GLUT4

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関

GLUT

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/27 00:57:43」(JST)

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Solute carrier family 2 (facilitated glucose transporter), member 4
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
Identifiers
Symbols	SLC2A4 ; GLUT4
External IDs	OMIM: 138190 MGI: 95758 HomoloGene: 74381 IUPHAR: 878 ChEMBL: 5874 GeneCards: SLC2A4 Gene
Gene ontology Molecular function • glucose transmembrane transporter activity • protein binding • D-glucose transmembrane transporter activity Cellular component • multivesicular body • plasma membrane • integral component of plasma membrane • coated pit • external side of plasma membrane • endomembrane system • vesicle membrane • membrane • clathrin-coated vesicle • trans-Golgi network transport vesicle • insulin-responsive compartment • sarcolemma • perinuclear region of cytoplasm • extracellular vesicular exosome Biological process • carbohydrate metabolic process • hexose transport • amylopectin biosynthetic process • glucose transport • cellular response to insulin stimulus • glucose homeostasis • small molecule metabolic process • response to ethanol • glucose import • brown fat cell differentiation • transmembrane transport • membrane organization • cellular response to osmotic stress Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6517	20528
Ensembl	ENSG00000181856	ENSMUSG00000018566
UniProt	P14672	P14142
RefSeq (mRNA)	NM_001042	NM_009204
RefSeq (protein)	NP_001033	NP_033230
Location (UCSC)	Chr 17: 7.18 – 7.19 Mb	Chr 11: 69.94 – 69.95 Mb
PubMed search	[1]	[2]

Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

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.

Tissue distribution

GLUT4 is primarily found in:

• Skeletal muscle
• Cardiac muscle
• Adipose tissue

Regulation

Insulin

Under conditions of low insulin, GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. Insulin induces a rapid increase in the uptake of glucose by inducing the translocation of GLUT4 from these vesicles to the plasma membrane. As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases.

Insulin binds to the insulin receptor in its dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then phosphorylates and subsequently recruits Insulin Receptor Substrate or IRS-1, which in turn binds the enzyme PI-3 kinase through the binding of the enzyme's SH2 domain to the pTyr of IRS. PI-3 kinase converts the membrane lipid PIP2 to PIP3. PIP3 is specifically recognized by the PH domains of PKB (protein kinase B)or AKT, and also for PDK1 which, being localized together with PKB, can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates TBC1D4, which inhibits the GAP domain or 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.

At the cell surface, GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. Once within cells, glucose is rapidly phosphorylated by glucokinase in the liver and hexokinase in other tissues to form glucose-6-phosphate, which then enters glycolysis or is polymerized into glycogen. Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells.

Knockout mice that are heterozygous for GLUT4 develop insulin resistance in their muscles as well as diabetes.

Muscle contraction

Muscle contraction stimulates muscle cells to translocate GLUT4 receptors to their surfaces. This is especially true in cardiac muscle, where continuous contraction can be relied upon; but is observed to a lesser extent in skeletal muscle.

Interactions

GLUT4 has been shown to interact with death-associated protein 6.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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Glycolysis and Gluconeogenesis edit

