Glucose transporter-1(GLUT-1)

Glucose travels across the cell membrane on a transport protein. Hereditary deficiency of GLUT-1, insulin -independent transporter, results in decreased glucose transport. Patients manifest with intractable seizures in infancy and a developmental delay. GLUT-1 transporter is expressed in which of the following cell types?

A. Liver, kidney and pancreatic β cells

B. Brain (neurons)

C. Adipose tissue, skeletal muscle and cardiac muscle

D. Erythrocytes, Blood -brain barrier, blood-retinal barrier

E. Intestinal epithelium, Spermatozoa.

The correct answer is- D, Erythrocytes, Blood -brain barrier, blood-retinal barrier.

Basic concept

Glucose transport across the cell membrane is a facilitated transport, a carrier mediated transport. These Glucose transporters comprise a family of at least 14 members. The most well characterized members of the family are GLUT1, GLUT2, GLUT3, GLUT4 and GLUT5.  These transporters mediate the thermodynamically downhill movement of glucose across the plasma membranes of animal cells (figure-1). These are bidirectional; they can transport glucose both into and out of cells and are driven by the concentration gradient. However, export of glucose from tissues to the circulation is limited to organs that produce sugar (liver and kidney) or to organs that receive sugar from the outer milieu (the small intestine).

GLUT-1 DETAILS

Figure-1- Facilitated transport of glucose by GLUT-1

The members of this family have distinctive roles:

1. GLUT1 and GLUT3, present in nearly all mammalian cells, are responsible for basal glucose uptake. Their Km value for glucose is about 1 mM, significantly less than the normal serum-glucose level, which typically ranges from 4 mM to 8 mM. Hence, GLUT1 and GLUT3 continually transport glucose into cells at an essentially constant rate.

GLUT -1 is especially  expressed in cells with barrier functions, such as Blood- Brain barrier(figure), blood-retinal barrier, blood placental barrier, blood testes barrier and most importantly it is expressed in human erythrocytes.

GLUT-3 is mainly expressed in neurons (brain) – figure.

2. GLUT2, present in liver and pancreatic β cells, is distinctive in having a very high K m value for glucose (15- 20 mM). Hence, glucose enters these tissues at a biologically significant rate only when there is much glucose in the blood. The pancreas can thereby sense the glucose level and accordingly adjust the rate of insulin secretion. Insulin signals the need to remove glucose from the blood for storage as glycogen or conversion into fat. The high Km value of GLUT2 also ensures that glucose rapidly enters liver cells only in times of plenty. Thus it is a high-capacity but a low affinity transporter.

GLUT-1

Figure- Glucose transport through GLUT-1 and 3 in the brain.

3. GLUT4, which has a Km value of 5 mM, transports glucose into muscle and fat cells. The presence of insulin, which signals the fed state, leads to a rapid increase in the number of GLUT4 transporters in the plasma membrane. Hence, insulin promotes the uptake of glucose by muscle and fat. The number of these transporters present in muscle membranes increase in response to endurance exercise training.

glut-4

Figure-3- The insulin dependent GLUT-4 transporters expressed in adipose tissue, skeletal muscle and cardiac muscle, increase in the fed state in response to insulin.

4. GLUT5, present in the small intestine, and spermatozoa, functions primarily as a fructose transporter.

5. GLUT 6– is a product of pseudo gene.

6. GLUT-7 is present at the surface of endoplasmic reticulum and is related with perhaps the export of glucose from endoplasmic reticulum to cytoplasm, after the action of glucose-6 phosphatase.

Clinical significance

There is increased expression of GLUT1 and GLUT3 transporters on the surface of cancer cells. Cancer cells grow more rapidly than the blood vessels to nourish them; thus, as solid tumors grow, they are unable to obtain oxygen efficiently. In other words, they begin to experience hypoxia. Under these conditions, glycolysis leading to lactic acid fermentation becomes the primary source of ATP. Glycolysis is made more efficient in hypoxic tumors by the action of a transcription factor, hypoxiainducible transcription factor (HIF-1). In the absence of oxygen, HIF-1 increases the expression of most glycolytic enzymes and the glucose transporters GLUT1 and GLUT3. In fact, glucose uptake correlates with tumor aggressiveness and a poor prognosis.

As regards options in the given question

A. Liver, kidney and pancreatic β cells- GLUT-2 transporter is expressed in these cell types

B. Brain (neurons) – GLUT-3.

C. Adipose tissue, skeletal muscle and cardiac muscle- GLUT-4

D.Erythrocytes, Blood -brain barrier, blood-retinal barrier

E. Intestinal epithelium, Spermatozoa- GLUT-5.

 

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