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Insulin

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

                                                                   Insulin

                                                          Insulin crystals
                                                      Other names: insulin
                                                              Genetic data
                                                      Locus: Chr. 11 p15.5
                                                 Gene code: HUGO code: INS
                                                 Gene type: Protein coding
                                                Protein Structure/Function
                                              Molecular Weight: 11982 (Da)
            Structure: Solution Structure of Human pro-Insulin Polypeptide
                                              Protein type: insulin family
                                             Functions: glucose regulation
                                                       Domains: INS domain
                                                          Motifs: SP motif
                                                                     Other
            Taxa expressing: Homo sapiens; homologs: in metazoan taxa from
                                                  invertebrates to mammals
              Cell types: pancreas: beta cells of the Islets of Langerhans
                            Subcellular localization: extracellular fluids
                   Covalent modifications: glycation, proteolytic cleavage
           Pathway(s): Insulin signaling pathway ( KEGG); Type II diabetes
        mellitus ( KEGG); Type I diabetes mellitus ( KEGG); Maturity onset
   diabetes of the young ( KEGG); Regulation of actin cytoskeleton ( KEGG)
                                                      Receptor/Ligand data
                     Antagonists: glucagon, steroids, most stress hormomes
                                             Medical/Biotechnological data
                 Diseases: familial hyperproinsulinemia, Diabetes mellitus
   Pharmaceuticals: insulin ( Humulin Novolin), insulin lispro ( Humalog),
   insulin aspart ( Novolog), insulin detemir ( Levemir), insulin glargine
                                                            ( Lantus), etc
                                                            Database Links
       Codes: EntrezGene 3630; Mendelian Inheritance in Man (OMIM) 176730;
                                          UniProt P01308; RefSeq NM_000207

   Insulin (from Latin insula, "island", as it is produced in the Islets
   of Langerhans in the pancreas) is a polypeptide hormone that regulates
   carbohydrate metabolism. Apart from being the primary effector in
   carbohydrate homeostasis, it has effects on fat metabolism and it can
   change the liver's ability to release fat stores. Insulin's
   concentration has extremely widespread effects throughout the body.

   Insulin is used medically in some forms of diabetes mellitus. Patients
   with type 1 diabetes mellitus depend on exogenous insulin (commonly
   injected subcutaneously) for their survival because of an absolute
   deficiency of the hormone; patients with type 2 diabetes mellitus have
   either relatively low insulin production or insulin resistance or both,
   and a non-trivial fraction of type 2 diabetics eventually require
   insulin administration when other medications become inadequate in
   controlling blood glucose levels.

   Insulin has a molecular weight of 5808 Da. It has the molecular formula
   C[257]H[383]N[65]O[77]S[6].

   Insulin structure varies slightly between species of animal. Its
   carbohydrate metabolism regulatory function strength in humans also
   varies. Porcine (pig) insulin is particularly close to humans'.

Discovery and characterization

   In 1869 Paul Langerhans, a medical student in Berlin, was studying the
   structure of the pancreas under a microscope when he noticed some
   previously-unidentified cells scattered in the exocrine tissue. The
   function of the "little heaps of cells," later known as the Islets of
   Langerhans, was unknown, but Edouard Laguesse later argued that they
   may produce a secretion that plays a regulatory role in digestion.

   In 1889, the Polish-German physician Oscar Minkowski in collaboration
   with Joseph von Mehring removed the pancreas from a healthy dog to
   demonstrate this assumed role in digestion. Several days after the
   dog's pancreas was removed, Minkowski's animal keeper noticed a swarm
   of flies feeding on the dog's urine. On testing the urine they found
   that there was sugar in the dog's urine, demonstrating for the first
   time the relationship between the pancreas and diabetes. In 1901,
   another major step was taken by Eugene Opie, when he clearly
   established the link between the Islets of Langerhans and diabetes:
   Diabetes mellitus.... is caused by destruction of the islets of
   Langerhans and occurs only when these bodies are in part or wholly
   destroyed. Before this demonstration, the link between the pancreas and
   diabetes was clear, but not the specific role of the islets.
   The structure of insulin. The left-hand side is a space-filling model
   of the insulin monomer, believed to be biologically active. Carbon is
   green, hydrogen white, oxygen red, and nitrogen blue. On the right-hand
   side is a cartoon of the hexamer, believed to be the stored form. A
   monomer unit is highlighted with the A chain in blue and the B chain in
   cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc
   ions.
   Enlarge
   The structure of insulin. The left-hand side is a space-filling model
   of the insulin monomer, believed to be biologically active. Carbon is
   green, hydrogen white, oxygen red, and nitrogen blue. On the right-hand
   side is a cartoon of the hexamer, believed to be the stored form. A
   monomer unit is highlighted with the A chain in blue and the B chain in
   cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc
   ions.

