Biochemistry/Regulation of Glucose Transporter Translocator in Health and Diabetes

Introduction
Due to the high level of biological importance that glucose plays in providing energy and a readily usable source of carbon, the mechanism of the transportation of glucose has elicited interest in the labs of researchers. For half a century scientists have been aware of insulin’s role in the uptake of glucose in the blood into surrounding tissues; more recently, however, scientists have pondered over what causes insulin-resistance. This study proposes that the mechanism of glucose transport involves the GLUT4 glucose transporter being stimulated by insulin, causing it to relocate and be absorbed into tissues. However, this mechanism is proposed to be negatively affected in the scenario of an excess of glucose that results from a consistently high calorie diet. NMR spectroscopy has confirmed that the extent in which insulin can cause glucose to be transported into the cell is impaired in cases of patients with type 2 diabetes. Some scientists have suggested that this could be the result of overloading a system that has evolved and favored the ability to maintain a storage of energy; that is, the body is unsure what to do in a situation of “over-nutrition” because it has adapted to survive in situations of unpredictable food availability.

Background: Glucose
The body obtains its energy from the food it consumes, which is broken down into its simplest components. In the case of complex carbohydrates, the large polymers are broken down into glucose. The presence of glucose in the blood causes the release of the hormone insulin, which is secreted from the beta cells of the pancreas. Once in the bloodstream, insulin signal s the cells to store glucose as glycogen, which can be accessed as needed. When the cells need access to this energy storage deposit, the hormone glucagon is released, stimulating the glycogen to be broken down, releasing glucose into the bloodstream. It is this homeostasis that maintains a relatively constant blood sugar level.

Glucose Transporters
It has been determined that there are two main transporters of glucose in the cell: GLUT1 and GLUT4. The latter of the two is of primary interest seeing as it is the transporter that is stimulated by insulin. With this information scientists are aware of the molecules involved in this process the general inquiry of insulin’s affect on glucose absorption, can be focused narrowly to a question of insulin’s affect on the GLUT4 transporters. GLUT4 has been shown to be present inside the cell in special storage vesicles. Upon activation by insulin, these vesicles move to the surface of the cell where GLUT4 inserts itself into the plasma membrane. Once there, glucose binds GLUT4, resulting in a change in the three-dimensional shape of the transporter, causing the transporter to move the glucose and release it in the cell.

As for the actual mechanism of insulin stimulating glucose uptake, the presence of insulin in the bloodstream results in a few signal pathways that serve to control GLUT4 tracking. The first of these signal pathways is triggered when insulin binds to AS160, resulting in its phosphorylation. Interestingly enough, it has been shown that the act of phosphorylation is hampered in the case of type 2 diabetes. The second of these signal pathways involves insulin-recruiting phospholipase, which ensures that the GLUT4-containg vesicle is correctly positioned into the cell membrane.

Relation to Insulin Resistance
In the analysis of type two diabetes, which is caused by insulin resistance, scientists have been attempting to propose what causes a lack of affinity for insulin, reducing its activity. Although there is still much to be learned about this subject, researchers believe that insulin resistance is the result of a problem with normal pathway of insulin signaling due to the an excess of lipids, such as diaclyglyerols and sphingolipids, which are believed to impede the normal pathway.