Insulin therapy is the treatment of diabetes by administration of exogenous

Exogenous

Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....

 insulin

Insulin

Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

.

Insulin is used medically to treat some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus

Diabetes mellitus type 1

Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...

 depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with Type 2 diabetes mellitus

Diabetes mellitus type 2

Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

 are insulin resistant

Insulin resistance

Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

, have relatively low insulin production, or both; certain patients with Type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately.

Principles

Amino Acid Sequence of Insulin Preparations
Amino Acid Substitutions
	A-Chain Position			B-Chain Position
Source Species	A-8	A-10	A-21	B-28	B-29	B-30	B-31 B-32
Bovine	Ala	Val	Asn	Pro	Lys	Ala	N/A
Porcine	Thr	Ilc	Asn	Pro	Lys	Ala	N/A
Human	Thr	Ilc	Asn	Pro	Lys	Thr	N/A
Aspart (Novolog)	Thr	Ilc	Asn	Aspartic Acid	Lys	Thr	N/A
Lispro (Humalog)	Thr	Ilc	Asn	Lys	Pro	Thr	N/A
Glulisine (Apidra)	Thr	Ilc	Asn	Pro	Glu	Thr	N/A
Lantus (glargine)	Thr	Ilc	Gly	Pro	Lys	Thr	Arg
Levemir(detemir)	Thr	Ilc	Asn	Pro	Lys	N/A	Myristic Acid
Ala=Alanine Val=Valine Asn=Asparagine Pro-Proline Lys=Lysine Thr=Threonine Ilc=Isoleucine Glu-Glutamine Gly=Glycine

Insulin is required for all animal life (excluding certain insects). Its mechanism of action is almost identical in nematode worms (e.g.C. elegans), fish, and mammals, and it is a protein that has been highly conserved across evolutionary time. Insulin must be administered to patients who experience such a deprivation. Clinically, this condition is called diabetes mellitus type 1

Diabetes mellitus type 1

Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...

.

The initial sources of insulin for clinical use in humans were cow, horse

Horse

The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...

, pig

Pig

A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...

 or fish

Fish

Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...

 pancreases. Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Differences in suitability of beef-, pork-, or fish-derived insulin for individual patients have historically been due to lower preparation purity resulting in allergic reactions to the presence of non-insulin substances. Though purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods, but minor allergic reactions still occur occasionally, although the same types of allergic reactions have also been known to occur in response to synthetic "human" insulin varieties. Insulin production from animal pancreases was widespread for decades, but very few patients today rely on insulin from animal sources, largely because few pharmaceutical companies sell it anymore.

Biosynthetic "human" insulin is now manufactured for widespread clinical use using genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities, although there is no clinical evidence to substantiate this claim. Eli Lilly

Eli Lilly and Company

Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

 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 a synthetic version of human insulin. However, the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects; an example is the absence of C-peptide

C-peptide

C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...

 which has in recent years been shown to have systemic effects itself.
Genentech

Genentech

Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...

 developed the technique Lilly used to produce Humulin, although the company never commercially marketed the product themselves.

Novo Nordisk

Novo Nordisk

Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...

 has also developed a genetically engineered insulin independently using a yeast process. According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries, approximately 70% of the insulin that is currently sold in the world is recombinant, biosynthetic 'human' insulin. A majority of insulin used clinically today is produced this way, although the clinical evidence has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Also, the International Diabetes Federation's position statement is very clear in stating that "there is NO overwhelming evidence to prefer one species of insulin over another" and "[modern, highly-purified] animal insulins remain a perfectly acceptable alternative."

Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic "human" insulins or their analogues. A special FDA importation process is required to obtain bovine or porcine derived insulin for use in the U.S., although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier, and porcine insulin is also sold and marketed under the brand name Vetsulin(SM) in the U.S. for veterinary usage in the treatment of companion animals with diabetes. Wockhardt

Wockhardt

Wockhardt Ltd. is a pharmaceutical and biotechnology company headquartered in Mumbai, India. The company has manufacturing plants in India, UK, Ireland, France and US, and subsidiaries in US, UK, Ireland and France. It is a global company with a more than half of its revenue coming from Europe. The...

/

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 intake timing, amounts, and types.
• Adjusting dosage and timing to fit exercise undertaken.
• Adjusting dosage, type, and timing to fit other conditions, for instance the increased stress of illness.
• Variability in absorption into the bloodstream via subcutaneous delivery
• The dosage is non-physiological in that a subcutaneous bolus
  Bolus (medicine)
  In medicine, a bolus is the administration of a medication, drug or other compound that is given to raise its concentration in blood to an effective level...
  
   dose of insulin alone is administered instead of combination of insulin and C-peptide
  C-peptide
  C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...
  
   being released gradually and directly into the portal vein.
• It is simply a nuisance for patients to inject whenever they eat carbohydrate or have a high blood glucose reading.
• It is dangerous in case of mistake (most especially 'too much' insulin).