   Over the next two decades, several attempts were made to isolate the
   secretion of the islets as a potential treatment. In 1906 George Ludwig
   Zuelzer was partially successful treating dogs with pancreatic extract,
   but was unable to continue his work. Between 1911 and 1912, E.L. Scott
   at the University of Chicago used aqueous pancreatic extracts and noted
   a slight diminution of glycosuria, but was unable to convince his
   director and the research was shut down. Israel Kleiner demonstrated
   similar effects at Rockefeller University in 1919, but his work was
   interrupted by World War I and he was unable to return to it. Nicolae
   Paulescu, a professor of physiology at the Romanian School of Medicine,
   published similar work in 1921 that was carried out in France and
   patented in Romania, and it has been argued ever since that he is the
   rightful discoverer.

   However, the Nobel prizes committee in 1923 credited the practical
   extraction of insulin to a team at the University of Toronto. In
   October 1920, Frederick Banting was reading one of Minkowski's papers
   and concluded that it is the very digestive secretions that Minkowski
   had originally studied that were breaking down the secretion, thereby
   making it impossible to extract successfully. He jotted a note to
   himself Ligate pancreatic ducts of the dog. Keep dogs alive till acini
   degenerate leaving islets. Try to isolate internal secretion of these
   and relieve glycosurea.

   He travelled to Toronto to meet with J.J.R. Macleod, who was not
   entirely impressed with his idea. Nevertheless, he supplied Banting
   with a lab at the University, an assistant, medical student Charles
   Best, and ten dogs, while he left on vacation during the summer of
   1921. Their method was tying a ligature (string) around the pancreatic
   duct, and, when examined several weeks later, the pancreatic digestive
   cells had died and been absorbed by the immune system, leaving
   thousands of islets. They then isolated the protein from these islets
   to produce what they called isletin. Banting and Best were then able to
   keep a pancreatectomized dog alive all summer.
   Computer-generated image of insulin hexamers highlighting the threefold
   symmetry, the zinc ions holding it together, and the histidine residues
   involved in zinc binding. Enlarge
   Computer-generated image of insulin hexamers highlighting the threefold
   symmetry, the zinc ions holding it together, and the histidine residues
   involved in zinc binding.

   Macleod saw the value of the research on his return from Europe, but
   demanded a re-run to prove the method actually worked. Several weeks
   later it was clear the second run was also a success, and he helped
   publish their results privately in Toronto that November. However, they
   needed six weeks to extract the isletin, dramatically slowing testing.
   Banting suggested that they try to use fetal calf pancreas, which had
   not yet developed digestive glands; he was relieved to find that this
   method worked well. With the supply problem solved, the next major
   effort was to purify the protein. In December 1921, Macleod invited the
   biochemist James Collip to help with this task, and, within a month, he
   felt ready to test.

   On January 11, 1922, Leonard Thompson, a fourteen-year-old diabetic,
   was given the first injection of insulin. However, the extract was so
   impure that he suffered a severe allergic reaction, and further
   injections were canceled. Over the next 12 days, Collip worked day and
   night to improve the extract, and a second dose injected on the 23rd.
   This was completely successful, not only in not having obvious
   side-effects, but in completely eliminating the symptoms of diabetes.
   However, Banting and Best never worked well with Collip, regarding him
   as something of an interloper, and Collip left soon after.

   Over the spring of 1922, Best managed to improve his techniques to the
   point where large quantities of insulin could be extracted on demand,
   but the extract remained impure. However, they had been approached by
   Eli Lilly and Company with an offer of help shortly after their first
   publications in 1921, and they took Lilly up on the offer in April. In
   November, Lilly made a major breakthrough, and were able to produce
   large quantities of pure insulin. Insulin was offered for sale shortly
   thereafter.

