Management of Carbohydrate Metabolism

As described above, glucose plays a central role in whole body metabolism as the concentration of glucose in the blood provides an important signal to the master system, the endocrine system, that regulates overall metabolic activity.

A. Glucose Storage During the Fed State

Glucose is a critical fuel for the function of some specialized tissues, particularly the central nervous system (CNS). Under normal circumstances the CNS uses only glucose as a source of energy, and is therefore completely depended on blood glucose. As described above, blood glucose levels rise following a meal and fall as the body enters the fasting state. Because of the essential role of glucose in supporting CNS function, it is vital that these changes in blood glucose concentration be managed in a way that prevents excessively low levels of glucose (hypoglycemia). Liver plays a unique role in achieving this goal.

Glucose is stored in many tissues, generally for meeting the need for glucose during fasting, or when extra fuel is needed as during intense muscle activity. Storage is achieved through the synthesis of a large, highly branched complex carbohydrate molecule named glycogen. Glycogen is composed entirely of glucose molecules linked to one another is a highly regular way. It provides a compact storage molecule that can be quickly broken down when glucose is needed.

Glycogen synthesis is limited in most tissues by means of an inhibitory feedback mechanism that limits the amount of glucose that is taken up by

the cell. This is achieved by limiting the rate of conversion of glucose to glucose- 6-phosphate. This is the first step in the metabolism of glucose and the addition of a phosphate group "traps" glucose inside the cell.

Glucose-6- Phosphate (G-6-P) can enter any one of three major pathways (three different series of biochemical reactions) involved in the overall metabolism of glucose. One of these pathways leads to the formation of glycogen.

Unlike all other tissues, liver has not one but two ways of making G-6-P, each catalyzed by a different enzyme. One of these is identical to that of most other tissues and is feedback inhibited. The other is not regulated and, under conditions where the blood glucose levels are high (fed state), actively supports the formation of G-6-P. Together, these two mechanisms assure that the liver has lots of G-6-P available, and thus assure that glycogen synthesis in the liver is very active. Indeed, the liver accounts for approximately half of the total synthesis of glycogen in the human body with half of the total glucose stored being contained in liver.

B. Glucose Release During the Fasting State

During the transition from fed to fasting, the concentration of glucose in the blood falls, signaling the need for additional fuel (fatty acid from adipose tissue) and signaling the need to prevent glucose levels from becoming too low. Once again, the liver plays a unique and critical role as it works to maintain blood glucose at a stable level. Two processes come into action; the breakdown of glycogen that was accumulated in the fed state, and the actual synthesis of more glucose.

1) Glycogen Breakdown

All cells capable of making glycogen (most cells of the body) can also break glycogen down, forming G-6-P. However, as mentioned above, so long as the glucose has a phosphate attached, it is trapped within the cell. In these cells, G-6-P is used as a fuel, used to support the production

of energy from other fuels (fatty acids and ketone bodies), or used in other parts of metabolism.

In the context of glycogen breakdown, once again the liver has a unique ability. Like other cells, the liver breaks glycogen down to glucose-6- phosphate. But only the liver has the ability to removing the phosphate group from G-6-P, forming free glucose. This free glucose easily leaves the liver and enters the blood. Since liver is the only tissue that can support blood glucose levels during fasting, it is easy to understand the importance of the ability of the liver to store large amounts of glucose as glycogen during fed periods when blood glucose is plentiful.

2) Glucose synthesis (Gluconeogenesis)

In most tissues, glucose is eventually degraded as part of cellular metabolism. However, during the fasting state when there is an ongoing demand for glucose by other cells, the liver is capable of synthesizing G-6-P from a variety of carbohydrates and from the carbon "skeletons" of many of the amino acids. This process, termed "gluconeogenesis," occurs at a high rate in liver and is, again, unique to liver cells. As above, the removal of the phosphate from G- 6-P forms free glucose, allowing this newly synthesized glucose to enter the blood.

The release of glucose from stored liver glycogen and the synthesis of glucose by the liver acts to keep the blood glucose concentration stable during the fasting state. Taken together, these processes maintain blood glucose at a level adequate to support the activities of other tissues in the body, particularly the central nervous system. It is difficult to overstate the importance of the role of the liver in glucose storage and release to the healthy functioning of the whole body.