Types

Medical preparations of insulin (from the major suppliers – Eli Lilly

Eli Lilly and Company

Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

, Novo Nordisk

Novo Nordisk

Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...

, and Sanofi Aventis – or from any other) are never just 'insulin in water'. Clinical insulins are specially prepared mixtures of insulin plus other substances including preservatives. These delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on.

Slight variations of the human insulin molecule are called insulin analog

Insulin analog

An insulin analog is an altered form of insulin, different from any occurring in nature, but still available to the human body for performing the same action as human insulin in terms of glycemic control...

ues, (technically "insulin receptor ligand

Ligand

In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

s") so named because they are not technically insulin, rather they are analogues which retain the hormone's glucose management functionality. They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper. They are either absorbed rapidly in an attempt to mimic real beta cell insulin (as with Lilly's lispro, Novo Nordisk

Novo Nordisk

Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...

's aspart and Sanofi Aventis' glulisine), or steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (as with Novo Nordisk's version Insulin detemir and Sanofi Aventis's Insulin glargine), all while retaining insulin's glucose-lowering action in the human body. However, a number of meta-analyses

Meta-analysis

In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...

, including those done by the Cochrane Collaboration

Cochrane Collaboration

The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...

 in the United Kingdom in 2002, Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] released in 2007, and the Canadian Agency for Drugs and Technology in Health (CADTH) also released in 2007 have shown no unequivocal advantages in clinical use of insulin analogues over more conventional insulin types.

Choosing insulin type and dosage/timing should be done by an experienced medical professional working closely with the diabetic patient.

The commonly used types of insulin are:

• Rapid-acting types are presently insulin analogues, such as the insulin analogues aspart or lispro. these begin to work within 5 to 15 minutes and are active for 3 to 4 hours. Most insulins form hexamer
  Hexamer
  A hexamer is a thing composed out of six sub-units.In microbiology, a hexamer is one of the proteins composing the polyhedral protein shell that encloses the bacterial micro-compartments known as carboxysomes....
  
  s which delay entry into the blood in active form; these analog insulins do not, but have normal insulin activity. Newer varieties are now pending regulatory approval in the U.S. which are designed to work rapidly, but retain the same genetic structure as regular human insulin.

• Short-acting, such as regular insulin – starts working within 30 minutes and is active about 5 to 8 hours.
• Intermediate-acting, such as NPH
  NPH insulin
  NPH insulin , is an intermediate-acting insulin given to help control the blood sugar level of those with diabetes...
  
  – 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 well beyond 32 hours.
• Insulin glargine
  Insulin glargine
  Insulin glargine, marketed by Sanofi-Aventis under the name Lantus, is a long-acting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. It consists of microcrystals that slowly release insulin, giving a long duration of action of 18 to 26 hours,...
  
  and Insulin detemir
  Insulin detemir
  Insulin detemir is a long-acting human insulin analogue for maintaining the basal level of insulin. Novo Nordisk markets it under the trade name Levemir. It is an insulin analogue in which a fatty acid is bound to the lysine amino acid at position B29. It is quickly absorbed after which it binds...
  
  – both insulin analogues which start working within 1 to 2 hours and continue to be active, without major peaks or dips, for about 24 hours, although this varies in many individuals.
• 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.
• A mixture of Semilente and Ultralente (typically in the proportion 30% Semilente to 70% Ultralente), known as Lente, is typically active for an entire 24 hour period. Beef Lente, in particular, has a very 'flat' profile.

Yeast-based

In late 2003, Wockhardt

Wockhardt

Wockhardt Ltd. is a pharmaceutical and biotechnology company headquartered in Mumbai, India. The company has manufacturing plants in India, UK, Ireland, France and US, and subsidiaries in US, UK, Ireland and France. It is a global company with a more than half of its revenue coming from Europe. The...

 commenced manufacture of a yeast

Yeast

Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...

-based insulin costing $3.25 in India claiming it eliminated the risk of contracting diseases such as BSE

Bovine spongiform encephalopathy

Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...

 and CJD

Creutzfeldt-Jakob disease

Creutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...

 associated with insulin derived from pigs and cattle. However, the company continues to manufacture insulin derived from pigs and cows in the United Kingdom under the Hypurin/CP Pharmaceuticals brand name.

Modes of administration

Unlike many medicines, insulin cannot be taken orally at the present time. Like nearly all other proteins introduced into the gastrointestinal tract

Gastrointestinal tract

The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

, it is reduced to fragments (even single amino acid components), whereupon all 'insulin activity' is lost. There has been some research into ways to protect insulin from the digestive tract, so that it can be administered in a pill. So far this is entirely experimental.

Subcutaneous

Insulin is usually taken as subcutaneous injection

Injection (medicine)

An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...

s by single-use syringe

Syringe

A syringe is a simple pump consisting of a plunger that fits tightly in a tube. The plunger can be pulled and pushed along inside a cylindrical tube , allowing the syringe to take in and expel a liquid or gas through an orifice at the open end of the tube...

s with needle

Hypodermic needle

A hypodermic needle is a hollow needle commonly used with a syringe to inject substances into the body or extract fluids from it...

s, an insulin pump

Insulin pump

The insulin pump is a medical device used for the administration of insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin infusion therapy.The device includes:...

