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Regulation of glucose transport by insulin: traffic control of GLUT4

Key Points

  • The glucose transporter GLUT4 facilitates insulin-stimulated glucose uptake into muscle and adipose tissue. Defects in glucose uptake represent an early step in the development of type 2 diabetes mellitus.

  • GLUT4 is distributed between the plasma membrane, the trans-Golgi network (TGN), endosomes and small heterogeneous vesicles that consist of sorting intermediates of the endosomal system and GLUT4 storage vesicles (GSVs). Treatment of muscle or adipose cells with insulin stimulates exocytosis of GLUT4 from multiple intracellular compartments, which results in increased GLUT4 levels at the plasma membrane for shuttling of glucose into the cell.

  • In the absence of insulin, at least 50% of GLUT4 is sequestered in specialized immobile GSVs. Stimulation with insulin results in regulated exocytosis of GSVs.

  • GSV mobilization, targeting and fusion at the plasma membrane requires coordinated control of the trafficking machinery by insulin. Trafficking proteins that are regulated by insulin include multiple small GTPases of the RAB, RAL and RHO families, molecular motor proteins, the exocyst complex and SNARE regulatory proteins.

  • Total internal reflection fluorescence microscopy (TIRFM) studies performed in live adipocytes have helped to elucidate the mechanisms by which insulin regulates specific trafficking proteins during GLUT4 exocytosis.

Abstract

Despite daily fasting and feeding, plasma glucose levels are normally maintained within a narrow range owing to the hormones insulin and glucagon. Insulin increases glucose uptake into fat and muscle cells through the regulated trafficking of vesicles that contain glucose transporter type 4 (GLUT4). New insights into insulin signalling reveal that phosphorylation events initiated by the insulin receptor regulate key GLUT4 trafficking proteins, including small GTPases, tethering complexes and the vesicle fusion machinery. These proteins, in turn, control GLUT4 movement through the endosomal system, formation and retention of specialized GLUT4 storage vesicles and targeted exocytosis of these vesicles. Understanding these processes may help to explain the development of insulin resistance in type 2 diabetes and provide new potential therapeutic targets.

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Figure 1: Insulin signalling regulates GLUT4 exocytosis by engaging the trafficking machinery.
Figure 2: Molecular mechanisms of GLUT4 internalization.
Figure 3: The GLUT4 trafficking itinerary.
Figure 4: Insulin targets several steps in GLUT4 storage vesicle exocytosis.

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Acknowledgements

This work was supported by a US National Institutes of Health (NIH) grant R01DK076906. The authors thank M. Uhm and D. Bridges for their critical reading and discussions of the manuscript.

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Glossary

Gluconeogenesis

De novo synthesis of glucose from non-carbohydrate carbon sources.

Trans-Golgi network

(TGN). The terminal Golgi stack where proteins are sorted and packaged into vesicles for delivery to their cellular destination.

Insulin resistance

Physiological condition that is defined by a failure of tissues and organs to respond to normal concentrations of insulin.

Type 2 diabetes mellitus

A chronic metabolic disorder that is characterized by increased plasma glucose levels that result from an inability of tissues to respond to insulin.

Anabolic hormone

Secreted peptide that signals to cells to upregulate metabolic processes that convert simple energy sources into macromolecules.

Adipokines

Hormones and cytokines that are released by adipocytes and signal to other tissues to alter feeding behaviour and metabolism.

Small GTPases

20–35 kDa guanine nucleotide-binding proteins that switch between an inactive GDP-bound conformation and an active GTP-bound conformation.

Guanine nucleotide exchange factors

(GEFs). A family of enzymes that activate GTPases by catalysing GDP release, thus allowing cytoplasmic GTP to bind to the GTPase.

GTPase-activating proteins

(GAPs). A family of enzymes that inactive GTPases by catalysing GTP hydrolysis.

SNARE regulatory proteins

(Soluble N-ethylmaleimide-sensitive factor attachment protein receptor regulatory proteins). A family of small helical proteins that bridge two membranes and drive membrane fusion events.

Lipid rafts

Rigid regions of the plasma membrane that are enriched in cholesterol and glycosphingolipids.

Effector

A protein that preferentially binds to an activated small GTPase.

Exocyst

An evolutionarily conserved protein complex that consists of eight subunits and targets exocytic vesicles to sites of docking and fusion at the plasma membrane.

Hypoglycaemia

Physiological condition that is defined by abnormally low blood glucose levels.

Clathrin-mediated endocytosis

A mechanism for internalizing extracellular molecules and portions of the plasma membrane. This pathway is dependent on the membrane curvature-inducing coat protein clathrin.

Cholesterol-dependent endocytosis

A clathrin-independent mechanism for internalizing molecules. This mechanism is blocked by drugs that deplete cellular cholesterol and often requires the lipid raft protein caveolin.

Sorting endosome

A membrane compartment that is localized close to the cell surface where recently endocytosed proteins are delivered and sorted for degradation or recycling.

Recycling endosomes

Membrane compartments that many recycling proteins pass through before returning to the cell surface.

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Leto, D., Saltiel, A. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 13, 383–396 (2012). https://doi.org/10.1038/nrm3351

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