Question

Case 2 

Regulation of glucose uptake by the cell 

The above brain MRI shows a large glioblastoma tumor with areas of necrosis within the tumor (tumor is the bright white area within the brain field on MRI). On the right is a PET scan from the same individual following administration of fluorescently labeled D-glucose. 

Use the following series of questions to determine how/if glucose uptake differs in the tumor when compared to the surrounding tissues. 

In normal tissue, how is glucose uptake regulated in the following tissues: 

Liver 

Skeletal Muscle 

Brain 

Adipose 

How does glucose uptake in normal tissue compare to glucose uptake by tumor cells in the above image and why would this be advantageous to the invasive tumor? 

What modifications may have occurred in cancer cells to alter glucose uptake as predicted above?

Answer 1

1)Liver is a vital organ that regulates glucose metabolism under an array of conditions. After a carbohydrate rich meal excess glucose signals the release of insulin and the entry of glucose through the oral/enteral/portal vein increases the rate of net hepatic glucose uptake (NHGU). Glucose entry into the portal vein stimulates a portal glucose signal that enhances NHGU but reduces muscle glucose uptake for proper partitioning of the glucose load. Thus, glucose uptake via the portal vein was an indicative of the fact that glycogen synthesis will be stimulated by a carbohydrate-rich meal. It was previously thought that a gut factor is responsible but later studies demonstrated it was wrong and the portal vein signal was actually responsible. This is how glucose uptake in the skeletal muscles and liver is done.

Entry of glucose in the skeletal muscles occurs via a carrier-mediated system which consists of protein transport molecules like GLUT-1 transporter isoform normally found in the sarcolemmal (SL) membrane. This is involved in glucose transport under basal conditions. After a carbohydrate rich meal we see that there is an increase in the GLUT-4 transporters to the T-tubule and SL membrane. When insulin binds to its receptor, autophosphorylation of tyrosine and serine residues on the beta-subunit of the receptor takes place. It is thought that the tyrosine residues activate tyrosine kinases, which in turn phosphorylates some unknown second messengers. When Insulin receptor antibodies were administered,glucose transport was increased but not the kinase activity.Thus, in this manner glucose uptake is regulated in the skeletal muscles.

For brain glucose is solely responsible for providing energy followed by ketone bodies. In brain glucose uptake mainly occurs by facilitated diffusion performed by the glucose transporter members namely GLUT-1 and GLUT-3. Thus when there is an enhanced glucose metabolism required these GLUT-1 and GLUT-3 transporters expression is also seen to increase in certain regions of the brain. Thus, glucose uptake in the brain is regulated in such a manner.

In adipocytes glucose uptake is mainly brought about by the glucose transporter GLUT-4. In the presence of insulin, the exocytosis of Glut4 occurs upon activation of the small G protein RalA, via inhibition of its GTPase activating complex RalGAP. It was observed in several experiments that RalA was activated in brown adipose tissue after feeding, and Glut4 exocytosis was prevented upon its inactivation. Thus, an important role is played in glucose transport in adipose tissue in vivo by RalA.

2)In tumor cells, glucose uptake is much higher than normal cells. They require more amount of glucose, and the reason of this method being advantageous to them, is because it allows them to produce cellular metabolites in abundance and promote nutrient signalling. Also, this process helps them to add essential nutrients required for proliferation into biomass.

3)The modification in the cancer cell which leads to such abundant uptake of glucose is that, they perform aerobic glycolysis. In general, normal cells depend on oxidative phosphorylation for production of energy and perform glycolysis in anaerobic conditions. But, even though oxidative phosphorylation is much more efficient than glycolysis, tumor cells perform glycolysis even in the presence of oxygen in order to produce energy and cellular metabolites. Recent findings have shown that this process is advantageous because it helps in rapid proliferation of the tumor cells. Also, there are certain oncogenes that induce the over expression of certain glucose transporters in order to take in glucose from the tumor microenvironment.