = Mu J, Brozinick JT, Valladares O, Bucan M, Birnbaum MJ | title = A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle | journal = Molecular Cell | volume = 7 | issue = 5 | pages = 1085–1094 | date = May 2001 | pmid = 11389854 | doi = 10.1016/s1097-2765(01)00251-9 | doi-access = free }} Contraction-induced glucose uptake involves the phosphorylation of RabGaps, TBC1D1 and TBC1D4, by AMPK and other kinases such as SNARK.{{Cite journal |last1=Skalka |first1=George L. |last2=Whyte |first2=Declan |last3=Lubawska |first3=Dominika |last4=Murphy |first4=Daniel J. |date=2024-11-18 |title=NUAK: never underestimate a kinase |url=https://portlandpress.com/essaysbiochem/article/68/3/295/234651/NUAK-never-underestimate-a-kinase |journal=Essays in Biochemistry |volume=68 |issue=3 |pages=295–307 |doi=10.1042/EBC20240005 |issn=0071-1365 |pmc=11576189 |pmid=38939918}}{{Cite journal |last1=Peifer-Weiß |first1=Leon |last2=Al-Hasani |first2=Hadi |last3=Chadt |first3=Alexandra |date=January 2024 |title=AMPK and Beyond: The Signaling Network Controlling RabGAPs and Contraction-Mediated Glucose Uptake in Skeletal Muscle |journal=International Journal of Molecular Sciences |language=en |volume=25 |issue=3 |pages=1910 |doi=10.3390/ijms25031910 |doi-access=free |pmid=38339185 |pmc=10855711 |issn=1422-0067}} This mechanism remains functional in insulin-resistant states, establishing the muscle-contraction pathway's independence from insulin stimulation. 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.

AMPK plays a crucial role in the contraction pathway.{{Cite journal |last1=Winder |first1=William W. |last2=Taylor |first2=Eric B. |last3=Thomson |first3=David M. |date=November 2006 |title=Role of AMP-Activated Protein Kinase in the Molecular Adaptation to Endurance Exercise |url=https://journals.lww.com/acsm-msse/fulltext/2006/11000/role_of_amp_activated_protein_kinase_in_the.10.aspx |journal=Medicine & Science in Sports & Exercise |language=en-US |volume=38 |issue=11 |pages=1945 |doi=10.1249/01.mss.0000233798.62153.50 |pmid=17095928 |issn=0195-9131}} ATP is known as an energy-sensing enzyme, as it's highly responsive to an increase in the AMP to ATP ratio. ATP is hydrolyzed to ADP during muscle contraction by actomyosin ATPase.{{Cite journal |last1=Barclay |first1=C. J. |last2=Curtin |first2=N. A. |date=2023-07-01 |title=Advances in understanding the energetics of muscle contraction |url=https://www.sciencedirect.com/science/article/pii/S0021929023002385 |journal=Journal of Biomechanics |volume=156 |pages=111669 |doi=10.1016/j.jbiomech.2023.111669 |pmid=37302165 |issn=0021-9290|doi-access=free }} Adenylate kinase subsequently converts ADP through the following reaction: 2ADP→ATP+AMP. This ensures rapid replenishment of ATP, while increasing AMP concentration. 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. 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. This ultimately results in the phosphorylation and activation of AMPK by LKB1{{Cite journal |last1=Huang |first1=Shaohui |last2=Czech |first2=Michael P. |date=2007-04-04 |title=The GLUT4 Glucose Transporter |url=https://www.sciencedirect.com/science/article/pii/S1550413107000678 |journal=Cell Metabolism |volume=5 |issue=4 |pages=237–252 |doi=10.1016/j.cmet.2007.03.006 |pmid=17403369 |issn=1550-4131|doi-access=free }} and triggers a cascade of signaling events driven by AMPK, leading to the translocation of GLUT4.

Muscle stretching also stimulates GLUT4 translocation and glucose uptake in rodent muscle via RAC1.{{cite journal | vauthors = Sylow L, Møller LL, Kleinert M, Richter EA, Jensen TE | title = Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1 | journal = The Journal of Physiology | volume = 593 | issue = 3 | pages = 645–656 | date = February 2015 | pmid = 25416624 | pmc = 4324711 | doi = 10.1113/jphysiol.2014.284281 }}

GLUT4 has been shown to interact with death-associated protein 6, also known as Daxx. Daxx, which is used to regulate apoptosis, 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. So this interaction aids in the translocation of Daxx within the cell.{{cite journal | vauthors = Lalioti VS, Vergarajauregui S, Pulido D, Sandoval IV | title = The insulin-sensitive glucose transporter, GLUT4, interacts physically with Daxx. Two proteins with capacity to bind Ubc9 and conjugated to SUMO1 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 22 | pages = 19783–19791 | date = May 2002 | pmid = 11842083 | doi = 10.1074/jbc.M110294200 | doi-access = free }}

In addition, recent reports demonstrated the presence of GLUT4 gene in central nervous system such as the hippocampus. 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.{{cite journal | vauthors = Patel SS, Udayabanu M | title = Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice | journal = Metabolic Brain Disease | volume = 29 | issue = 1 | pages = 121–130 | date = March 2014 | pmid = 24435938 | doi = 10.1007/s11011-014-9480-0 | s2cid = 10955351 }}{{cite journal | vauthors = Piroli GG, Grillo CA, Reznikov LR, Adams S, McEwen BS, Charron MJ, Reagan LP | title = Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus | journal = Neuroendocrinology | volume = 85 | issue = 2 | pages = 71–80 | date = 2007 | pmid = 17426391 | doi = 10.1159/000101694 | s2cid = 38081413 }}{{cite journal | vauthors = Huang CC, Lee CC, Hsu KS | title = The role of insulin receptor signaling in synaptic plasticity and cognitive function | journal = Chang Gung Medical Journal | volume = 33 | issue = 2 | pages = 115–125 | year = 2010 | pmid = 20438663 }}

{{GlycolysisGluconeogenesis_WP534|highlight=GLUT4}}

{{reflist|33em}}

• {{MeshName|GLUT4+Protein}}
• [https://web.archive.org/web/20110927134141/http://www.signaling-gateway.org/molecule/query?afcsid=A001046 ''USCD—Nature molecule pages: The signaling pathway", "GLUT4"]; contains a high-resolution network map. Accessed 25 December 2009.

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Category:Solute carrier family