References

Further reading

• Slot JW, Geuze HJ, Gigengack S, Lienhard GE, James DE (April 1991). "Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat". J. Cell Biol. 113 (1): 123–35. doi:10.1083/jcb.113.1.123. PMC 2288909. PMID 2007617. 
• Govers R, Coster AC, James DE (July 2004). "Insulin increases cell surface GLUT4 levels by dose dependently discharging GLUT4 into a cell surface recycling pathway". Mol. Cell. Biol. 24 (14): 6456–66. doi:10.1128/MCB.24.14.6456-6466.2004. PMC 434240. PMID 15226445. 
• Ng Y, Ramm G, Lopez JA, James DE (April 2008). "Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes". Cell Metab. 7 (4): 348–56. doi:10.1016/j.cmet.2008.02.008. PMID 18396141. 
• Foster LJ, Klip A (2000). "Mechanism and regulation of GLUT-4 vesicle fusion in muscle and fat cells". Am. J. Physiol., Cell Physiol. 279 (4): C877–90. PMID 11003568. 
• Bryant NJ, Govers R, James DE (2002). "Regulated transport of the glucose transporter GLUT4". Nature Reviews Molecular Cell Biology 3 (4): 267–77. doi:10.1038/nrm782. PMID 11994746. 
• Baumann MU, Deborde S, Illsley NP (2003). "Placental glucose transfer and fetal growth". Endocrine 19 (1): 13–22. doi:10.1385/ENDO:19:1:13. PMID 12583599. 
• Olson AL, Knight JB (2004). "Regulation of GLUT4 expression in vivo and in vitro". Front. Biosci. 8 (1-3): s401–09. doi:10.2741/1072. PMID 12700047. 
• McCarthy AM, Elmendorf JS (2007). "GLUT4's itinerary in health & disease". Indian J. Med. Res. 125 (3): 373–88. PMID 17496362. 
• Buse JB, Yasuda K, Lay TP et al. (1992). "Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation". Diabetes 41 (11): 1436–45. doi:10.2337/diabetes.41.11.1436. PMID 1397719. 
• O'Rahilly S, Krook A, Morgan R et al. (1992). "Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population". Diabetologia 35 (5): 486–89. doi:10.1007/BF02342449. PMID 1521731. 
• Liu ML, Olson AL, Moye-Rowley WS et al. (1992). "Expression and regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice". J. Biol. Chem. 267 (17): 11673–36. PMID 1601840. 
• Choi WH, O'Rahilly S, Buse JB et al. (1992). "Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects". Diabetes 40 (12): 1712–18. doi:10.2337/diabetes.40.12.1712. PMID 1756912. 
• Kusari J, Verma US, Buse JB et al. (1991). "Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus". J. Clin. Invest. 88 (4): 1323–30. doi:10.1172/JCI115437. PMC 295602. PMID 1918382. 
• Fukumoto H, Kayano T, Buse JB et al. (1989). "Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues". J. Biol. Chem. 264 (14): 7776–79. PMID 2656669. 
• Chiaramonte R, Martini R, Taramelli R, Comi P (1993). "Identification of the 5' end of the gene encoding a human insulin-responsive glucose transporter". Gene 130 (2): 307–08. doi:10.1016/0378-1119(93)90438-9. PMID 7916714. 
• Verhey KJ, Birnbaum MJ (1994). "A Leu-Leu sequence is essential for COOH-terminal targeting signal of GLUT4 glucose transporter in fibroblasts". J. Biol. Chem. 269 (4): 2353–56. PMID 8300557. 
• Lee W, Samuel J, Zhang W et al. (1997). "A myosin-derived peptide C109 binds to GLUT4-vesicles and inhibits the insulin-induced glucose transport stimulation and GLUT4 recruitment in rat adipocytes". Biochem. Biophys. Res. Commun. 240 (2): 409–14. doi:10.1006/bbrc.1997.7671. PMID 9388492. 
• Shi Y, Samuel SJ, Lee W et al. (1999). "Cloning of an L-3-hydroxyacyl-CoA dehydrogenase that interacts with the GLUT4 C-terminus". Arch. Biochem. Biophys. 363 (2): 323–32. doi:10.1006/abbi.1998.1088. PMID 10068455. 
• Abel ED, Kaulbach HC, Tian R et al. (2000). "Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart". J. Clin. Invest. 104 (12): 1703–14. doi:10.1172/JCI7605. PMC 409881. PMID 10606624. 
• Abel ED, Peroni O, Kim JK et al. (2001). "Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver". Nature 409 (6821): 729–33. doi:10.1038/35055575. PMID 11217863. 

External links

• GLUT4 Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
• USCD—Nature molecule pages: The signaling pathway", "GLUT4"; contains a high-resolution network map. Accessed 25 December 2009.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 2型糖尿病の病因 pathogenesis of type 2 diabetes mellitus
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English Journal

• Distinct Properties of Telmisartan on Agonistic Activities for Peroxisome Proliferator-Activated Receptor γ among Clinically Used Angiotensin II Receptor Blockers: Drug-Target Interaction Analyses.

