GLUT4

GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle (skeletal and cardiac) that is responsible for insulin-regulated glucose disposal. It was discovered by Morris Birnbaum.cite journal |author=Birnbaum MJ |title=Identification of a novel gene encoding an insulin-responsive glucose transporter protein |journal=Cell |volume=57 |issue=2 |pages=305–15 |year=1989 |pmid=2649253 |doi=]

Reaction to insulin

In the absence of insulin, GLUT4 is sequestered in the interior of muscle and fat cells, within the lipid bilayer of vesicles.

Insulin induces the redistribution of GLUT4 from intracellular storage sites to the plasma membrane.

Once at the cell surface, GLUT4 facilitates the passive diffusion of circulating glucose down its concentration gradient into muscle and fat cells.

Once inside cells, glucose is rapidly phosphorylated by hexokinase to form glucose-6-phosphate, which then enters glycolysis.

Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells. [cite journal |author=Watson RT, Kanzaki M, Pessin JE |title=Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes |journal=Endocr. Rev. |volume=25 |issue=2 |pages=177–204 |year=2004 |pmid=15082519 |doi=]

Pathway

The pathway in which GLUT4 is expressed on the plasma membrane begins with insulin binding to the receptor in its dimer form. The receptor phosphorylates and subsequently activates IRS-1, which converts PIP2 to PIP3. PIP3 is bound to PKB (protein kinase B), signaling for PDK1 to phosphorylate PKB. Once phosphorylated, PKB is in its active form and phosphorylates other targets that stimulate GLUT4 to be expressed on the plasma membrane.

Contraction

Contraction also stimulates the cell to translocate GLUT4 receptors to the surface. This is especially true in cardiac muscle, where continuous contraction can be relied upon; but is observed to a lesser extent in skeletal muscle. [cite journal |author=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=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=13 |pages=5817–21 |year=1995 |pmid=7597034 |doi=]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Foster LJ, Klip A |title=Mechanism and regulation of GLUT-4 vesicle fusion in muscle and fat cells. |journal=Am. J. Physiol., Cell Physiol. |volume=279 |issue= 4 |pages= C877–90 |year= 2000 |pmid= 11003568 |doi=
*cite journal | author=Bryant NJ, Govers R, James DE |title=Regulated transport of the glucose transporter GLUT4. |journal=Nat. Rev. Mol. Cell Biol. |volume=3 |issue= 4 |pages= 267–77 |year= 2002 |pmid= 11994746 |doi= 10.1038/nrm782
*cite journal | author=Baumann MU, Deborde S, Illsley NP |title=Placental glucose transfer and fetal growth. |journal=Endocrine |volume=19 |issue= 1 |pages= 13–22 |year= 2003 |pmid= 12583599 |doi=
*cite journal | author=Olson AL, Knight JB |title=Regulation of GLUT4 expression in vivo and in vitro. |journal=Front. Biosci. |volume=8 |issue= |pages= s401–9 |year= 2004 |pmid= 12700047 |doi=
*cite journal | author=McCarthy AM, Elmendorf JS |title=GLUT4's itinerary in health & disease. |journal=Indian J. Med. Res. |volume=125 |issue= 3 |pages= 373–88 |year= 2007 |pmid= 17496362 |doi=
*cite journal | author=Buse JB, Yasuda K, Lay TP, "et al." |title=Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation. |journal=Diabetes |volume=41 |issue= 11 |pages= 1436–45 |year= 1992 |pmid= 1397719 |doi=
*cite journal | author=O'Rahilly S, Krook A, Morgan R, "et al." |title=Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population. |journal=Diabetologia |volume=35 |issue= 5 |pages= 486–9 |year= 1992 |pmid= 1521731 |doi=
*cite journal | author=Liu ML, Olson AL, Moye-Rowley WS, "et al." |title=Expression and regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice. |journal=J. Biol. Chem. |volume=267 |issue= 17 |pages= 11673–6 |year= 1992 |pmid= 1601840 |doi=
*cite journal | author=Choi WH, O'Rahilly S, Buse JB, "et al." |title=Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects. |journal=Diabetes |volume=40 |issue= 12 |pages= 1712–8 |year= 1992 |pmid= 1756912 |doi=
*cite journal | author=Kusari J, Verma US, Buse JB, "et al." |title=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. |journal=J. Clin. Invest. |volume=88 |issue= 4 |pages= 1323–30 |year= 1991 |pmid= 1918382 |doi=
*cite journal | author=Bell GI, Murray JC, Nakamura Y, "et al." |title=Polymorphic human insulin-responsive glucose-transporter gene on chromosome 17p13. |journal=Diabetes |volume=38 |issue= 8 |pages= 1072–5 |year= 1989 |pmid= 2568955 |doi=
*cite journal | author=Birnbaum MJ |title=Identification of a novel gene encoding an insulin-responsive glucose transporter protein. |journal=Cell |volume=57 |issue= 2 |pages= 305–15 |year= 1989 |pmid= 2649253 |doi=
*cite journal | author=Fukumoto H, Kayano T, Buse JB, "et al." |title=Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues. |journal=J. Biol. Chem. |volume=264 |issue= 14 |pages= 7776–9 |year= 1989 |pmid= 2656669 |doi=
*cite journal | author=Chiaramonte R, Martini R, Taramelli R, Comi P |title=Identification of the 5' end of the gene encoding a human insulin-responsive glucose transporter. |journal=Gene |volume=130 |issue= 2 |pages= 307–8 |year= 1993 |pmid= 7916714 |doi=
*cite journal | author=Verhey KJ, Birnbaum MJ |title=A Leu-Leu sequence is essential for COOH-terminal targeting signal of GLUT4 glucose transporter in fibroblasts. |journal=J. Biol. Chem. |volume=269 |issue= 4 |pages= 2353–6 |year= 1994 |pmid= 8300557 |doi=
*cite journal | author=Lee W, Samuel J, Zhang W, "et al." |title=A myosin-derived peptide C109 binds to GLUT4-vesicles and inhibits the insulin-induced glucose transport stimulation and GLUT4 recruitment in rat adipocytes. |journal=Biochem. Biophys. Res. Commun. |volume=240 |issue= 2 |pages= 409–14 |year= 1997 |pmid= 9388492 |doi= 10.1006/bbrc.1997.7671
*cite journal | author=Shi Y, Samuel SJ, Lee W, "et al." |title=Cloning of an L-3-hydroxyacyl-CoA dehydrogenase that interacts with the GLUT4 C-terminus. |journal=Arch. Biochem. Biophys. |volume=363 |issue= 2 |pages= 323–32 |year= 1999 |pmid= 10068455 |doi=
*cite journal | author=Abel ED, Kaulbach HC, Tian R, "et al." |title=Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. |journal=J. Clin. Invest. |volume=104 |issue= 12 |pages= 1703–14 |year= 2000 |pmid= 10606624 |doi=
*cite journal | author=Abel ED, Peroni O, Kim JK, "et al." |title=Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. |journal=Nature |volume=409 |issue= 6821 |pages= 729–33 |year= 2001 |pmid= 11217863 |doi= 10.1038/35055575

External links

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