, or by repeated-use insulin pen

Insulin pen

An insulin pen is used to inject insulin for the treatment of diabetes. It is composed of an insulin cartridge and a dial to measure the dose, and is used with disposable Pen needles to deliver the dose.-Types of pens:...

s with needles. Patients who wish to reduce repeated skin puncture of insulin injections often use an injection port

Injection port

An injection port is a medical device used for the administration of insulin or other physician approved medicine into the subcutaneous tissue...

 in conjunction with syringes.

Administration schedules often attempt to mimic the physiologic secretion of insulin by the pancreas. Hence, both a long-acting insulin and a short-acting insulin are typically used.

Insulin pump

Insulin pump

Insulin pump

The insulin pump is a medical device used for the administration of insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin infusion therapy.The device includes:...

s are a reasonable solution for some. Advantages to the patient are better control over background or 'basal' insulin dosage, bolus doses calculated to fractions of a unit, and calculators in the pump that may help with determining 'bolus' infusion dosages. The limitations are cost, the potential for hypoglycemic and hyperglycemic episodes, catheter problems, and no "closed loop" means of controlling insulin delivery based on current blood glucose levels.

Insulin pumps may be like 'electrical injectors' attached to a temporarily implanted catheter

Catheter

In medicine, a catheter is a tube that can be inserted into a body cavity, duct, or vessel. Catheters thereby allow drainage, administration of fluids or gases, or access by surgical instruments. The process of inserting a catheter is catheterization...

 or cannula

Cannula

A cannula or canula is a tube that can be inserted into the body, often for the delivery or removal of fluid or for the gathering of data...

. Some who cannot achieve adequate glucose control by conventional (or jet) injection are able to do so with the appropriate pump.

As with injections, if too much insulin is delivered or the patient eats less than he or she dosed for, there will be hypoglycemia. On the other hand, if too little insulin is delivered, there will be hyperglycemia. Both can be life-threatening. In addition, indwelling catheters pose the risk of infection and ulceration, and some patients may also develop lipodystrophy

Lipodystrophy

Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...

 due to the infusion sets. These risks can often be minimized by keeping infusion sites clean. Insulin pumps require care and effort to use correctly. However, some patients with diabetes are capable of keeping their glucose in reasonable control only with an insulin pump.

Inhalation

In 2006 the U.S. Food and Drug Administration

Food and Drug Administration

The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 approved the use of Exubera, the first inhalable insulin. It was withdrawn from the market by its maker as of third quarter 2007, due to lack of acceptance.

Inhaled insulin claimed to have similar efficacy to injected insulin, both in terms of controlling glucose levels and blood half-life. Currently, inhaled insulin is short acting and is typically taken before meals; an injection of long-acting insulin at night is often still required. When patients were switched from injected to inhaled insulin, no significant difference was observed in Hb_A1c levels over three months. Accurate dosing was a particular problem, although patients showed no significant weight gain or pulmonary function decline over the length of the trial, when compared to the baseline.

Following its commercial launch in 2005 in the UK, it was not (as of July 2006) recommended by National Institute for Health and Clinical Excellence

National Institute for Health and Clinical Excellence

The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...

 for routine use, except in cases where there is "proven injection phobia diagnosed by a psychiatrist or psychologist".

In January 2008, the world's largest insulin manufacturer, Novo Nordisk

Novo Nordisk

Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...

 A/S, also announced that the company was discontinuing all further development of the company's own version of inhalable insulin, known as the AERx iDMS inhaled insulin system. Similarly, Eli Lilly and Company

Eli Lilly and Company

Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

 ended its efforts to develop its inhaled Air Insulin in March 2008. However, MannKind Corp. (majority owner, Alfred E. Mann

Alfred E. Mann

Alfred E. Mann , who is also known as Al Mann, is an American entrepreneur and philanthropist. According to Forbes magazine, his estimated net worth exceeded $2.2 billion as of 2007, ranking him the 204th richest man in America and the 390th richest man in the world.Born and raised in Portland, his...

) remains optimistic about the concept.

Transdermal

There are several methods for transdermal delivery of insulin. Pulsatile insulin

Pulsatile Insulin

Pulsatile insulin, sometimes called metabolic activation therapy, or cellular activation therapy describes in a literal sense the intravenous injection of insulin in pulses versus continuous infusions. Injection of insulin in pulses mimics the physiological secretions of insulin by the pancreas...

 uses microjets to pulse insulin into the patient, mimicking the physiological secretions of insulin by the pancreas. Jet injection

Jet injector

A jet injector is a type of medical injecting syringe that uses a high-pressure narrow jet of the injection liquid instead of a hypodermic needle to penetrate the epidermis...

 had different insulin delivery peaks and durations as compared to needle injection. Some diabetics find control possible with jet injectors, but not with hypodermic injection.

