CARBOHYDRATE METABOLISM

Fates of dietary glucose

The major source of dietary carbohydrate for humans is starch from consumed plant material. This is supplemented with a small amount of glycogen from animal tissue, disaccharides such as sucrose from products containing refined sugar and lactose in milk.

Digestion in the gut converts all carbohydrate to monosaccharides which are transported to the liver and converted to glucose. The liver has a central role in the storage and distribution within the body of all fuels, including glucose.

Glucose in the body undergoes one of three metabolic fates :

it is catabolised to produce ATP
This occurs in all peripheral tissues, particularly in brain, muscle and kidney.
it is stored as glycogen
This storage occurs in liver and muscle.
it is converted to fatty acids
Once converted to fatty acids, these are stored in adipose tissue as triglycerides.

Glucose catabolism

Glucose will be oxidised by all tissues to synthesise ATP. The first pathway which begins the complete oxidation of glucose is called glycolysis.

Glycolysis

This pathway cleaves the six carbon glucose molecule (C₆H₁₂O₆) into two molecules of the three carbon compound pyruvate (C₃H₃O₃^-). This oxidation is coupled to the nett production of two molecules of ATP/glucose.

The diagram below shows an outline of glycolysis. The full set of reactions and structures can be found in any biochemistry textbook.

One oxidation reaction occurs in the latter part of the pathway. It uses NAD as the electron acceptor. This cofactor is present only in limited amounts and once reduced to NADH, as in this reaction, it must be re-oxidised to NAD to permit continuation of the pathway.

This re-oxidation occurs by one of two methods :

Anaerobic glycolysis

pyruvate is reduced to a compound called lactate
This single reaction occurs in the absence of oxygen (anaerobically) and is ideally suited to utilisation in heavily exercising muscle where oxygen supply is often insufficient to meet the demands of aerobic metabolism. The reduction of pyruvate to lactate is coupled to the oxidation of NADH to NAD.

Aerobic metabolism of glucose

pyruvate is transported inside mitochondria and oxidised to a compound called acetyl coenzyme A (abbreviated to "acetyl CoA").
This is an oxidation reaction and uses NAD as an electron acceptor.

By a further series of reactions collectively called the citric acid cycle, acetyl CoA is oxidised ultimately to CO₂. These reactions are coupled to a process known as the electron transport chain which has the role of harnessing chemical bond energy from a series of oxidation/reduction reactions to the synthesis of ATP and simultaneously re-oxidising NADH to NAD. (These pathways will be discussed in more detail later.)

Fast twitch muscle fibres utilise the first of the two mechanisms described above almost exclusively. Very heavily exercising muscle can use this pathway as the sole source of ATP synthesis for a short period of time. This probably evolved in humans as a defence mechanism, but is now used by athletes in sprint events.

The formation of lactate as an end product from glucose extracts only a relatively small amount of the bond energy contained in glucose. Accumulation of lactate (actually lactic acid) also causes a reduction in intracellular pH.

The lactate formed is removed to other tissues and dealt with by one of two mechanisms :

it is converted back to pyruvate
The pyruvate then proceeds to be further oxidised by the second mechanism described above, finally producing a large amount of ATP.
it is converted back to glucose in the liver

Gluconeogenesis

The process of conversion of lactate to glucose is called gluconeogenesis, uses some of the reactions of glycolysis (but in the reverse direction) and some reactions unique to this pathway to re-synthesise glucose. This pathway requires an energy input (as ATP) but has the role of maintaining a circulating glucose concentration in the bloodstream (even in the absence of dietary supply) and also maintaining a glucose supply to fast twitch muscle fibres.

Cori cycle

It can be shown by a complex calculation of energy yields that this process of partially oxidising glucose to lactate in muscle, transporting it to the liver for conversion back to glucose and then re-supplying it to muscle, actually has a much higher energy yield than the 2 ATP/glucose produced by glycolysis alone. This co-operative cycle utilising both the muscle and liver tissue is called the Cori cycle. The process is shown in a diagram below.

Both of these mechanisms illustrate the interdependence of tissues on each other and the co-operative activities between organs which make up the total of the body's metabolic activities.

Glycogen and glucose interconversion
Glycogen is a highly branched polymer of glucose. The high degree of branching (about every twelve glucose residues) produces a molecule which is compact and thus can be efficiently stored in the limited space available in liver and muscle tissue.
Even though the branching is designed to make the molecule compact, it is still a polar molecule and thus must be stored with associated water. It is stored as aggregates of glycogen molecules within cells (visible microscopically as glycogen granules) with up to 70% of the aggregate being water.
Glycogen stores

	Organ mass	Glycogen (g/kg tissue)	Total glucose
Liver	1.6 kg	65	~100 g
Muscle	28 kg	14	~400 g

The amount of glycogen in muscle changes substantially between the fed state and following heavy exercise. The amount of glycogen stored in the liver is more constant and only falls substantially after prolonged starvation.