• Kakuta H1, Kurosaki E, Niimi T, Gato K, Kawasaki Y, Suwa A, Honbou K, Yamaguchi T, Okumura H, Sanagi M, Tomura Y, Orita M, Yonemoto T, Masuzaki H.Author information 1Drug Discovery Research, Astellas Pharma, Inc., Ibaraki, Japan (H.K., E.K., T.N., K.G., Y.K., A.S., K.H., T.Y., M.S., Y.T., M.O.);Medical Affairs, Astellas Pharma, Inc., Tokyo, Japan (H.O.); Shizuoka Prefectural General Hospital, Shizuoka, Japan (T.Y.); and Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan (H.M.).AbstractA proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.
• The Journal of pharmacology and experimental therapeutics.J Pharmacol Exp Ther.2014 Apr;349(1):10-20. doi: 10.1124/jpet.113.211722. Epub 2014 Jan 14.
• A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed
• PMID 24424487

• Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model.

• Fuhrmann A1, Lopes P1, Sereno J2, Pedro J1, Espinoza DO1, Pereira MJ3, Reis F2, Eriksson JW4, Carvalho E5.Author information 1Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.2Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.3Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal; Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden.4Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden.5Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal; The Portuguese Diabetes Association (APDP-ERC), 1250-203 Lisbon, Portugal. Electronic address: ecarvalh@cnc.uc.pt.AbstractCyclosporin A (CsA) and sirolimus (SRL) are immunosuppressive agents (IAs) associated with dyslipidemia, insulin resistance and new onset diabetes after transplantation (NODAT). However, the molecular mechanisms involved are not fully understood. We investigated the effects of six-week treatment of either CsA or SRL on glucose and lipid metabolism in Wistar rats. The results show that, compared with vehicle-treated rats, SRL-treated rats were significantly lighter starting at week 5. CsA or SRL caused glucose intolerance, increased storage of lipids in the liver and skeletal muscle, and decreased the insulin-stimulated glucose uptake in isolated adipocytes. Furthermore, these agents significantly decreased genes involved in insulin action and glucose uptake, such as, IRS-1, Glut4 and Glut1, and increased genes and/or proteins involved in hepatic lipogenesis and gluconeogenesis, while decreasing them in adipose tissue. After either treatment PGC1α gene expression was down regulated in skeletal muscle, an important player in fatty acid oxidation. Moreover, there was an increase in IL-6 gene expression in adipose tissue in the SRL-treated rats, suggesting stimulation of lipolysis. The results of the present study suggest that CsA and SRL lead to metabolic alterations in liver, muscle and adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
• Biochemical pharmacology.Biochem Pharmacol.2014 Mar 15;88(2):216-28. doi: 10.1016/j.bcp.2014.01.020. Epub 2014 Jan 22.
• Cyclosporin A (CsA) and sirolimus (SRL) are immunosuppressive agents (IAs) associated with dyslipidemia, insulin resistance and new onset diabetes after transplantation (NODAT). However, the molecular mechanisms involved are not fully understood. We investigated the effects of six-week treatment of
• PMID 24462915

• Regulation of myosin IIA and filamentous actin during insulin-stimulated glucose uptake in 3T3-L1 adipocytes.

• Stall R1, Ramos J1, Kent Fulcher F1, Patel YM2.Author information 1Department of Biology, University of North Carolina at Greensboro, 312 Eberhart Building, Greensboro, NC 27412, USA.2Department of Biology, University of North Carolina at Greensboro, 312 Eberhart Building, Greensboro, NC 27412, USA. Electronic address: ympatel@uncg.edu.AbstractInsulin stimulated glucose uptake requires the colocalization of myosin IIA (MyoIIA) and the insulin-responsive glucose transporter 4 (GLUT4) at the plasma membrane for proper GLUT4 fusion. MyoIIA facilitates filamentous actin (F-actin) reorganization in various cell types. In adipocytes F-actin reorganization is required for insulin-stimulated glucose uptake. What is not known is whether MyoIIA interacts with F-actin to regulate insulin-induced GLUT4 fusion at the plasma membrane. To elucidate the relationship between MyoIIA and F-actin, we examined the colocalization of MyoIIA and F-actin at the plasma membrane upon insulin stimulation as well as the regulation of this interaction. Our findings demonstrated that MyoIIA and F-actin colocalized at the site of GLUT4 fusion with the plasma membrane upon insulin stimulation. Furthermore, inhibition of MyoII with blebbistatin impaired F-actin localization at the plasma membrane. Next we examined the regulatory role of calcium in MyoIIA-F-actin colocalization. Reduced calcium or calmodulin levels decreased colocalization of MyoIIA and F-actin at the plasma membrane. While calcium alone can translocate MyoIIA it did not stimulate F-actin accumulation at the plasma membrane. Taken together, we established that while MyoIIA activity is required for F-actin localization at the plasma membrane, it alone is insufficient to localize F-actin to the plasma membrane.
• Experimental cell research.Exp Cell Res.2014 Mar 10;322(1):81-8. doi: 10.1016/j.yexcr.2013.12.011. Epub 2013 Dec 25.
• Insulin stimulated glucose uptake requires the colocalization of myosin IIA (MyoIIA) and the insulin-responsive glucose transporter 4 (GLUT4) at the plasma membrane for proper GLUT4 fusion. MyoIIA facilitates filamentous actin (F-actin) reorganization in various cell types. In adipocytes F-actin reo
• PMID 24374234