Both electricity using iontophoresis

Iontophoresis

Iontophoresis is a technique using a small electric charge to deliver a medicine or other chemical through the skin. It is basically an injection without the needle...

 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.

Researchers have produced a watch-like device that tests for blood glucose levels through the skin and administers corrective doses of insulin through pores

Sebaceous gland

The sebaceous glands are microscopic glands in the skin that secrete an oily/waxy matter, called sebum, to lubricate and waterproof the skin and hair of mammals...

 in the skin.

Intranasal insulin

Intranasal insulin is being investigated. CPEX Pharmaceuticals reported phase 2a clinical trial preliminary results for its intranasal drug, Nasulin, on March 19, 2010; there's no word on when it might be expected on the market.

Oral insulin

The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. However, insulin is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

, which is digested

Digestion

Digestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....

 in the stomach

Stomach

The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

 and gut

Gut (zoology)

In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...

 and in order to be effective at controlling blood sugar, cannot be taken orally in its current form.

The potential market for an oral form of insulin is assumed to be enormous, thus many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar. As of 2004, no products appear to be successful enough yet to bring to market.

Novo Nordisk announced on December 7, 2009, that it had initiated its first phase 1 trial with oral insulin analogue (NN1952). The aim of the trial is to investigate the safety, tolerance, pharmacokinetics (exposure to drug) and pharmacodynamics (effect) of NN1952 in healthy volunteers and people with type 1 and type 2 diabetes. Results from the trial, which is planned to enroll about 80 people, are expected to be reported in the first half of 2011. NN1952 has been designed to address some of the key challenges relating to oral insulin delivery. Furthermore, it uses the GIPET (R) formulation technology from Merrion Pharmaceuticals (IEX Quoted) to facilitate insulin absorption from the gut. In November 2008, Merrion entered into a development and license agreement to develop and commercialise oral formulations of Novo Nordisk's proprietary insulin analogues, using Merrion's proprietary GIPET (R).

A Connecticut-based biopharmaceutical company called Biodel, Inc. is developing what it calls VIAtab, an oral formulation of insulin designed to be administered sublingually. This therapy is a tablet that dissolves in minutes when placed under the tongue. In a Phase I study, VIAtab delivered insulin to the blood stream quickly and resembled the first-phase insulin release spike found in healthy individuals. The company claims that an oral insulin therapy would be more convenient than currently available injectable or inhalable therapies, and they expect that convenience to result in increased insulin usage among the currently underserved early-stage patients with Type 2 diabetes, thus helping to create better long-term outcomes for that patient population.

Oramed Pharmaceuticals, Inc., a biotechnology

Biotechnology

Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...

 company based in Jerusalem, Israel

Israel

The State of Israel is a parliamentary republic located in the Middle East, along the eastern shore of the Mediterranean Sea...

, is currently conducting Phase 2B clinical trials of its oral insulin capsule, ORMD-0801, on 30 patients diagnosed with type 2 diabetes. An article published in the Journal of Diabetes Science and Technology indicates that Oramed's platform technology has two components: 1) A chemical make-up that protects insulin during passage through the gastrointestinal tract

Gastrointestinal tract

The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

, and 2) absorption enhancers so that insulin could be absorbed by the intestine

Intestine

In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...

. Oramed Pharmaceuticals, Inc. through Phase 1 clinical trials, has demonstrated that its oral insulin is safe, well tolerated, and has consistently reduced glucose

Glucose

Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 and c-peptide

C-peptide

C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...

 levels in patients.

Australia

Australia

Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

n biopharmaceutical company Apollo Life Sciences plans to enter the phase I trial of its oral insulin tablet in mid-2008.

Biocon

Biocon

Biocon Limited is a global biopharmaceutical company with products and research services ranging from pre-clinical to clinical development through to commercialization. Within biopharmaceuticals, the Company manufactures generic active pharmaceutical ingredients like Statins and...

, Asia

Asia

Asia is the world's largest and most populous continent, located primarily in the eastern and northern hemispheres. It covers 8.7% of the Earth's total surface area and with approximately 3.879 billion people, it hosts 60% of the world's current human population...

's largest biopharmaceutical company, based in Bangalore

Bangalore

Bengaluru , formerly called Bengaluru is the capital of the Indian state of Karnataka. Bangalore is nicknamed the Garden City and was once called a pensioner's paradise. Located on the Deccan Plateau in the south-eastern part of Karnataka, Bangalore is India's third most populous city and...

, India

India

India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

, is also developing an oral insulin product. It has recently entered phase III trials; the company hopes to launch their product, IN-105, in 2011.

Pancreatic transplantation

Another improvement would be a transplantation

Organ transplant

Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...

 of the pancreas or beta cell to avoid periodic insulin administration. This would result in a self-regulating insulin source. Transplantation of an entire pancreas (as an individual organ

Organ (anatomy)

In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...

