Insulin

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 acids, and pork insulin in one. 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 moleucle -- proinsulin -- that is later transformed by proteolytic action into the active hormone.

The remaining part is called peptide C. 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.

• cellular intake of certain substances, most prominently glucose
• increase of DNA replication and protein synthesis
• modification of the activity of numerous enzymes (allosteric effect)

• increased glycogen synthesis -- insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; absence of insulin causes liver cells to convert glycogen to glucose and dump it into the blood
• increased fatty acid synthesis -- insulin forces fat cells to take in glucose which is converted to fatty acids; lack of insulin causes the reverse
• increased esterification of fatty acids -- forces adipose tissue to make fats (ie, triglycerides) from fatty acid esters; lack of insulin causes the reverse
• decreased proteinolysis -- forces reduction of protein degradation; lack of insulin increases protein degradation,
• decreased lipolysis -- forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse
• decreased gluconeogenesis -- decreases production of glucose from various substrates in liver; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere
• increased amino acid uptake -- forces cells to absorb circulating amono acids; lack of insulin inhibits absorbtion
• increased potassium uptake -- forces cells to absorb serum potassium; lack of insulin inhibits absorbtion
• aterial muscle tone -- forces arterial wall muscle to relax increasing blood flow, especially in micro arteries; lack of insulin allows reduced flow

Regulatory actions of insulin on blood glucose levels

There are two groups of antagonistic hormones affecting blood glucose levels:

• hyperglycemic hormones (such as glucagon, growth hormone, and adrenaline), which increase blood glucose
• and one hypoglycemic hormone (insulin), which decreases blood glucose

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, the insulin release slows or stops. Before the level of glucose drops dangerously low, hyperglycemic hormones come into play.

Misuse of any of three classes of medication are the usual causes of iatrogenic hypoglycemia:

• oral hypoglycemic agents (eg, any of the sulfonylureas which increase insulin release from beta cells in response to a particular blood glucose level)
• external insulin (usually injected subcutaneously)
• insulin resistance reducers (eg, one of a new class of drugs (troglitazone Rezulin was the first) which increase cellular sensitivity to insulin)

Intracellular transformation of the insulin signal

The insulin receptors control internal cellular mechanisms which directly perform 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.

• diabetes mellitus -- general term referring to all states characterized by hyperglycemia
  • diabetes mellitus type 1 -- autoimmune-mediated destruction of insulin producing beta cells in the pancreas resulting in absolute insulin deficiency
  • diabetes mellitus type 2 -- multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being obesity and physical inactivity, resulting in insulin insensitivity in cells requiring insulin for glucose absorption
  • other type of impaired glucose tolerance
• insulinoma or reactive hypoglycemia

Insulin as a medication

Although it was evident to researchers that some secretion from the pancreas was responsible for glucose control, efforts to isolate the active principle 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 pancrases was used instead. All have 'insulin activity' in humans. 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 substances 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:

• mode of administration
• selecting the 'right' dose and timing
• selecting an appropriate insulin preparation
• adjusting dosage and timing to fit food amounts and types
• adjusting dosage and timing to fit exercise undertaken

• non physiologic (the pancreas releases insulin (and C-peptide) gradually into the portal vein instead of subcutaneously in a bolus), and
• simply a nuisance for patients to inject themselves once or several times a day

Unlike many medicines, insulin cannot be taken orally. It is treated like 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 good solution. 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 mechanical device to be absorbed by the skin of the patient. The insulin adminstration aspect remains experimental at this writing. The blood glucose test aspect is, at this writing, commercially available essentially as described.

Another 'solution' to diabetes would be to avoid periodic insulin adminstration entirely by installing a self-regulating insulin source. For instance, pancreatic, or beta cell, transplantation. It is rather difficult technically, so transplantation of an entire pancreas (as an individual organ) is not common. Generally it is performed in conjunction with liver or kidney transplant surgery. However, transplantation of pancreatic beta cells alone 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.

Physiological regulation of blood glucose, as in the non-diabetic, would be best. Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas. The increased insulin level causes glucose absorption and storage, reducing blood glucose levels and reducing insulin release. The result is that the blood glucose level rises somewhat after eating, and within an hour or so returns to the normal 'fasting' level. Even the best diabetic treatment with human insulin, however administered, falls short of the glucose control in a non-diabetic.

Complicating matters is that the composition of the food eaten (see glycemic index) affects intestinal absorption rates. And, fats and proteins both cause delays in absorption of carbohydrate eaten at the same time. And, exercise reduces need for insulin even when all other factors remain the same.

It is 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 MD 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.

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 a 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 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, so long as they do not go high enough to cause acute hyperglycemic symptoms is not a reasonable 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, over days and weeks, and avoiding too high peaks after meals) the rate of diabetic complications goes down. If 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 (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.

• anatomy and physiolology
  • glucagon
  • pancreas
  • Islets of Langerhans
  • endocrinology
• forms of diabetes mellitus
  • diabetes mellitus
  • diabetes mellitus type 1
  • diabetes mellitus type 2
• treatment
  • intensive insulinotherapy
  • insulin pump
  • conventional insulinotherapy

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