Basic Physiology of Metabolism

Original article by Tom Leach | Last updated on 13/4/2015
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Introduction

Only 1% of pancreatic tissue is endocrine. This tissue is found in the Islets of langerhans. Surrounding the islets are adipose tissue deposits. The older you get, the more adipose tissue you have.
There are four types of cell in the islets of langerhans, alpha, beta, delta and F. Alpha and beta secreted substances involved with control of glucose, delta and F cells control the level of action of the gastrointestinal tract.   

Alpha cells

Secrete glucagon – a protein that causes break down of glycogen in liver and muscle cells, thus increasing the level of glucose in the blood. The three main effects of glucagon are:

  • Increase in breakdown of glycogen
  • Increase in breakdown of fat
  • Increased synthesis and release of glucose by the liver
 

Beta cells

Secrete insulin – this increases the rate of synthesis of glycogen.  The five effects of insulin are:

  • Increase in glucose uptake and utilisation by cells
  • Increased synthesis of glycogen
  • Increased synthesis of adipose tissue
  • Increased amnio acid absorption and protein synthesis
  • Increased rate of ATP production
 

Delta cells and F Cells

These secrete growth hormone inhibiting hormone - GHIH (also secreted by the hypothalamus). This is a regulatory hormone that inhibits the release of both glucagon and insulin. GHIH also reduces the motility and absorption of the GI tract.
F cells secrete pancreatic polypeptide (PP) – this is a hormone that reduces secretions of the gallbladder, and reduces the absorptive capacity of the GI tract

Glucose

  • The normal level of glucose is 4-6mmol/litre. Insulin will be released when blood glucose levels rise above this. Insulin is a peptide hormone.
  • At 2mmol/ you are in danger of unconsciousness
  • Levels of 10-15 are sometimes seen in healthy individuals after a meal – this is why when testing for diabetes fasting glucose is the most useful measurement.
  • In the post-absorptive state, levels are about 5-6, in the absorptive state, they are usually about 8-10.
  • Levels above 20 are getting quite serious and can cause electrolyte imbalance.
  • Insulin acts on a tyrosine kinase receptor.
  • Insulin itself is mostly responsible for the effects of the absorptive state. Insulin will act on nearly all cells of the body, the main exceptions are brain cells and erythrocytes.

ATP and energy production

ATP production occurs in the mitochondria. Here, ADP is turned into ATP. Only 40%of the energy produced in these reactions turns ADP into ATP; the other 60% is released as heat.
For molecules to enter the mitochondria they have to be small enough. Larger molecules are broken down in the cytoplasm until they are small enough. This process doesn’t use up much ATP. Once they are small enough we say they are part of the ‘nutrient pool’. The nutrient pool can then either be used in ‘anabolism’ – synthesis of new molecules that are used in cell repair and growth, or they can be used for metabolism – i.e. they are broken down to produce energy.
The nutrient pool is usually made up of lots of proteins, some fats, and a few carbohydrates, this is because carbohydrates and utilised first, then fats, the proteins. Proteins are the last resort, because they are more likely to be needed in anabolic processes.
By-products from the mitochondria are carbon dioxide, water and ATP.
Cells will store their excess nutrients – either in the form of triglycerides (in adipose cells) or glycogen (in liver and muscles cells). These stores are used to provide energy in the post-absorptive state.
Hexose sugars (glucose, fructose and galactose) are the type of sugars that are absorbed into the blood. A large proportion of them will be absorbed by the liver before being delivered into to the general circulation. In contrast to this, amino acids are absorbed in the form of chylomicrons in the lymph and thus they are released into venous circulation at the superior vena cava and bypass the liver. They are mostly taken up by adipose cells.

