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  • Review Article
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Regulated transport of the glucose transporter GLUT4

Nature Reviews Molecular Cell Biology volume 3, pages 267–277 (2002)Cite this article

Key Points

  • Following a meal, insulin secretion from the pancreas facilitates the removal of glucose from the bloodstream. One of the main events in this regulatory process is the stimulation of glucose entry into muscle and fat cells. This is mediated by the translocation of the facilitative glucose transporter GLUT4 from an intracellular store to the cell surface.

  • The insulin-responsive GLUT4 is retained intracellularly in muscle and fat cells. In response to insulin, GLUT4 is translocated to the cell surface, where it facilitates the uptake of glucose into these insulin-responsive tissues. Understanding the transport itinerary of GLUT4 in these cells, both in the absence and presence of insulin, has proved to be a very challenging cell-biology problem.

  • A model that we believe fits all of the available data available for GLUT4 transport at present is described. This model involves the intracellular cycling of GLUT4 between the trans-Golgi network, the endosomal system and the plasma membrane. The effect of insulin on this model is discussed in the article. Other potential models are also discussed.

  • It is likely that the delivery of GLUT4 to the cell surface of fat and muscle cells is insufficient to account for the increase in glucose uptake into these cells, and therefore other layers of regulation, such as enhancement of transporter activity, might also be regulated by insulin.

  • To understand how insulin leads to the translocation of GLUT4 to the cell surface of insulin-sensitive cells, it is necessary to identify a link between the insulin-signalling pathways and GLUT4 transport machinery.

Abstract

In muscle and fat cells, insulin stimulates the delivery of the glucose transporter GLUT4 from an intracellular location to the cell surface, where it facilitates the reduction of plasma glucose levels. Understanding the molecular mechanisms that mediate this translocation event involves integrating our knowledge of two fundamental processes — the signal transduction pathways that are triggered when insulin binds to its receptor and the membrane transport events that need to be modified to divert GLUT4 from intracellular storage to an active plasma membrane shuttle service.

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Figure 1: Schematic representation of the GLUT family of proteins.
Figure 2: Insulin triggers the translocation of GLUT4 from an intracellular location to the plasma membrane of adipocytes.
Figure 3: Relative GLUT4 distribution throughout organelles of cells from non-stimulated and insulin-stimulated brown adipose tissue.
Figure 4: A model that depicts the transport of GLUT4 in insulin-responsive cells.

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  1. Garvan Institute of Medical Research, 384 Victoria Road, Darlinghurst, 2010, New South Wales, Australia

    Nia J. Bryant, Roland Govers & David E. James

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DATABASES

Interpro

pleckstrin homology domain

LocusLink

Akt

TfR

OMIM

Type II diabetes

Swiss-Prot

ACRP30

adipsin

ANF

c-Cbl

Gap1

GLUT1

GLUT4

GLUT5

GLUT8

GLUT9

GLUT10

GLUT11

IRAP

IRS-1

IRS-2

p38

PKCζ

Rab4

sentrin

SNAP23

Syntaxin 4

Syntaxin 6

Syntaxin 16

Synip

TC10

TGN38

VAMP2

VAP33

Glossary

FACILITATIVE SUGAR TRANSPORTER

A polytopic membrane protein that transports sugars down a concentration gradient in an energy-independent manner.

TYPE II DIABETES

Also known as non-insulin-dependent diabetes or maturity onset diabetes.

DB/DB MOUSE

A genetic mouse model of type II diabetes and obesity. The defect has been mapped to the gene for the leptin receptor.

EVANESCENCE WAVE MICROSCOPY

A technique in which only fluorophores within a 100–220 nm field above a glass coverslip are excited, which allows localization of molecules very close to the cell surface.

ATRIAL CARDIOMYOCYTE

A heart muscle cell.

AP-1

(Adaptor protein complex 1). Adaptor proteins link cargo molecules on membranes with coat proteins such as clathrin. Several classes of adaptor proteins have been identified and shown to be involved in different transport steps. AP-1 is thought to regulate transport from the trans-Golgi network to endosomes.

SNARE

(soluble N-ethylmaleimide sensitive factor attachment protein receptor). A family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity in the vacuolar system. They can be divided into v-SNAREs (vesicle) and t-SNAREs (target) on the basis of their localization, or into Q-SNAREs and R-SNAREs on the basis of a highly conserved amino acid.

CONVERTASE

An enzyme that is responsible for protein activation through proteolytic activity.

COAT-ASSOCIATED PROTEIN

A protein that links cargo molecules to vesicle coats.

ARNO

(ARF nucleotide binding-site opener). This activates ADP-ribosylating factors (ARFs), which are known to have a role in protein sorting and vesicle budding.

γ-EAR-CONTAINING

This represents a protein domain within the γ-subunit of coat adaptor proteins.

CD-MPR

(Cation-dependent mannose-6-phosphate receptor). This protein shuttles between the trans-Golgi network and endosomes.

GTPγS

A non-hydrolysable analogue of GTP.

BREFELDIN A

A fungal metabolite that affects membrane transport and the structure of the Golgi apparatus.

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Bryant, N., Govers, R. & James, D. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol 3, 267–277 (2002). https://doi.org/10.1038/nrm782

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