) is difficult and relatively uncommon. It is often performed in conjunction with liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 or kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

 transplant, although it can be done by itself. It is also possible to do a transplantation of only the pancreatic beta cells. However, islet transplants had been highly experimental for many years, but some researchers in Alberta, Canada, have developed techniques with a high initial success rate (about 90% in one group). Nearly half of those who got an islet cell transplant were insulin-free one year after the operation; by the end of the second year that number drops to about one in seven. However, researchers at the University of Illinois at Chicago (UIC) have slightly modified the Edmonton Protocol procedure for islet cell transplantation and achieved insulin independence in diabetes patients with fewer but better-functioning pancreatic islet cells. Longer-term studies are needed to validate whether it improves the rate of insulin-independence.

Beta cell transplant may become practical in the near future. Additionally, some researchers have explored the possibility of transplanting genetically engineered

Genetic engineering

Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...

 non-beta cells to secrete insulin. Clinically testable results are far from realization at this time. Several other non-transplant methods of automatic insulin delivery are being developed in research labs, but none is close to clinical approval.

The dosage units

One international unit of insulin (1 IU) is defined as the "biological equivalent" of about 45.5 μg

Microgram

In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...

 pure crystalline insulin (1/22 mg

Gram

The gram is a metric system unit of mass....

 exactly). This corresponds to the old USP

United States Pharmacopeia

The United States Pharmacopeia is the official pharmacopeia of the United States, published dually with the National Formulary as the USP-NF. The United States Pharmacopeial Convention is the nonprofit organization that owns the trademark and copyright to the USP-NF and publishes it every year...

 insulin unit, where one unit (U) of insulin was set equal to the amount required to reduce the concentration of blood glucose

Blood sugar

The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...

 in a fasting

Fasting

Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...

 rabbit

Rabbit

Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...

 to 45 mg

Gram

The gram is a metric system unit of mass....

/dl

Litér

- External links :*...

 (2.5 mmol

Mole (unit)

The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value...

/L

Litér

- External links :*...

).

The unit of measurement

Units of measurement

A unit of measurement is a definite magnitude of a physical quantity, defined and adopted by convention and/or by law, that is used as a standard for measurement of the same physical quantity. Any other value of the physical quantity can be expressed as a simple multiple of the unit of...

 used in insulin therapy is not part of the International System of Units

International System of Units

The International System of Units is the modern form of the metric system and is generally a system of units of measurement devised around seven base units and the convenience of the number ten. The older metric system included several groups of units...

  (abbreviated SI) which is the modern form of the metric system

Metric system

The metric system is an international decimalised system of measurement. France was first to adopt a metric system, in 1799, and a metric system is now the official system of measurement, used in almost every country in the world...

. Instead the pharmacological

Pharmacology

Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

 international unit (IU) is defined by the WHO Expert Committee on Biological Standardization

WHO Expert Committee on Biological Standardization

WHO Expert Committee on Biological Standardization is a functioning body of World Health Organization. The Expert Committee has been meeting annually since 1947.-Reports:...

.

The problem

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, reduces 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 synthetic human insulin or even insulin analogs, however administered, falls far short of normal glucose control in the non-diabetic.

Complicating matters is that the composition of the food eaten (see glycemic index

Glycemic index

The glycemic index, glycaemic index, or GI is a measure of the effects of carbohydrates on blood sugar levels. Carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream have a high GI; carbohydrates that break down more slowly, releasing glucose more...

) affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. In addition, fats and proteins cause delays in absorption of glucose from carbohydrates 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.

Because of the complex and interacting factors, it is, in principle, impossible to know for certain how much insulin (and which type) is needed to 'cover' a particular meal 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 (i.e., at the direction of a physician, PA, or in some places a specialist diabetic educator) and, further, specifically based on the individual experience of the patient. But it is not straightforward and should never be done by habit or routine. With some care however, it can be done reasonably well in clinical practice.

For example, some patients with diabetes 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 people with diabetes, 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 people with diabetes, especially for those taking insulin.

Patients with insulin-dependent diabetes typically require some base level of insulin (basal insulin), as well as short-acting insulin to cover meals (bolus insulin). Maintaining the basal rate and the bolus rate is a continuous balancing act that people with insulin-dependent diabetes must manage each day. This is normally achieved through regular blood tests, although continuous blood sugar testing equipment (Continuous Glucose Monitors or CGMs) are now becoming available which could help to refine this balancing act once widespread usage becomes common.

Strategies

A long-acting insulin is used to approximate the basal secretion of insulin by the pancreas. NPH/isophane, lente, ultralente, glargine, and detemir may be used for this purpose. The advantage of NPH is its low cost and the fact that you can mix it with short-acting forms of insulin, thereby minimizing the number of injections that must be administered. The disadvantage is that the activity of NPH is less steady and will peak 4–6 hours after administration, and this peak has the potential of causing hypoglycemia. NPH and regular insulin in combination are available as premixed solutions, which can sometimes simplify administration. The theoretical advantage of glargine and detemir is that they only need to be administered once a day, and they also have steady activity, generally without peaks, although in practice, many patients find that neither lasts a full 24 hours. Glargine and detemir are also significantly more expensive, and they cannot be mixed with other forms of insulin.

