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The exact sequence of amino acids comprising the insulin molecule, the so-called primary structure, was determined by British molecular biologist Frederick Sanger. It was the first protein whose structure was completely determined. For this he was awarded the Nobel Prize in Chemistry in 1958. In 1967, after decades of work, Dorothy Crowfoot Hodgkin determined the spatial conformation of the molecule, by means of x-ray diffraction studies. She also was awarded a Nobel Prize.
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Insulin structure and production
Insulin is synthesized in humans and other mammals within the beta cells (B-cells) of the Islets of Langerhans in the pancreas. One to three million Islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine part accounts for only 2% of the total mass of the pancreas. Within the Islets of Langerhans, beta cells constitute 60-80% of all the cells.
Insulin is built from 51 amino acids and is one of the smallest proteins known; shorter 'proteins' are usually referred to as a polypeptide. Beef insulin differs from human insulin in two amino acid residues, and pork insulin in one residue. Fish insulin is also close enough to human insulin to act as insulin in people. In humans, insulin has a molecular weight of 5734. Insulin is structured as 2 polypeptide chains linked by 2 sulfur bridges (see figure shown above). Chain A consists of 21, and chain B of 30 amino acids. Insulin is produced as a prohormone molecule – proinsulin – that is later transformed by proteolytic action into the active hormone.
The remaining part is called C-peptide. This polypeptide is released into the blood – one C-peptide for each two insulin molecules. Since external insulins currently contain no C-peptide component, serum amounts of peptide C are good indicators of internal insulin production. C-peptide has recently been discovered to have biological activity itself; the activity is apparently confined to an effect on the muscular layer of the arteries.
Actions of insulin on cell level and global metabolism level
The actions of insulin on the global human metabolism level include:
The actions of insulin on cells include:Regulatory actions of insulin on blood glucose levels
Despite long intervals between meals or the occasional consumption of meals with a substantial carbohydrate load (eg, half a birthday cake or a bag of potato chips), human blood glucose levels normally remain within a narrow range. In most humans this varies from person to person from about 70 miligrams/deciliter to perhaps 110 mg/dl except shortly after eating when the blood glucose level rises temporarily; this is a total of about 5 grams (1/5 of an ounce) of glucose in the 5 liters (1 1/4 gallons) of blood in the average adult male. This homeostatic process is the result of many factors, but hormone regulation is the most important.
There are two groups of antagonistic hormones affecting blood glucose levels:
Beta cells in the Islets of Langerhans are sensitive to variations in blood glucose levels because of the presence of glucokinase, which responds to glucose concentrations. If that level increases, more insulin from beta cell stores is released into the blood, and beta cell insulin production increases. When the glucose level comes down to the physiologic value, insulin release slows or stops. And, before the level of glucose drops dangerously low, hyperglycemic hormones come into play, forcing release of glucose into the blood from cellular stores.
Insulin and the brain
Though other cells can use other fuels for a while (most prominently fatty acids), neurons are dependent on glucose as a source of energy in the non-starving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue and they have very little internal stores of glycogen. Thus, a sufficiently low glucose level first and most dramatically manifests itself in impaired functioning of the functioning of the central nervous system – dizzness, speech problems, even loss of consciousness, are common. This phenomenon is known as hypoglycemia or, in cases producing unconsciousness, hypoglycemic coma (formerly termed insulin shock from the most common causative agent). Because endogenous causes of insulin excess (such as an insulinoma) are extremely rare naturally, the overwhelming majority of hypoglycemia cases are caused by human action (eg, iatrogenic (meaning caused by medicine)), and are usually accidental. There have been a few cases reported of murder or attempted murder using insulin overdoses, but most insulin shock appears to be due to mismangement of insulin (didn't eat as much as anticipated, or exercised more than expected), or a mistake (eg, 200 units of insulin instead of 20).
Misuse of any of three classes of medication are the usual causes of iatrogenic hypoglycemia:
Activation of insulin receptors leads to internal cellular mechanisms which directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane which transport glucose into the cell.
Two types of tissues are most strongly influenced by insulin: muscle cells (myocytes) and fat cells (adipocytes). The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess calories against future needs. Together, they account for about 2/3 of all cells in a typical human body.
Diseases and syndromes caused by an insulin disturbance
There are several conditions in which insulin disturbance is pathologic:Insulin as a medication
Insulin is absolutely required for all animal (including human) life. The mechanism is almost identical in nematode worms (ie, C. elegans) and in mammals. In humans, insulin deprivation due to the removal or destruction of the pancreas leads to death in days or at most weeks. Insulin must be administered to patients in whom there is a lack of the hormone for this, or any other, reason. Clinically, this is called diabetes mellitus type 1.
Although it was evident to researchers in the late 1800s that there was some connection between the pancreas and diabetic symptoms, efforts to isolate the active principle (secretion or whatever) were unsuccessful. Progress was only made when it was realised that the digestive enzymes also produced by the pancreas destroyed the active material during the attempts at extraction. Many around the world came close, but the announcment of isolation of insulin from the pancreases of foetal calves (which had not yet begun the production of digestive enzymes) was made on 27 July 1921 at the University of Toronto (by Frederick Banting, Charles Best, James Collip, and J.J.R. Macleod. For this breakthrough discovery, Macleod and Banting were awarded the Nobel Prize in Physiology or Medicine in 1923. Banting and MacLeod shared some of the Prize money with the others.