Nobel Prizes

     * Macleod and Banting were awarded the Nobel Prize in Physiology or
       Medicine in 1923 for the discovery of insulin. Banting, insulted
       that Best was not mentioned, shared his prize with Best, and
       MacLeod immediately shared his with Collip. The patent for insulin
       was sold to the University of Toronto for one dollar.
     * 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 to
       have its structure be completely determined. 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 had been awarded a Nobel Prize in
       Chemistry in 1964 for the development of crystallography.
     * Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for
       the development of the radioimmunoassay for insulin.

Structure and production

   Insulin undergoes extensive posttranslational modification along the
   production pathway. Production and secretion are largely independent;
   prepared insulin is stored awaiting secretion. Both C-peptide and
   mature insulin are biologically active. Cell components and proteins in
   this image are not to scale.
   Enlarge
   Insulin undergoes extensive posttranslational modification along the
   production pathway. Production and secretion are largely independent;
   prepared insulin is stored awaiting secretion. Both C-peptide and
   mature insulin are biologically active. Cell components and proteins in
   this image are not to scale.

   Insulin has been highly conserved across the animal kingdom; it is an
   ancient molecule. C. elegans, a nematode worm, uses insulin in very
   much the same way vertebrates do. Within vertebrates, the simularity of
   insulins is very close. Bovine insulin differs from human in only three
   amino acid residues, and porcine insulin in one. Even insulin from some
   species of fish is similiar enough to human to be effective in humans.

   In mammals, insulin is synthesized in the pancreas within the beta
   cells (β-cells) of the islets of Langerhans. One to three million
   islets of Langerhans (pancreatic islets) form the endocrine part of the
   pancreas, which is primarily an exocrine gland. The endocrine portion
   only accounts for 2% of the total mass of the pancreas. Within the
   islets of Langerhans, beta cells constitute 60–80% of all the cells.

   In beta cells, insulin is synthesized from the proinsulin precursor
   molecule by the action of proteolytic enzymes known as prohormone
   convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase
   E. These modifications of proinsulin remove the centre portion of the
   molecule, or C-peptide, from the C- and N- terminal ends of the
   proinsulin. The remaining polypeptides (51 amino acids in total), the
   B- and A- chains, are bound together by disulfide bonds. Confusingly,
   the primary sequence of proinsulin goes in the order "B-C-A", since B
   and A chains were identified on the basis of mass, and the C peptide
   was discovered after the others.

Actions on cellular and metabolic level

   Effect of insulin on glucose uptake and metabolism. Insulin binds to
   its receptor (1) which in turn starts many protein activation cascades
   (2). These include: translocation of Glut-4 transporter to the plasma
   membrane and influx of glucose (3), glycogen synthesis (4), glycolysis
   (5) and fatty acid synthesis (6).
   Enlarge
   Effect of insulin on glucose uptake and metabolism. Insulin binds to
   its receptor (1) which in turn starts many protein activation cascades
   (2). These include: translocation of Glut-4 transporter to the plasma
   membrane and influx of glucose (3), glycogen synthesis (4), glycolysis
   (5) and fatty acid synthesis (6).

   The actions of insulin on the global human metabolism level include:
     * Control of cellular intake of certain substances, most prominently
       glucose in muscle and adipose tissue (about ⅔ of body cells).
     * Increase of DNA replication and protein synthesis via control of
       amino acid uptake.
     * Modification of the activity of numerous enzymes ( allosteric
       effect).

   The actions of insulin on cells include:
     * Increased glycogen synthesis – insulin forces storage of glucose in
       liver (and muscle) cells in the form of glycogen; lowered levels of
       insulin cause liver cells to convert glycogen to glucose and
       excrete it into the blood. This is the clinical action of insulin
       which is directly useful in reducing high blood glucose levels as
       in diabetes.
     * Increased fatty acid synthesis – insulin forces fat cells to take
       in blood lipids which are converted to triglycerides; 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
       amino acids; lack of insulin inhibits absorption.
     * Increased potassium uptake – forces cells to absorb serum
       potassium; lack of insulin inhibits absorption.
     * Arterial muscle tone – forces arterial wall muscle to relax,
       increasing blood flow, especially in micro arteries; lack of
       insulin reduces flow by allowing these muscles to contract.

