The Importance of Glucose Transporters

THE IMPORTANCE OF GLUCOSE TRANSPORTERS

By the end of this course you should know what a glucose transporter is, where the various types are found in the body and the role they play in diabetes.

This should give you an overview of the importance of glucose and how it is transported within the cells of our body.

Before you start...

You should know a bit about glucose transporters already. Test your knowledge by matching up several key terms to their definitions.

Key terms and their definitions

Below are some key terms you may have come across before. Test your knowledge by matching the terms with their definitions!
  • Insulin
    A hormone that regulates blood glucose concentration.
  • ATP
    The main form of energy constantly being used and produced by the body.
  • GLUT
    The protein through which glucose can enter a cell.
  • Passive process
    This does not require energy.
  • Type 1 Diabetes Mellitus
    A form of diabetes where the body does not produce insulin.
  • Type 2 Diabetes Mellitus
    A form of diabetes where the body does not respond to insulin.
  • Facilitative Diffusion
    The passive transfer of molecules down a concentration gradient that goes from high to low.

Glucose

  • Glucose is a key component because it provides energy in the form of ATP. This energy is required for the many processes the body carries out, such as anaerobic/aerobic respiration and muscle contractions. ATP cannot be stored in the same way that other energy sources can so it is constantly being produced.

  • The brain is limited in what it can use as fuel therefore glucose is unique in that it can be processed for energy. Therefore it can be said that glucose has an impact on both our cognitive and physiological processes.

Can ATP be stored in the body for later use?

  • No.
  • Yes, in the same way that glucose can be stored as glycogen.
  • Yes, but only a small amount is stored.

Glucose

Cells contain proteins on their membrane surface which allow the entry and exit of glucose molecules. These are called glucose transporters.

Glucose Transporters

  • Glucose transporters are more commonly referred to as GLUTs. They are proteins which facilitate the passive transfer of glucose from one side of the cell membrane to the other side. 

  • The movement of glucose relies on concentration gradients instead of energy input.

  • When there is a higher concentration of glucose outside the cell compared to the inside of the cell then glucose will move in via the GLUTs. 

Glucose Transporters

  • As more glucose enters the cell and is used up in processes such as respiration and cell growth, the concentration of glucose in the blood decreases.

  • There are different types of glucose transporters depending on where they are found in the body.

Problems with Glucose Transporters in Diabetes

  • After a meal, blood glucose concentration increases. This leads to production of a hormone called insulin from the beta cells of the Islets of Langerhans found in the pancreas.

  • Insulin is important for glucose homeostasis. When blood glucose levels rise to a concentration that is considered above normal, insulin initiates the opening of GLUTs on the surface of cells. This allows increased uptake of glucose from the blood.

  • The regulation of insulin is very important because prolonged production of it will eventually lead to blood sugar levels becoming too low. In response to decrease blood glucose, glucagon is produced from the alpha cells of the Islets of Langerhans.

The hormones of the pancreas

  • Insulin is produced when blood glucose levels get too low.
  • Insulin is produced when blood glucose levels get too high.
  • Glucagon is produced by the beta cells of the Islets of Langerhans.
  • Glucagon is produced by the alpha cells of the Islets of Langerhans.

Problems with Glucose Transporters in Diabetes

  • In type 1 diabetes mellitus, insulin is not produced by the pancreas. 

  • In type 2 diabetes mellitus, insulin is produced but the cells of the body do not respond to it. 

  • The problem that sufferers of diabetes face is that they are not able to regulate their blood glucose concentrations. In type 1 diabetes, regular insulin injections are required. In type 2 diabetes the patient is encouraged to make several lifestyle and dietary changes.

The features of the GLUT1 receptor and its mechanism of action.

Where are they found?

The GLUT1 receptor is found in the...

  • Endothelial of barrier tissues
  • E.g. blood vessels
  • E.g. blood brain barrier

It has the following features...

  • A plasma membrane uniporter
  • Use facilitative diffusion
  • Quite specific - they have a higher affinity for the substrate D-glucose

Animation of GLUT1 and glucose transport

  1. Glucose binds to GLUT1 on the surface of the cell
  2. A conformational change occurs so that the binding site of GLUT1 faces the inside of the cell
  3. The molecule of glucose is released 
  4. GLUT1 returns to its original conformation (with the binding site facing outwards)

Now it's your turn!

Can you remember the sequence of events that occur when a glucose molecule is taken up?
  • Glucose binds to GLUT1
  • Conformational change occurs, binding site now faces cell interior
  • Glucose released from GLUT1 to the celll
  • GLUT1 returns to original conformation

Kinetics

Different types of glucose transporters will have differing kinetic properties in relation to their function. There are some key terms which you may or may not have come across before. 
  • Km
    Also known as the Michaelis constant, this is the measure of when the reaction is at half the maximum rate.
  • vMax
    This is the maximum rate of the reaction. At this point, the graph has levelled off to a constant rate.
  • Specificity
    How "fussy" the receptor is. If a receptor is said to not be very specific, then any molecule which is similar to the substrate will be able to bind to the binding site of the receptor.
  • Affinity
    How well a substrate is able to remain attached to its binding site.