Harvesting pancreases from human corpses was not possible in practice, so insulin from cows or pigs or fish pancreases was used instead. All have 'insulin activity' in humans as they are nearly identical to human insulin (2 amino acid differnce for bovine insulin, 1 amino acid difference for porcine). Insulin is a protein which has been very strongly conserved across evolutionary time. Differences in suitability of beef, pork, or fish insulin preparations for particular patients have been primarily the result of preparation purity and of allergic reactions to assorted non-insulin substances remaining in those preparations. Human insulin can now manufactured, using genetic engineering molecular biology techniques, in sufficient quantity for widespread clinical use, much reducing impurity reaction problems. Eli Lilly marketed the first such synthetic insulin, Humulin, in 1982. Genentech Inc developed the technique Lilly used.
There are several difficulties with the use of insulin as a clinical treatment for diabetes:
Unlike many medicines, insulin cannot be taken orally. It is treated precisely as any other protein in the gastrointestinal tract. Like all other ingested proteins, it is reduced to its amino acid components and loses all 'insulin activity'. There are research efforts underway to develop methods of protecting insulin from the digestive tract so that it can be taken orally, but none has yet proven both safe and effective.
Inhaled insulin is under active investigation as are several other, more exotic, techniques.
An insulin pump is a reasonable solution for some. However there are several major limitations - cost, the potential for hypoglycemic episodes, and, thus far, no approvable means of controlling insulin delivery based on blood glucose levels. If too much insulin is delivered or the patient eats less than normal, there will be hypoglycemia. On the other hand, if too little insulin is delivered by the pump, there will be hyperglycemia. Both of these can lead to potentially life-threatening conditions. In addition, indwelling catheters pose considerable risk of infection and ulceration. Thus far, insulin pumps require considerable care and effort to use correctly. Some diabetics are able to keep their glucose in reasonable control only on a pump.
Researchers have produced a watch-like device that tests for insulin levels in the blood through the skin and administers corrective doses through pores in the skin of the patient. Both electricity and ultrasound have been found to make the skin temporarily porous. The insulin administration aspect remains experimental at this writing. The blood glucose test aspect is, at this writing, commercially available essentially as described.
Another 'improvemetn' would be to avoid periodic insulin administration entirely by installing a self-regulating insulin source. For instance, pancreatic, or beta cell, transplantation. Transplantation of an entire pancreas (as an individual organ) is rather difficult technically, so it is not common. Generally, it is performed in conjunction with liver or kidney transplant surgery. However, transplantation of only pancreatic beta cells is a possibility. It has been highly experimental (ie, prone to failure) for many years, but some researchers in Alberta, Canada, have developed techniques which have produced a much higher success rate (about 90% in one group). Beta cell transplant may become practical, and common, in the near future. Several other non-transplant methods of automatic insulin delivery are being developed in the research labs as this is written. None is currently close to clinical approval.
The central problem for those requiring external insulin is picking the right dose of insulin and the right timing.
Complicating matters is that the composition of the food eaten (see glycemic index) affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. And, fats and proteins both cause delays in absorption of glucose from carbohydrate eaten at the same time. As well, exercise reduces the need for insulin even when all other factors remain the same.
It is in principle impossible to know for certain how much insulin (and which type) is needed to 'cover' a particular meal in order to achieve a reasonable blood glucose level within an hour or two after eating. Non-diabetics' beta cells routinely and automatically manage this by continual monitoring and adjustment of insulin release. All such decisions by a diabetic must be based on general experience and training (ie, at the direction of a physician or PA) and, further, specifically based on the individual experience of the patient. It is not straightforward and should never be done by habit or routine, but with care can be done quite successfully in practice.
For example, some diabetics require more insulin after drinking skim milk than they do after taking an equivalent amount of fat, protein, carbohydrate, and fluid in some other form. Their particular reaction to skim milk is different than other diabetics', but the same amount of whole milk is likely to cause a still different reaction even in that same person. Whole milk contains considerable fat while skim milk has much less. It is a continual balancing act for all diabetics, especially for those taking insulin.
Medical preparations of insulin (from the major suppliers – Eli Lilly and Novo Nordisk -- or from any other) are never just 'insulin in water'. Clinical insulins are specially prepared mixtures of insulin plus other substances. These delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on. Some recent insulins are not even precisely insulin, but so called insulin analogs. The insulin molecule in an insulin analog is slightly modified so that they are
Allowing blood glucose levels to rise, though not to levels which cause acute hyperglycemic symptoms, is not a sensible choice. Several large, well designed, long term studies have conclusively shown that diabetic complications decrease markedly, linearly, and consistently as blood glucose levels approach 'normal' patterns over long periods. In short, if a diabetic closely controls blood glucose levels (ie, on average, both over days and weeks, and avoiding too high peaks after meals) the rate of diabetic complications goes down. If glucose levels are very closely controlled, that rate can even approach 'normal'. The chronic diabetic complications include cerebrovascular accidents (CVA or stroke), heart attack, blindness (from proliferative diabetic retinopathy), toehr vascular damage, nerve damage from diabetic neuropathy, or kidney failure from diabetic nephropathy. These studies have demonstrated beyond doubt that, if it is possible for a patient, so-called intensive insulinotherapy is superior to conventional insulinotherapy. However, close control of blood glucose levels (as in intensive insulinotherapy) does require care and considerable effort, for hypoglycemia is dangerous and can be fatal.
A good measure of long term diabetic control (approx 90 days in most people) is the serum level of glycoslyated hemoglobin (HbA1c). A shorter term integrated measure (over two weeks or so) is the so-called 'fructosamine' level, which is a measure of similarly glyclosylated proteins (chiefly albumin) with a shorter half life in the blood. There is a commercial meter available which measures this level in the field.
Insulin abuse
There are reports that some patients abuse insulin by injecting larger doses that lead to mild hypoglycemic states. This is EXTREMELY dangerous and is essentially equivalent to suffocation experimentation. Severe acute or prolonged hypoglycemia can result in brain damage.
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