Regulatory action on blood glucose

   Despite long intervals between meals or the occasional consumption of
   meals with a substantial carbohydrate load (e.g., 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 about 70 mg/dl
   to perhaps 110 mg/dl (3.9 to 6.1 mmol/litre) except shortly after
   eating when the blood glucose level rises temporarily. This homeostatic
   effect is the result of many factors, of which hormone regulation is
   the most important.

   It is usually a surprise to realize how little glucose is actually
   maintained in the blood, and body fluids. The control mechanism works
   on very small quantities. In a healthy adult male of 75 kg with a blood
   volume of 5 litres, a blood glucose level of 100 mg/dl or 5.5 mmol/l
   corresponds to about 5 g (1/5 ounce) of glucose in the blood and
   approximately 45 g (1½ ounces) in the total body water (which obviously
   includes more than merely blood and will be usually about 60% of the
   total body weight in men). A more familiar comparison may help -- 5
   grams of glucose is about equivalent to a commercial sugar packet (as
   provided in many restaurants with coffee or tea).

   There are two types of mutually antagonistic metabolic hormones
   affecting blood glucose levels:
     * catabolic hormones (such as glucagon, growth hormone, and
       catecholamines), which increase blood glucose
     * and one anabolic hormone (insulin), which decreases blood glucose

   Mechanisms which restore satisfactory blood glucose levels after
   hypoglycemia must be quick, and effective, because of the immediate
   serious consequences of insufficient glucose (in the extreme, coma,
   less immediately dangerously, confusion or unsteadiness, amongst many
   other effects). This is because, at least in the short term, it is far
   more dangerous to have too little glucose in the blood than too much.
   In healthy individuals these mechanisms are indeed generally efficient,
   and symptomatic hypoglycemia is generally only found in diabetics using
   insulin or other pharmacologic treatment. Such hypoglycemic episodes
   vary greatly between persons and from time to time, both in severity
   and swiftness of onset. In severe cases prompt medical assistance is
   essential, as damage (to brain and other tissues) and even death will
   result from sufficiently low blood glucose levels.
   Mechanism of glucose dependent insulin release
   Enlarge
   Mechanism of glucose dependent insulin release

   Beta cells in the islets of Langerhans are sensitive to variations in
   blood glucose levels through the following mechanism (see figure to the
   right):
     * Glucose enters the beta cells through the glucose transporter GLUT2
     * Glucose goes into the glycolysis and the respiratory cycle where
       multiple high-energy ATP molecules are produced by oxidation
     * Dependent on blood glucose levels and hence ATP levels, the ATP
       controlled potassium channels (K^+) close and the cell membranes
       depolarize
     * On depolarisation, voltage controlled calcium channels (Ca^2+) open
       and calcium flows into the cells
     * An increased calcium level causes activation of phospholipase C,
       which cleaves the membrane phospholipid phosphatidyl inositol
       4,5-bisphosphate into inositol 1,4,5-triphosphate and
       diacylglycerol.
     * Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the
       membrane of endoplasmic reticulum (ER). This allows the release of
       Ca^2+ from the ER via IP3 gated channels, and further raises the
       cell concentration of calcium.
     * Significantly increased amounts of calcium in the cells causes
       release of previously synthesised insulin, which has been stored in
       secretory vesicles
     * The calcium level also regulates expression of the insulin gene via
       the calcium responsive element binding protein ( CREB).

   This is the main mechanism for release of insulin and regulation of
   insulin synthesis. In addition some insulin synthesis and release takes
   place generally at food intake, not just glucose or carbohydrate
   intake, and the beta cells are also somewhat influenced by the
   autonomic nervous system. The signalling mechanisms controlling this
   are not fully understood.

   Other substances known which stimulate insulin release are
   acetylcholine, released from vagus nerve endings ( parasympathetic
   nervous system), cholecystokinin, released by enteroendocrine cells of
   intestinal mucosa and gastrointestinal inhibitory peptide (GIP). The
   first of these act similarly as glucose through phospholipase C, while
   the last acts through the mechanism of adenylate cyclase.