Japanese Journal

• Fucoxanthin promotes translocation and induction of glucose transporter 4 in skeletal muscles of diabetic/obese KK-Ay mice

• Nishikawa Sho,Hosokawa Masashi,Miyashita Kazuo
• Phytomedicine 19(5), 389-394, 2012-03-15
• … In the soleus muscle of KK-Ay mice that were fed Fx, glucose transporter 4 (GLUT4) translocation to plasma membranes from cytosol was promoted. … On the other hand, Fx increased GLUT4 expression levels in the extensor digitorum longus (EDL) muscle, although GLUT4 translocation tended to increase. …
• NAID 120004094728

• Oleuropein and hydroxytyrosol inhibit adipocyte differentiation in 3 T3-L1 cells

• Drira Riadh,Shu Chen,Sakamoto Kazuichi,坂本 和一
• Life sciences 89(19-20), 708-716, 2011-11
• … PPARγ, C/EBPα and SREBP-1c transcription factors and their downstream targets genes (GLUT4, CD36 and FASN) were down-regulated after treatment by oleuropein and hydroxytyrosol. …
• NAID 120003551304

Related Links

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ブドウ糖（グルコース）は、細胞のエネルギー源となる重要な栄養素。血液中のグルコース濃度は、さまざまなホルモンの働きによって、通常は一定になるように調節されているが、この恒常性を維持するメカニズムが働かなくなり、血液中 ...

• 2型糖尿病に関わるグルコース輸送体「GLUT4」上の糖鎖の ...

糖の一種であるグルコース（ブドウ糖）は、細胞のエネルギー源として生物に必須の栄養素です。血液中のグルコース濃度はさまざまなホルモンの働きによって常に一定となる（恒常性）ように調節されていますが、最近の研究から ...

• GLUT4（グルット4）とは - 進藤医師のブログ - Yahoo!ブログ

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Related Pictures

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★リンクテーブル★

リンク元	「グルコース輸送体」「glucose transporter 4」「4型グルコース輸送体」「グルコーストランスポーター4」
関連記事	「GLUT」

「グルコース輸送体」

　　[★]

英

glucose transporter, GLUT, glucose transporters

同

ブドウ糖輸送担体、 糖輸送体 糖輸送担体 sugar transporter

• グルコースの促通拡散を担う

GLUTの種類

GLUT	発現部位	機能
GLUT1	赤血球、脳、筋肉、脂肪、その他。×肝臓
GLUT2	肝臓、脾臓β細胞	KM≒60mM、hexokinase IV(glucokinase)(50kDa)
GLUT3	脳、神経	グルコース需要が多い場所で発現
GLUT4	筋と脂肪組織のみ	インスリン→Vmax↑。KM=2-5mM、hexokinase II(100kDa)
GLUT5	小腸上皮管腔側	フルクトースの受動輸送
GLUT7	肝臓小胞体	G6Pの脱リン酸化に関与(FB. 453)

-GLUT

-GLUT

「glucose transporter 4」

　　[★]

4型グルコース輸送体、グルコース輸送体4、グルコーストランス・ーター4

関

glucose transporter type 4、GLUT4

「4型グルコース輸送体」

　　[★]

英

glucose transporter 4、glucose transporter type 4、GLUT4

関

グルコーストランス・ーター4、グルコース輸送体4

「グルコーストランスポーター4」

　　[★]

英

glucose transporter 4、glucose transporter type 4、GLUT4

関

4型グルコース輸送体、グルコース輸送体4

「GLUT」

　　[★] グルコース輸送体 glucose transporter glucose transporters