A short-acting insulin is used to simulate the endogenous insulin surge produced in anticipation of eating. Regular insulin, lispro, aspart and glulisine can be used for this purpose. Regular insulin should be given with about a 30 minute lead-time prior to the meal to be maximally effective and to minimize the possibility of hypoglycemia. Lispro, aspart and glulisine are approved for dosage with the first bite of the meal, and may even be effective if given after completing the meal. The short-acting insulin is also used to correct hyperglycemia.

The usual schedule for checking fingerstick blood glucose and administering insulin is before all meals and sometimes also at bedtime. More recent guidelines also call for a check 2 hours after a meal to ensure the meal has been 'covered' effectively. When insulin glargine or insulin detemir is used, it can be administered at any time during the day, provided that it is given at the same time every day.

Sliding scales

Insulin prescriptions generally specify fixed amounts of long-acting insulin to be given routinely, and fixed amounts of short-acting insulin prior to every meal (the 'sliding scale' approach). However, the amount of short-acting insulin may be varied depending on the patient's preprandial fingerstick glucose, in order to correct pre-existing hyperglycemia. The so-called "sliding-scale" is still widely taught, although it is controversial. It was first described in 1934.

Sample regimen using insulin NPH and regular insulin

	before breakfast	before lunch	before dinner	at bedtime
NPH dose	12 units		6 units
regular insulin dose if fingerstick glucose is (mg/dl) [mmol/L]:
70-100       [3.9-5.5]	4 units		4 units
101-150     [5.6-8.3]	5 units		5 units
151-200     [8.4-11.1]	6 units		6 units
201-250     [11.2-13.9]	7 units		7 units
251-300     [14.0-16.7]	8 units	1 unit	8 units	1 unit
>300         [>16.7]	9 units	2 units	9 units	2 units

Sample regimen using insulin glargine and insulin lispro

insulin glargine 20 units at bedtime

insulin lispro to be given as follows:

if fingerstick glucose is (mg/dl) [mmol/L]:	before breakfast	before lunch	before dinner	at bedtime
70-100       [3.9-5.5]	5 units	5 units	5 units
101-150     [5.6-8.3]	6 units	6 units	6 units
151-200     [8.4-11.1]	7 units	7 units	7 units
201-250     [11.2-13.9]	8 units	8 units	8 units	1 unit
251-300     [14.0-16.7]	9 units	9 units	9 units	2 units
>300         [>16.7]	10 units	10 units	10 units	3 units

Carb counting and DAFNE

A more complicated method that allows greater freedom with meal times and snacks is "carb counting." This approach is taught to diabetic patients in the UK and elsewhere as "Dose Adjustment For Normal Eating" or DAFNE.

In Europe, patients that are not familiar with the DAFNE regime can take an educational course where the basic starting insulin dose guideline is "for every 10g of carbohydrates you eat, take 1 unit of insulin". DAFNE courses also cover topics that naturally work along side this regime, such as blood glucose monitoring, exercise and carbohydrate estimation to help the patient work out their personal control requirements.

The patient also can use his or her total daily dose (TDD) of insulin to estimate how many grams of carbohydrates will be "covered" by 1 unit of insulin, and using this result, the patient can estimate how many units of insulin should be administered depending on the carbohydrate concentration of their meal. For example, if the patient determines that 1 unit of insulin will cover 15 grams of carbohydrates, then they must administer 5 units of insulin before consuming a meal that contains 75 grams of carbohydrates.

Some alternative methods also consider the protein content of the meal (since excess dietary protein can be converted to glucose via gluconeogenesis

Gluconeogenesis

Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

).

With DAFNE, most dosages involve a fair degree of guesswork, especially with non-labeled foods, and will only work fairly consistently from one dosage to the next if the patient is aware of their body's requirements. For example, a patient finds they can take 1 unit to 10g of carbohydrates in the morning and the evening, but find that their body requires more insulin for a meal in the middle of the day so they have to adjust to 1 unit per 8.5g of carbohydrates.

You also have to factor in that things like a hot day can effect how your body uses the insulin. Using the hot day as an example, some patients may find that their bodies process insulin much better on these days so require less insulin. With this, the patient again has to adjust their dose to the best of their understanding from their past experiences.

Unfortunately, because the DAFNE regime requires the patient to learn about their body's needs through experience, it can be a very frustrating process to take on, but the results can be worthwhile in the long term.