The liver converts all absorbed sugars to glucose, thus glucose is the only sugar that enters generally circulation.
Liver and muscle cells will absorb glucose and turn it into glycogen. Adipose cells will absorb glucose and turn it into triacyglycerol (made up of fatty acids and glycerol – both of which are made from glucose).
Triacylglycerol is also produced by the liver. It can be transported in the blood as either a component of VLDL’s, or as big droplets of triacylglycerol coated with protein, known as chylomicrons. Once in the blood, these two forms of TAG can be taken up by adipose tissue for storage. In the uptake process they are broken apart, and then reconstituted as TAG once inside the cell. This process releases a very small amount of free fatty acid into the circulation.
The liver itself does not use glucose as its main source of energy – it uses amino acids. These are ‘deaminated’ to from ketoacids, which are then converted to TAG. The deamination process also produces ammonia, which is converted to urea.
TAG is as very efficient way of storing glucose – 1g of TAG has twice as much energy as 1g of protein or glycogen.

 

Insulin

Insulin causes the absorptive state

Control of insulin release

  • Insulin is released by beta cells as a result of increased intracellular calcium. Beta cells respond both to a high glucose level, and a relative increase in glucose levels. High glucose in the blood will mean an increase in glucose uptake by beta cells. This then causes an increase in ATP in the cell due to an increase in cellular metabolism. This increase in ATP will cause the closure of an ATP regulated potassium channel, which will then result in the opening of voltage dependent calcium channels and an influx of calcium into the cell. This sets off a second messenger system, causing ultimately a release of insulin by exocytosis.
  • Meals high in carbohydrate will cause a sharp rise and early peak in insulin levels, and may also result in glucose levels dropping to below normal levels an hour or so after the meal is eaten. In some people, with reactive hypoglycaemia there is an exaggerated response, similar t that described above. Patients who have had a gastrectomy can suffer similar consequences due to rapid influx of food to the small intestine. This can be treated by eating lots of small meals regularly and limiting the intake of carbohydrate.
  • Large numbers of amino acids can also cause the release of glucose, because they are cationic, and will thus depolarise the membrane of beta cells ad result in an influx of calcium into the cell.
  • In obese people, the normal insulin response is altered. They release more insulin than a normal individual, however, this does not cause reactive hypoglycaemia, and thus from this we can deduce that obese people have a higher insulin tolerance than normal people, and thus have to secrete more insulin to compensate for this.
 
Insulin is released in pulses about every 9-13 minutes. The peak amount of insulin released roughly corresponds to the amount eaten. Insulin secretion drops dramatically at night.
This pulsing release mechanism is important because it is thought that this keeps cells sensitive to insulin. this is one of the first things that disappears when insulin sensitivity disappears.
Insulin release is also regulated by the GI tract. More insulin is released when glucose is eaten, than when the same amount of glucose is given intravenously.
The circulating half-life of insulin is only a few minutes – 30% of insulin is removed by the liver, and thus only 70% of the total amount secreted makes it out of the portal venous system. The kidneys will soon remove systemically circulating insulin.
C-peptide is a protein that is cleaved from proiinsulin when it is activated. This has a much longer half-life than insulin itself, and thus is a useful measure of insulin secretion (it is more accurate than measuring insulin itself). The level of this can be measured in the urine. However, it is easier to measure glucose levels, and since these reflect insulin levels, this is normally the test performed.
 
GLUT-4 is the main insulin responsive glucose transporter. Once insulin activates tyrosine kinase, tyrosine kinase will activate (normally glucose finds it difficult to diffuse through the cell membrane because it is not lipid soluble.) Glucose is moved into a cell WITH potassium. So in hyperkalaemia, you can give dextrose with insulin via infusion, and this will cause an influx of potassium to the cells – reducing the amount in the blood.
Insulin will cause decreased catabolism within a cell, thus allowing for glucose to be utilised as the main energy source during the absorptive state.

Glycolysis

Glycolysis in the first stage of glucose metabolism. It occurs outside the mitochondria, and is a catabolic process. This process produces two pyruvate molecules from one glucose molecule.
Glycolysis produces a net gain of 2 ATP molecules.
Only liver, renal tubule, and specialised GI tract cells are able to reverse the process and release glucose from storage.
In cells that lack mitochondria (e.g. RBC’s), and also in times of anaerobic metabolism, then glycolysis is the main way in which cells get their energy.
The citric acid (Krebb) cycle is the way in which glucose is utilised by the mitochondria in the presence of oxygen. It is the way in which we get most of our energy.
In this process, pyruvic acid (pyruvate) has its hydrogen atoms removed, and then the remaining oxygen and carbon molecules are re-arranged as carbon dioxide and water. This is a process called decarboxylation.