   The sympathetic nervous system (via α[2]-adrenergic agonists such as
   norepinephrine) inhibits the release of insulin.

   When the glucose level comes down to the usual physiologic value,
   insulin release from the beta cells slows or stops. If blood glucose
   levels drop lower than this, especially to dangerously low levels,
   release of hyperglycemic hormones (most prominently glucagon from Islet
   of Langerhans' alpha cells) forces release of glucose into the blood
   from cellular stores, primarily liver cell stores of glycogen. Release
   of insulin is strongly inhibited by the stress hormone norepinephrine
   (noradrenaline), which leads to increased blood glucose levels during
   stress.

Signal transduction

   There are special transporter proteins in cell membranes through which
   glucose from the blood can enter a cell. These transporters are,
   indirectly, under insulin control in certain body cell types (eg,
   muscle cells). Low levels of circulating insulin, or its absence, will
   prevent glucose from entering those cells (eg, in untreated Type 1
   diabetes). However, more commonly there is a decrease in the
   sensitivity of cells to insulin (eg, the reduced insulin sensitivity
   characteristic of Type 2 diabetes), resulting in decreased glucose
   absorption. In either case, there is 'cell starvation', weight loss,
   sometimes extreme. In a few cases, there is a defect in the release of
   insulin from the pancreas. Either way, the effect is,
   characteristically, the same: elevated blood glucose levels.

   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. The genes which specify the proteins which make
   up the insulin receptor in cell membranes have been identified and the
   structure of the interior, cell membrane section, and now, finally
   after more than a decade, the extra-membrane structure of receptor
   (Australian researchers announced the work 2Q 2006).

   Two types of tissues are most strongly influenced by insulin, as far as
   the stimulation of glucose uptake is concerned: 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 food energy against future needs.
   Together, they account for about ⅔ of all cells in a typical human
   body.

Hypoglycemia

   Although other cells can use other fuels for a while (most prominently
   fatty acids), neurons depend 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 small internal
   stores of glycogen. Glycogen stored in liver cells (unlike glycogen
   stored in muscle cells) can be converted to glucose, and released into
   the blood, when glucose from digestion is low or absent, and the
   glycerol backbone in triglycerides can also be used to produce blood
   glucose. Exhaustion of these sources can, either temporarily or on a
   sustained basis, if reducing blood glucose to a sufficiently low level,
   first and most dramatically manifest itself in impaired functioning of
   the central nervous system – dizziness, speech problems, even loss of
   consciousness, are not unknown. This is known as hypoglycemia or, in
   cases producing unconsciousness, "hypoglycemic coma" (formerly termed
   "insulin shock" from the most common causative agent). Endogenous
   causes of insulin excess (such as an insulinoma) are very rare, and the
   overwhelming majority of hypoglycemia cases are caused by human action
   (e.g. iatrogenic, caused by medicine), and are usually accidental.
   There have been a few reported cases of murder, attempted murder or
   suicide using insulin overdoses, but most insulin shocks appear to be
   due to mismanagement of insulin (didn't eat as much as anticipated, or
   exercised more than expected), or a mistake (e.g. 20 units of insulin
   instead of 2).

   Possible causes of hypoglycemia include:
     * Oral hypoglycemic agents (e.g., any of the sulfonylureas, or
       similar drugs, which increase insulin release from beta cells in
       response to a particular blood glucose level).
     * External insulin (usually injected subcutaneously).
     * Ingestion of low-carbohydrate sugar substitutes (animal studies
       show these can trigger insulin release according to a report in
       Discover magazine August 2005, p18).