Dietary control of insulin

Many popular weight-loss regimes claim to manipulate weight gain forcing insulin levels (often characterized as insulin overload) by control of carbohydrate intake. Insulin release is controlled by several factors; the carbohydrate stimulus is blood glucose which is not produced by all kinds of carbohydrate. Some types of amino acids also stimulate insulin release. In addition, overly high levels of insulin are seen only in those with pathologies such as Type 2 diabetes mellitus, and only in some of those. The typical person cannot have insulin overload and still have blood glucose levels which do not force symptoms of hypoglycemia. In the non-diabetic, the feedback control mechanism connecting insulin release and blood glucose level is very effective, and it is not possible to adjust it except that blood glucose levels rise slightly during digestion and absorption of glucose. The decrease in blood glucose levels is directly attributable to release of insulin, and that release ceases as blood glucose levels drop. On the other hand, prolonged abnormally low levels of insulin, if it were possible to produce them by control of diet composition and amount, would produce problems with electrolyte balance and with amino acid uptake in cells, among many other effects.

Abuse

There are reports that some abuse insulin by injecting large doses that lead to 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 the ex-spouse had used insulin as a way of 'energizing' the body. There is no evidence to suggest it should act as a performance enhancer in non-diabetics. Poorly controlled diabetics are more prone than others to exhaustion and tiredness, and properly-administered insulin can relieve such symptoms.

Game of Shadows

Game of Shadows

Game of Shadows: Barry Bonds, BALCO, and the Steroids Scandal that Rocked Professional Sports is a bestselling non-fiction book published on March 23, 2006 and written by Mark Fainaru-Wada and Lance Williams, reporters for the San Francisco Chronicle...

, by reporters Mark Fainaru-Wada and Lance Williams, includes allegations that Barry Bonds

Barry Bonds

Barry Lamar Bonds is an American former Major League Baseball outfielder. Bonds played from 1986 to 2007, for the Pittsburgh Pirates and San Francisco Giants. He is the son of former major league All-Star Bobby Bonds...

 used insulin in the apparent belief that it would increase the effectiveness of the growth hormone he was alleged to be taking. On top of this, non-prescribed insulin is a banned drug at the Olympics and other global competitions.

The use and abuse of exogenous insulin is claimed to be widespread amongst the bodybuilding community. Insulin, human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1) are self-administered by those looking to increase muscle mass beyond the scope offered by anabolic steroids alone. Their rationale is that since insulin and HGH act synergistically to promote growth, and since IGF-1 is a primary mediator of musculoskeletal growth, the 'stacking' of insulin, HGH and IGF-1 should offer a synergistic growth effect on skeletal muscle. This theory has been supported in recent years by top-level bodybuilders whose competition weight is in excess of 50 lb (22.7 kg) of muscle, larger than that of competitors in the past, and with even lower levels of body fat. There has even been some reaction to the 'freakish' appearance of some of today's top-level professionals.

Bodybuilders are claimed to inject up to 10 IU

International unit

In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, as UI , or as IE...

 of quick-acting synthetic insulin following meals containing starchy carbohydrates and protein, but little fat, in an attempt to 'force feed' muscle cells with nutrients necessary for growth, whilst preventing growth of adipocytes (i.e., fat cells). This may be done up to four times each day, following meals, for a total usage of perhaps 40 IU of synthetic insulin per day. However, there have been reports of substantially heavier usage, amongst even 'recreational' bodybuilders.

The abuse of exogenous insulin carries with it an attendant risk of hypoglycemic coma and death when the amount used is in excess of that required to handle ingested carbohydrate. Acute risks include brain damage, paralysis, and death. Long-term risks may include development of type 2 diabetes and, potentially, a lifetime dependency on exogenous insulin. However, no studies have been conducted showing that exogenous insulin abuse may lead to increased risk of type 2 diabetes.

Detection in biological fluids

Insulin is often measured in serum, plasma or blood in order to monitor therapy in diabetic patients, confirm a diagnosis of poisoning in hospitalized persons or assist in a medicolegal investigation of suspicious death. Interpretation of the resulting insulin concentrations is complex, given the numerous types of insulin available, various routes of administration, the presence of anti-insulin antibodies in insulin-dependent diabetics and the ex vivo instability of the drug. Other potential confounding factors include the wide-ranging cross-reactivity of commercial insulin immunoassays for the biosynthetic insulin analogs, the use of high-dose intravenous insulin as an antidote to antihypertensive drug overdosage and postmortem redistribution of insulin within the body. The use of a chromatographic technique for insulin assay may be preferable to immunoassay in some circumstances, to avoid the issue of cross-reactivity affecting the quantitative result and also to assist identifying the specific type of insulin in the specimen.

Combination with other antidiabetic drugs

A combination therapy of insulin and other antidiabetic drugs appears to be most beneficial in diabetic patients who still have residual insulin secretory capacity. A combination of insulin therapy and sulphonylurea is more effective than insulin alone in treating patients with type 2 diabetes after secondary failure to oral drugs, leading to better glucose profiles and/or decreased insulin needs.

History

• 1922 Banting
  Frederick Banting
  Sir Frederick Grant Banting, KBE, MC, FRS, FRSC was a Canadian medical scientist, doctor and Nobel laureate noted as one of the main discoverers of insulin....
  
