Glycogen



Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue. Glycogen is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach.

Glycogen is the analogue of starch, a glucose polymer in plants, and is sometimes referred to as animal starch, having a similar structure to amylopectin but more extensively branched and compact than starch. Glycogen is a polymer of α(1→4) glycosidic bonds linked, with α(1→6)-linked braches. Glycogen is found in the form of granules in the cytosol/cytoplasm in many cell types, and plays an important role in the glucose cycle. Glycogen forms an energy reserve that can be quickly mobilized to meet a sudden need for glucose, but one that is less compact than the energy reserves of triglycerides (lipids).

In the liver hepatocytes, glycogen can compose up to eight percent of the fresh weight (100–120 g in an adult) soon after a meal. Only the glycogen stored in the liver can be made accessible to other organs. In the muscles, glycogen is found in a low concentration (one to two percent of the muscle mass). However, the amount of glycogen stored in the body—especially within the muscles, liver, and red blood cells  —mostly depends on physical training, basal metabolic rate, and eating habits such as intermittent fasting. Small amounts of glycogen are found in the kidneys, and even smaller amounts in certain glial cells in the brain and white blood cells. The uterus also stores glycogen during pregnancy to nourish the embryo.

Function and regulation of liver glycogen
As a meal containing carbohydrates is eaten and digested, blood glucose levels rise, and the pancreas secretes insulin. Glucose from the portal vein enters liver cells (hepatocytes). Insulin acts on the hepatocytes to stimulate the action of several enzymes, including glycogen synthase. Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases.

After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis stops. When it is needed for energy, glycogen is broken down and converted again to glucose. Glycogen phosphorylase is the primary enzyme of glycogen breakdown. For the next 8–12 hours, glucose derived from liver glycogen will be the primary source of blood glucose to be used by the rest of the body for fuel.

Glucagon is another hormone produced by the pancreas, which in many respects serves as a counter-signal to insulin. In response to insulin level below normal (when blood levels of glucose begin to fall below the normal range), glucagon is secreted in increasing amounts to stimulate glycogenolysis and gluconeogenesis pathways.

In muscle and other cells
Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells. Other cells that contain small amounts use it locally as well. Muscle cells lack the enzyme glucose-6-phosphatase, which is required to pass glucose into the blood, so the glycogen they store is destined for internal use and is not shared with other cells. (This is in contrast to liver cells, which, on demand, readily do break down their stored glycogen into glucose and send it through the blood stream as fuel for the brain or muscles). Glycogen is also a suitable storage substance due to its insolubility in water, which means it does not affect the osmotistic levels and pressure of a cell.

Glycogen depletion and endurance exercise
Long-distance athletes such as marathon runners, cross-country skiers, and cyclists often experience glycogen depletion, where almost all of the athlete's glycogen stores are depleted after long periods of exertion without enough energy consumption. This phenomenon is referred to as "hitting the wall". In marathon runners, it normally happens around the 20-mile (32 km) point of a marathon, depending on the size of the runner and the race course.

Glycogen depletion can be forestalled in four possible ways. First, during exercise carbohydrates with the highest possible rate of conversion to blood glucose per time (high GI) are ingested continuously. The best possible outcome of this strategy replaces about 35% of glucose consumed at heart rates above about 80% of maximum. Second, through training, the body can be conditioned to burn fat earlier, faster, and more efficiently, sparing carbohydrate use from all sources. Third, by consuming foods low on the glycemic index for 12–18 hours before the event, the liver and muscles will store the resulting slow but steady stream of glucose as glycogen, instead of fat. This process is known as carbohydrate loading. Finally, taking breaks while continuing to ingest carbohydrate with a high GI allows the body to catch-up with consumption, in part, by the continued conversion of fat into glucose in the liver.

When experiencing glycogen debt, athletes often experience extreme fatigue to the point that it is difficult to move. As a reference, the very best professional cyclists in the world will usually finish a 4-5hr stage race right at the limit of glycogen depletion using the first 3 strategies.

A study published in the Journal of Applied Physiology (online May 8, 2008) suggests that, when athletes ingest both carbohydrate and caffeine following exhaustive exercise, their glycogen is replenished more rapidly.

Disorders of glycogen metabolism
The most common disease in which glycogen metabolism becomes abnormal is diabetes, in which, because of abnormal amounts of insulin, liver glycogen can be abnormally accumulated or depleted. Restoration of normal glucose metabolism usually normalizes glycogen metabolism as well.

In hypoglycemia caused by excessive insulin, liver glycogen levels are high, but the high insulin level prevents the glycogenolysis necessary to maintain normal blood sugar levels. Glucagon is a common treatment for this type of hypoglycemia.

Various inborn errors of metabolism are caused by deficiencies of enzymes necessary for glycogen synthesis or breakdown. These are collectively referred to as glycogen storage diseases.

Synthesis


Glycogen synthesis is, unlike its breakdown, endergonic. This means that glycogen synthesis requires the input of energy. Energy for glycogen synthesis comes from UTP, which reacts with glucose-1-phosphate, forming UDP-glucose, in reaction catalysed by UDP-glucose pyrophosphorylase. Glycogen is synthesized from monomers of UDP-glucose by the enzyme glycogen synthase, which progressively lengthens the glycogen chain with (α1→4) bonded glucose. As glycogen synthase can lengthen only an existing chain, the protein glycogenin is needed to initiate the synthesis of glycogen. The glycogen-branching enzyme, amylo (α1→4) to (α1→6) transglycosylase, catalyzes the transfer of a terminal fragment of 6-7 glucose residues from a nonreducing end to the C-6 hydroxyl group of a glucose residue deeper into the interior of the glycogen molecule. The branching enzyme can act upon only a branch having at least 11 residues, and the enzyme may transfer to the same glucose chain or adjacent glucose chains.

Breakdown
Glycogen is cleaved from the nonreducing ends of the chain by the enzyme glycogen phosphorylase to produce monomers of glucose-1-phosphate, which is then converted to glucose 6-phosphate by phosphoglucomutase. A special debranching enzyme is needed to remove the alpha(1-6) branches in branched glycogen and reshape the chain into linear polymer. The G6P monomers produced have three possible fates:


 * G6P can continue on the glycolysis pathway and be used as fuel.
 * G6P can enter the pentose phosphate pathway via the enzyme Glucose-6-phosphate dehydrogenase to produce NADPH and 5-carbon sugars.
 * In the liver and kidney, G6P can be dephosphorylated back to Glucose by the enzyme Glucose 6-phosphatase. This is the final step in the gluconeogenesis pathway.