Diseases and syndromes

   There are several conditions in which insulin disturbance is
   pathologic:
     * Diabetes mellitus – general term referring to all states
       characterized by hyperglycemia.
          + Type 1 – autoimmune-mediated destruction of insulin producing
            beta cells in the pancreas resulting in absolute insulin
            deficiency.
          + Type 2 – multifactoral syndrome with combined influence of
            genetic susceptibility and influence of environmental factors,
            the best known being obesity, age, and physical inactivity,
            resulting in insulin resistance in cells requiring insulin for
            glucose absorption. This form of diabetes is strongly
            inherited.
          + Other types of impaired glucose tolerance (see the diabetes
            article).
     * Insulinoma or reactive hypoglycemia.
     * Metabolic syndrome – a precondition first called Metabolic Syndrome
       X by Gerald Reaven, and sometimes called prediabetes. It is
       characterized by elevated blood pressure, dyslipidemia
       (disturbances in blood cholesterol forms and other blood lipids),
       and increased waist circumference (at least in populations in much
       of the developed world). The basic underlying cause is insulin
       resistance, a diminished capacity for insulin response in some
       tissues (eg, muscle, fat, liver) to respond to insulin. Untreated,
       Metabolic Syndrome can lead to morbidities such as essential
       hypertension, obesity, Type 2 diabetes, and cardiovascular disease
       (CVD).
     * Polycystic ovary syndrome – a complex syndrome in women in the
       reproductive years where there is anovulation and androgen excess
       commonly displayed as hirsutism. In many cases of PCOS insulin
       resistance is present.

As a medication

Principles

   Insulin is absolutely required for all animal (including human) life.
   The mechanism is almost identical in nematode worms (e.g. C. elegans),
   fish, 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.

   The initial source of insulin for clinical use in humans was from cow,
   horse, pig or fish pancreases. Insulin from these sources is effective
   in humans as it is nearly identical to human insulin (three amino acid
   difference for bovine insulin, one amino acid difference for porcine).
   Insulin is obviously 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. Purity has
   improved more or less steadily since the 1920s, but allergic reactions
   have continued though slowly reducing in severity. Insulin production
   from animal pancreases was widespread for decades, but there are very
   few patients today relying on insulin from these sources.

   Human insulin is now manufactured for widespread clinical use using
   genetic engineering techniques, which significantly reduces impurity
   reaction problems. Eli Lilly marketed the first such insulin, Humulin,
   in 1982. Humulin was the first medication produced using modern genetic
   engineering techniques, in which actual human DNA is inserted into a
   host cell (E. coli in this case). The host cells are then allowed to
   grow and reproduce normally, and due to the inserted human DNA, they
   produce actual human insulin.

   Genentech developed the technique Lilly used to produce Humulin. Novo
   Nordisk has also developed a genetically engineered insulin
   independently. Most insulins used clinically are produced this way, for
   they avoid most of the allergic reaction problem.

   Since January 2006, all insulins distributed in the U.S. and some other
   countries are human insulins or their analogs. A special FDA
   importation process is required to obtain beef or pork insulin for use
   in the U.S., though there may be some remaining stocks of pork insulin
   made by Lilly in 2005 or earlier.

Modes of administration

   Unlike many medicines, insulin cannot be taken orally; like other
   proteins in the gastrointestinal tract, it is reduced to its amino acid
   components, whereupon all 'insulin activity' is lost. There is research
   underway to develop methods of protecting insulin so that it can be
   taken orally, but none has yet reached clinical use. Instead insulin is
   usually taken as subcutaneous injections by single-use syringes with
   needles, an insulin pump or by repeated-use insulin pens with needles.

   There are several problems with insulin as a clinical treatment for
   diabetes:
     * Mode of administration.
     * Selecting the 'right' dose and timing.
     * Selecting an appropriate insulin preparation (typically on 'speed
       of onset and duration of action' grounds).
     * Adjusting dosage and timing to fit food amounts and types.
     * Adjusting dosage and timing to fit exercise undertaken.
     * Adjusting dosage, type, and timing to fit other conditions as for
       instance the increased stress of illness.
     * The dosage is non-physiological in that a subcutaneous bolus dose
       of insulin alone is administered instead of combination of insulin
       and C-peptide being released gradually and directly into the portal
       vein.
     * It is simply a nuisance for patients to inject themselves once or
       several times a day.
     * It may be dangerous in the case of mistake (most especially 'too
       much' insulin).

   There have been attempts to improve upon this mode of administering
   insulin, as many people find injection awkward and painful. One
   alternative is jet injection (also sometimes used for vaccinations),
   which has different insulin delivery peaks and durations as compared to
   needle injection. Some diabetics find control possible with jet
   injectors, but not with hypodermic injection. There are also 'insulin
   pumps' of various types which are 'electrical injectors' attached to a
   semi-permanently implanted needle (i.e. a catheter). Some who cannot
   achieve adequate glucose control by conventional injection (or
   sometimes jet injection) are able to do so with the appropriate pump.