A graph to show the kinetic properties of GLUT1

At 1.5mM, half of the transporters with outward facing binding sites are bound to glucose.

The features of the GLUT2 receptor and its mechanism of action.

Where are they found?

The GLUT2 receptor is found in the...

  • Liver
  • Intestine
  • Kidney
  • Pancreatic B cells

It has the following features...

  • Bidirectional uniporter (glucose can flow in two directions)
  • Encoded by the SLC2A2 gene
  • Does not rely on insulin (unlike GLUT4)
  • Low-affinity but high capacity for glucose
  • Associated with the enzyme glucokinase

Mechanism of action

  • The mechanism of action of GLUT2 is similar to GLUT1 in that it uses facilitative diffusion. GLUT2 works by sensing glucose concentration and altering the rate of glucose uptake into liver cells in response to this. 

  • Therefore, it can be said that it is important for glucose homeostasis.

Kinetics

GLUT2 differs from GLUT1 in that it has a higher Km. This explains its lower affinity for glucose however, as mentioned before, it does have a higher capacity.

The features of the GLUT4 receptor and its mechanism of action.

Where are they found?

The GLUT4 receptor is found in the...

  • Adipose tissues
  • Heart muscles
  • Skeletal muscles

It has the following features...

  • Key in regulating glucose uptake
  • Sequestering of GLUT4 within the cell when there is no insulin
  • GLUT4 containing vesicles fuse with plasma membrane and they get internalised to the storage pool

Animation of GLUT4 and glucose transport

Glucose transport in GLUT4

 regulates glucose uptake into these cells by recruiting  containing  from the cell interior to the cell surface.  diffusion occurs and  enters the cytoplasm and is phosphorylated. This is a reversible process.

Kinetics

On this graph, you can see the different Kms and vMaxs of the different GLUTs.

Mutations in the GLUT4 receptor

GLUT4 is the only glucose transporter which responds to insulin therefore mutations in GLUT4 are associated with type 2 diabetes. Current studies suggest that insulin is used to regulate...

  • Docking of GLUT4 vesicles to the plasma membrane of the cell
  • Fusion machinary e.g. SNARE proteins
  • The trafficking of GLUT4 to the plasma membrane

GLUT4 mutations affect all three of the mechanisms mentioned above.

What are the respective Kms of GLUT1, GLUT2 and GLUT4?

  • 1.5Mm, 15Mm and 4.3Mm
  • 2.3Mm, 25Mm and 3Mm
  • 6Mm, 4Mm and 1Mm
  • 12Mm, 4Mm and 4Mm
  • 5Mm, 2Mm, 1Mm

Why is GLUT4 different to GLUT1 and GLUT2?

Write the similarities and differences between the different GLUTs.

Where are the different glucose transporters found?

  • GLUT1 is in the liver, GLUT2 is in the heart muscles and GLUT4 is in the endothelial of barrier tissues
  • GLUT1 is in the heart muscles, GLUT2 is in the liver and GLUT4 is in the endothelial of barrier tissues
  • GLUT1 is in the heart muscles, GLUT2 is in the endothelial of barrier tissues and GLUT4 is in the liver
  • GLUT1 is in the endothelial of barrier tissues, GLUT2 is in the liver and GLUT4 is in the heart muscles

Diabetes

Diabetes

  • It is thought that a loss of selective permeability is seen in the GLUT1 receptors of sufferers of type 2 diabetes. This leads to a decrease in glucose transport from the blood to the cell.

  • Studies show that mutations in the GLUT2 gene may be associated with type 2 diabetes mellitus. It was discovered that in patients with type 2 diabetes, there was a decrease in production of GLUT2 mRNA in comparison to a patient who did not suffer from diabetes.

  • Type 2 diabetes can also be linked to GLUT4 receptors due to the fact that insulin can no longer stimulate the uptake of glucose into fat and muscle cells.

In your opinion, what area should scientists focus their future research on in order to develop effective treatments for type 2 diabetes?

Using the information you have learnt in this resource, your lecture notes and science articles write a couple of paragraphs on what you believe to be the key areas of focus.

Relevant research

  • In order to one day develop an effective treatment for diabetes, it would be beneficial to focus on the various glucose transporters, in particular GLUT4 as its function depends on insulin.
  • Another area of interest could be GLUT2. The resistance in this receptor which is seen during diabetes has been shown to be reversible when in certain conditions.

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