  , Best, Collip
  James Collip
  James Bertram Collip, Ph.D. was part of the Toronto group which isolated insulin. He served as the Chair of the Department of Biochemistry at McGill University from 1928-1941 and Dean of Medicine at the University of Western Ontario from 1947-1961, where he was a charter member of The Kappa Alpha...
  
   use bovine insulin extract in humans
• 1922 Leonard Thompson
  Leonard Thompson (diabetic)
  Leonard Thompson is regarded as the very first person to have received injection of insulin as a treatment for diabetes. He received his first injection in Toronto, Ontario, on January 11, 1922, at 14 years of age. The first injection had an apparent impurity which was the likely cause for the...
  
   and then Elizabeth Hughes Gossett
  Elizabeth Hughes Gossett
  Elizabeth Hughes Gossett the daughter of U.S. Politician Charles Evans Hughes, was one of the first patients treated with insulin...
  
   are treated
• 1923 Eli Lilly
  Eli Lilly and Company
  Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
  
   produces commercial quantities of much purer bovine insulin than Banting et al. had used
• 1923 Farbwerke Hoechst
  Hoechst AG
  Hoechst AG was a German chemicals then life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999...
  
  , one of the forerunner's of today's Sanofi Aventis, produces commercial quantities of bovine insulin in Germany
• 1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark – forerunner of today's Novo Nordisk
  Novo Nordisk
  Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
  
  
• 1926 Nordisk
  Novo Nordisk
  Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
  
   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 it to Novo
  Novo Nordisk
  Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
  
  
• 1936 Hagedorn discovers that adding protamine to insulin prolongs the duration of action of insulin
• 1946 Nordisk formulates Isophane porcine insulin aka Neutral Protamine Hagedorn or NPH insulin
  NPH insulin
  NPH insulin , is an intermediate-acting insulin given to help control the blood sugar level of those with diabetes...
  
  
• 1946 Nordisk crystallizes a protamine and insulin mixture
• 1950 Nordisk markets NPH insulin
  NPH insulin
  NPH insulin , is an intermediate-acting insulin given to help control the blood sugar level of those with diabetes...
  
  
• 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer lasting insulin
• 1955 Frederick Sanger
  Frederick Sanger
  Frederick Sanger, OM, CH, CBE, FRS is an English biochemist and a two-time Nobel laureate in chemistry, the only person to have been so. In 1958 he was awarded a Nobel prize in chemistry "for his work on the structure of proteins, especially that of insulin"...
  
   determines the amino acid sequence of insulin
• 1966 Synthesized by total synthesis by C.L. Tsou, Wang Yinglai, and coworkers
• 1969 Dorothy Crowfoot Hodgkin
  Dorothy Crowfoot Hodgkin
  Dorothy Mary Hodgkin OM, FRS , née Crowfoot, was a British chemist, credited with the development of protein crystallography....
  
   solves the crystal structure of insulin by x-ray crystallography
  X-ray crystallography
  X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
  
  
• 1973 Purified monocomponent (MC) insulin is introduced
• 1973 The U.S. officially "standardized" insulin sold for human use in the U.S. to U-100 (100 units per milliliter). Prior to that, insulin was sold in different strengths, including U-80 (80 units per milliliter) and U-40 formulations (40 units per milliliter), so the effort to "standardize" the potency aimed to reduce dosage errors and ease doctors' job of prescribing insulin for patients. Other countries also followed suit.
• 1978 Genentech
  Genentech
  Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
  
   produces biosynthetic 'human' insulin in Escheria coli bacteria using recombinant DNA techniques, licenses to Eli Lilly
• 1981 Novo Nordisk
  Novo Nordisk
  Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
  
   chemically and enzymatically converts porcine to 'human' insulin
• 1982 Genentech
  Genentech
  Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
  
   synthetic 'human' insulin (above) approved
• 1983 Eli Lilly and Company
  Eli Lilly and Company
  Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
  
   produces biosynthetic 'human' insulin with recombinant DNA
  Recombinant DNA
  Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
  
   technology, Humulin
• 1985 Axel Ullrich
  Axel Ullrich
  Axel Ullrich in is a German cancer researcher and has been the Director of the Molecular biology dept. at the Max Planck Institute of Biochemistry in Martinsried, Germany since 1988. This deptartment's research has primarily focused on signal transduction...
  
   sequences a human cell membrane insulin receptor.
• 1988 Novo Nordisk
  Novo Nordisk
  Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
  
   produces recombinant biosynthetic 'human' insulin
• 1996 Lilly
  Eli Lilly and Company
  Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
  
   Humalog "lispro" insulin analogue approved.
• 2000 Sanofi Aventis Lantus insulin "glargine" analogue approved for clinical use in the US and Europe.
• 2004 Sanofi Aventis Apidra insulin "glulisine" insulin analogue approved for clinical use in the US.
• 2005 MedActiv invents the world's smallest fridge, the Medifridge, to safely transport insulin for patients.
• 2006 Novo Nordisk
  Novo Nordisk
  Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
  
   Levemir "detemir" insulin analogue approved for clinical use in the US.