   An insulin pump is a reasonable solution for some. However there are
   limitations - cost, the potential for hypoglycemic episodes, catheter
   problems, and, so far, no approvable means of controlling insulin
   delivery in the field based on current 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, there will be hyperglycemia. Both of these can lead to
   life-threatening conditions. In addition, indwelling catheters pose the
   risk of infection and ulceration. However, that risk can be minimized
   by keeping catheter sites clean. Thus far, insulin pumps require care
   and effort to use correctly. However, 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 blood
   glucose levels through the skin and administers corrective doses of
   insulin through pores in the skin. Both electricity and ultrasound have
   been found to make the skin temporarily porous. The insulin
   administration aspect remains experimental, but the blood glucose test
   aspect of 'wrist appliances' is commercially available.

   Another 'improvement' would be to avoid periodic insulin administration
   by a self-regulating insulin source, for instance, pancreatic, or beta
   cell, transplantation. Transplantation of an entire pancreas (as an
   individual organ) is difficult, and is not common. Generally, it is
   performed in conjunction with liver or kidney transplant. However,
   transplantation of only pancreatic beta cells is a possibility. It has
   been highly experimental (for which read 'prone to failure') for many
   years, but some researchers in Alberta, Canada, have developed
   techniques with a high initial success rate (about 90% in one group).
   Beta cell transplant may become practical and common in the near
   future. Additionally, some researchers have explored the possibility of
   transplanting genetically engineered non-beta cells to secrete
   insulin.^Clinically testable results are far from realization. Several
   other non-transplant methods of automatic insulin delivery are being
   developed in research labs, but none is close to clinical approval.

   Inhaled insulin is under investigation, as are several other insulin
   administration techniques. Currently the only inhalable insulin
   approved by the Food and Drug Administration is Exubera. Inhaled
   insulin has been shown to have similar efficacy to injected insulin,
   both in terms of controlling glucose levels and blood half-life. When
   patients were switched from injected to inhaled insulin, no significant
   difference was found in HBA1c levels over three months. Patients showed
   no significant weight gain or pulmonary function over the length of the
   trial, when compared to the baseline. However following its commercial
   launch in 2005 into the UK, it has not (as of July 2006) been
   recommended by National Institute for Health and Clinical Excellence
   for routine use, except in cases where there is "proven injection
   phobia diagnosed by a psychiatrist or psychologist". Several clinical
   studies reported greater patient satisfaction compared with
   subcutaneous insulin in both type 1 and type 2 diabetes.

   An additional method of administration of insulin to diabetics is
   pulsatile insulin. In this method insulin is pulsed into the patient,
   mimicking the physiological secretions of insulin by the pancreas.

Dosage and timing

   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 in cells, reducing
   glycogen to glucose conversion, reducing blood glucose levels, and so
   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 normal glucose control in
   the non-diabetic.

   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, since working muscle has some ability to take up
   glucose without the help of insulin.

   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 glucose level monitoring and insulin release. All
   such decisions by a diabetic must be based on experience and training
   (ie, at the direction of a physician or PA, or in some places a
   specialist diabetic educator) 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 skimmed milk is different from other diabetics', but the same amount
   of whole milk is likely to cause a still different reaction even in
   that person. Whole milk contains considerable fat while skimmed milk
   has much less. It is a continual balancing act for all diabetics,
   especially for those taking insulin.

   Insulin dependent diabetics require a base level of insulin (Basal
   Insulin), as well as extra short acting insulin to cope with meals
   (Bolus Insulin). Maintaining the basal rate and the bolus rate is a
   continuous balancing act that all insulin diabetics have to manage each
   day. This is normally achieved through regular blood tests, although
   there is work being undertaken on continuous blood sugar testing
   equipment.

   It is important to notice that diabetics generally need more insulin
   than the usual -- not less -- during physical stress like infections or
   surgeries.

Types

   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.

   The insulin molecules in an insulin analog is slightly modified so that
   they are:
     * Absorbed rapidly enough to mimic real beta cell insulin (Lilly's is
       lispro, Novo Nordisk's is aspart).
     * Steadily absorbed after injection instead of having a 'peak'
       followed by a more or less rapid decline in insulin action ( Novo
       Nordisk' version is Insulin detemir and Aventis' version is Insulin
       glargine).
     * All while retaining insulin action in the human body.