In both muscle and liver there is interconversion between the monomer glucose and the polymer glycogen. This has the potential to be a futile cycle wasting energy if the interconversion occurred continuously; thus it is controlled to meet the body's glucose requirements at a particular time.

Hormonal control of glycogen metabolism

The control which operates is via different enzymes catalysing the synthesis and breakdown (degradation) of glycogen. The activity of these enzymes is controlled such that only one is active at any one time and thus the pathway can proceed in only one direction - either towards glycogen synthesis OR towards glycogen breakdown and mobilisation of free glucose.

The control is exerted by hormones acting to control the activity of the key enzymes. There are some differences in the hormone action in liver and muscle.

HORMONE	Source	Target tissue	Action
Glucagon	Pancreas	Liver	Stimulates glycogen breakdown
Adrenaline	Adrenals	Muscle	Stimulates glycogen breakdown
Insulin	Pancreas	Liver and Muscle	Stimulates glycogen synthesis

Utilisation of glucose in the fed and fasting states

Glucose utilisation after a meal

A high circulating glucose concentration is present after a meal. Carbohydrate is digested and the glucose absorbed into the blood stream. Insulin is secreted in response.

Insulin :

stimulates uptake of glucose into both muscle and liver
stimulates increased glycogen synthesis in both muscle and liver

This is achieved by activation of the key synthesis enzymes.

The amount of glycogen which can be stored in these two tissues is limited and once the stores are saturated, excess glucose will be diverted to the synthesis of fats - this will be discussed later.

Maintenance of blood glucose between meals

When there is no dietary glucose intake (between meals), circulating glucose concentration must be maintained.

The pancreas secretes more glucagon and less insulin.

The glucagon :

stops liver glycogen synthesis (by deactivating the synthesis enzymes)
increases liver glycogen breakdown (by activating the degradation enzymes)
stimulates gluconeogenesis in the liver to further increase the circulating blood glucose concentration

These mechanisms maintain an appropriate circulating blood glucose to supply tissues such as the brain which are major glucose consumers but do not store glycogen.

Supply of glucose to exercising muscle

Increasing muscle activity requires adequate fuel supply for ATP synthesis by muscle.

When muscle activity is anticipated, the adrenal glands secrete adrenaline.

Adrenaline increases muscle glycogen degradation (by activating the breakdown enzymes and de-activating the synthesis enzymes).

When muscle activity ceases, adrenaline secretion is switched off. When glucose becomes available again after a meal glycogen stores in muscle are replenished. Glucose can only be supplied to muscle cells either by utilising stored muscle glycogen or supply from the liver via the bloodstream.

Muscle does not carry out gluconeogenesis.

Glycogen metabolism in liver and muscle

Energy yield from glycogen breakdown

The energy yield from the hydrolysis of stored glycogen and the subsequent oxidation of the released glucose is the same in muscle and liver.

When glycogen is hydrolysed, the product is glucose 1-phosphate. This is easily converted to glucose 6-phosphate (these are molecules with the phosphate group attached to different carbon atoms on the glucose). Glucose 6-phosphate is the first product in the glycolysis pathway and its formation from glucose requires the expenditure of 1 ATP molecule/glucose.

As glucose 6-phosphate is formed directly from glycogen hydrolysis, glucose that is derived from glycogen and enters the glycolysis pathway (rather than starting as monomeric glucose) yields a nett production of 3 ATP/glucose rather than just 2. This is a 50% increase in yield.

Role of glucose 6-phosphatase

Muscle and liver have different metabolic needs. Liver supplies other organs with glucose so must be able to export glucose released from glycogen hydrolysis. Muscle is a major consumer of glucose and thus does not export glucose.

Glucose 6-phosphate formed as described in the previous section is highly polar and cannot cross the cell's cytoplasmic membrane. To leave the cell it must be converted to glucose. This reaction is catalysed by an enzyme, glucose 6-phosphatase.

glucose 6-phosphate �� glucose + phosphate
glucose 6-phosphatase

Liver possesses this enzyme, so glucose released from liver glycogen can be exported to other tissues.

It is very important to be aware that muscle does not possess glucose 6-phosphatase so it does not export glucose released from its glycogen stores, but rather uses it as a fuel to power muscle contraction.

INTRODUCTORY METABOLISM MODULE