The mitochondria has two membranes – an outer and an inner. The right molecules (e.g. pyruvate) are able to diffuse through the outer, and then the inner has transport proteins to move needed molecules into the mitochondrial matrix.
In the first step, pyruvic acid is converted to acetyl-Coa by co-enzyme A.
As hydrogen ions are released from pyruvate they are pumped from the matrix back to the intermembranous space by the electron transfer system – this system transfers electrons that have also been released from pyruvate. This creates a negative charge in the mitochondrial matrix, which draws the positively charged hydrogen ions back into this space. However, the only way they can get back into the matric is through ATPsynthase molecules that generate ATP from the energy provided by the hydrogen. ATP synthase uses this energy to combine free phosphate ions (found in the mitochondrial matrix) to make ATP from ADP.

There is  a pool of hydrogen ions and electrons that contribute to this cycle. These are removed from this pool by carbon and water molecules that have also come from the breakdown of pyruvate, and join with them to form carbon dioxide and water.
For each 2 hydrogen ions released (and thus each2 electrons) in the TCA cycle, 3ATP’s are produced
However, some H+ gets bound to carrier proteins (FAD and NAD), and these hydrogens are converted to ATP at a different rate; NAD will give 2ATP per H, whilst FAD only gives 1ATP per H.

So, in total, 36 ATP are produced (2 of these in glycolysis). Actually, we produce 38 (4 in glycolysis), but glycolysis also requires 2 ATP to get it going, so the net output is only 2 ATP.
The more ATP in a cell, the more certain enzymes involved in the formation of pyruvate are inhibited (particularly phosphfructokinase).
Another mechanism is just that if there is no ADP, then quite simply, more ATP just cannot be formed!.
Insulin will increase the number of enzymes used in glucose metabolism, and this increase the metabolism through this mechanism.

 
  • Glycogenesis – the process of forming glycogen. This generally occurs in the liver and skeletal muscles.
  • Glucose-6-phosphate is a molecule that is formed both at the start of glycolysis and glycogenesis. Thus this molecule is the one that is the ‘intermediary’.
  • Glycogenolysis is the process of glycogen breakdown to form glucose from glycogen.
Only a certain amount og glycogen can be stored. Once the storage limit is reached (this limit is about 12-24 hours worth of metabolic needs), then excess glucose will be stored as fat!
 

Gluconeogenesis

Gluconeogenesis is the process by which glucose is formed from proteins and carbohydrates. You can’t use fats (and lots of amino acids) to make glucose, but you can break down fats to make acetyl-CoA, which can then be used in the Krebb’s cycle. So why use this method?! Because some cells (brain and RBC’s) can only utilise glucose and not other forms of energy. Thus, this is a method synthesising glucose when all other routes have been exhausted.
The liver is very important in this process – it can synthesis glucose both via glycogenolysis and gluconeogenesis. In the fasting state, about 75% of the glucose output of the liver is from glycogenolysis and 25% is from gluconeogenesis.

In times of severe fasting, the adrenal cortex can also perform gluconeogenesis.
60% of the body’s amino acids can be utilised by gluconeogenesis. Some more easily than others. The process will always involve deamination.
Gluconeogenesis is stimulated by low levels of glucose and high levels of cortisol (a hormone produced by the adrenal cortex in times of low carbohydrate levels).
Lactic acid formation – the law of mass action states that as the end products of a reaction build up, the rate of thee reaction will approach zero. In anaerobic metabolism, only glycolysis occurs (the TCA cycle cannot occur), and so the products of glycolysis build up. Pyruvic acid along with NADH and H+ will build up to high levels. To try and counteract this, the enzyme lactate dehydrogenase allows for the prodution of lactic acid from these products. This reaction is reversible, and thus an equilibrium is established – allowing for the breakdown of lactic acid when aerobic metabolism (hopefully!) resumes. Lactic acid can also easily diffuse o ut of cells, allowing the formation of more lactic acid, and thus allowing glycolysis to continue.