   The management of choosing insulin type and dosage / timing should be
   done by an experienced medical professional working with the diabetic.

   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), other 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 (over approximately 90
   days in most people) is the serum level of glycosylated 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.

   The commonly used types of insulin are:
     * Quick-acting, such as insulin lispro -- begins to work within 5 to
       15 minutes and is active for 3 to 4 hours.

     * Short-acting, such as regular insulin -- starts working within 30
       minutes and is active about 5 to 8 hours.

     * Intermediate-acting, such as NPH, or lente insulin -- starts
       working in 1 to 3 hours and is active 16 to 24 hours.

     * Long-acting, such as ultralente insulin -- starts working in 4 to 6
       hours, and is active 24 to 28 hours, and Insulin glargine or
       Insulin detemir -- both start working within 1 to 2 hours and
       continue to be active, without peaks or dips, for about 24 hours.

     * A mixture of NPH and regular insulin -- starts working in 30
       minutes and is active 16 to 24 hours. There are several variations
       with different proportions of the mixed insulins.

Abuse

   There are reports that some patients abuse insulin by injecting larger
   doses that lead to mild hypoglycemic states. This is extremely
   dangerous. Severe acute or prolonged hypoglycemia can result in brain
   damage or death.

   On July 23, 2004, news reports claimed that a former spouse of a
   prominent international track athlete said that, among other drugs, the
   ex-spouse had used insulin as a way of 'energizing' the body. The
   intended implication would seem to be that insulin has effects similar
   to those alleged for some steroids. This is not so; eighty years of
   insulin use has given no reason to believe it could be in any respect a
   performance enhancer for non diabetics. Improperly treated diabetics
   are, to be sure, more prone than others to exhaustion and tiredness,
   and in some cases, proper administration of insulin can relieve such
   symptoms. However, insulin is not, chemically or clinically, a steroid,
   and its use in non diabetics is dangerous and always an abuse outside
   of a well-equipped medical facility.

   " Game of Shadows," by reporters Mark Fainaru-Wada and Lance Williams,
   includes allegations that San Francisco Giant, Barry Bonds, used
   insulin in the apparent belief that it would increase the effectiveness
   of the growth hormone he was (also alleged to be) taking. On top of
   this, non-prescribed insulin is a banned drug at the Olympics and other
   global competitions.

Timeline

     * 1922 Banting and Best use bovine insulin extract in human
     * 1923 Eli Lilly produces commercial quantities of bovine insulin
     * 1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark --
       forerunner of Novo Nordisk
     * 1926 Nordisk receives a Danish charter to produce insulin as a non
       profit
     * 1936 Canadians D.M. Scott, A.M. Fisher formulate a zinc insulin
       mixture and license to Novo
     * 1936 Hagedorn discovers that adding protamine to insulin prolongs
       the effect of insulin
     * 1946 Nordisk formulates Isophane® porcine insulin aka Neutral
       Protamine Hagedorn or NPH insulin
     * 1946 Nordisk crystallizes a protamine and insulin mixture
     * 1950 Nordisk markets NPH insulin
     * 1953 Novo formulates Lente® porcine and bovine insulins by adding
       zinc for longer lasting insulin
     * 1973 Purified monocomponent (MC) insulin is introduced
     * 1978 Genentech produces human insulin in Escheria coli bacteria
       using recombinant DNA
     * 1981 Novo Nordisk chemically and enzymatically converts bovine to
       human insulin
     * 1982 Genentech human insulin (above) approved
     * 1983 Eli Lilly produces recombinant human insulin, Humulin®
     * 1985 Axel Ullrich sequences the human insulin receptor
     * 1988 Novo Nordisk produces recombinant human insulin
     * 1996 Lilly Humalog® "lyspro" insulin analogue approved
     * 2004 Aventis Lantus® "glargine" insulin analogue approved for
       clinical use
     * 2006 Novo Nordisk Levemir® "detemir" approved for clincal use in
       the US.

   Retrieved from " http://en.wikipedia.org/wiki/Insulin"
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   with only minor checks and changes (see www.wikipedia.org for details
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