Insulin analog
Encyclopedia
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. Through genetic engineering
of the underlying DNA
, the amino acid sequence of insulin can be changed to alter its ADME
(absorption, distribution, metabolism, and excretion) characteristics. Officially, the U.S. Food and Drug Administration
(FDA) refers to these as "insulin receptor ligands", although they are more commonly referred to as insulin analogs.
These modifications have been used to create two types of insulin analogs: those that are more readily absorbed from the injection site and therefore act faster than natural insulin injected subcutaneously, intended to supply the bolus level of insulin needed after a meal; and those that are released slowly over a period of between 8 and 24 hours, intended to supply the basal level of insulin for the day. Insulin analog was first manufactured by Eli Lilly and Company
.
ine insulin has only a single amino acid variation from the human variety, and bovine
insulin varies by three amino acids. Both are active on the human receptor
with approximately the same strength. Prior to the introduction of biosynthetic human insulin, insulin derived from sharks was widely used in Japan. Even insulin from some species of fish may be effective in humans. Non-human insulins can cause allergic
reactions in a tiny number of people, as can genetically engineered "human" insulin. This is usually caused by the preservatives used in the insulin rather than the insulin molecule itself. Biosynthetic "human" insulin has largely replaced animal insulin. With the advent of high-pressure liquid chromatography (HPLC) equipment, the level of purification of animal-sourced insulins has reached as high as 99%, whereas the purity level of synthetic human insulins made via recombinant DNA has only attained a maximum purity level of 97%, which raises questions about the claim of synthetic insulin's purity relative to animal-sourced insulin varieties.
analogues were available, porcine insulin was chemically converted into human insulin. Chemical modifications of the amino acid side chains at the N-terminus and/or the C-terminus were made in order to alter the ADME
characteristics of the analogue. Novo Nordisk
was able to enzymatically convert porcine insulin into 'human' insulin by removing the single amino acid that varies from the human variety, and chemically adding the correct one.
with zinc
in the blood, forming hexamer
s. Insulin in the form of a hexamer will not bind to its receptors, so the hexamer has to slowly equilibrate back into its monomers to be biologically useful. Hexameric insulin delivered subcutaneously is not readily available for the body when insulin is needed in larger doses, such as after a meal (although this is more a function of subcutaneously administered insulin, as intravenously dosed insulin is distributed rapidly to the cell receptors, and therefore, avoids this problem). Zinc combinations of insulin are used for slow release of basal insulin. Basal insulin is the amount the body needs through the day excluding the amount needed after meals. Non hexameric insulins were developed to be faster acting and to replace the injection of normal unmodified insulin before a meal.
had the first insulin analogue with "lispro" as a rapid acting insulin analogue. It is marketed under the trade name Humalog. It was engineered through recombinant DNA
technology so that the penultimate lysine
and proline
residues on the C-terminal end of the B-chain were reversed. This modification did not alter the insulin receptor binding, but blocked the formation of insulin dimer
s and hexamers. This allowed larger amounts of active monomeric insulin to be available for postprandial
(after meal) injections.
created "aspart" and marketed it as NovoLog/NovoRapid (UK-CAN) as a rapid acting insulin analogue. It was created through recombinant DNA
technology so that the amino acid, B28, which is normally proline
, is substituted with an aspartic acid
residue. The sequence was inserted into the yeast
genome, and the yeast expressed the insulin analogue, which was then harvested from a bioreactor
. This analogue also prevents the formation of hexamers, to create a faster acting insulin. It is approved for use in CSII pumps and Flexpen, Novopen delivery devices for subcutaneous injection.
, approved for use with a regular syringe, in an insulin pump
or the Opticlik Pen http://opticlik.com/home.do. Standard syringe delivery is also an option. It is sold under the name Apidra. The FDA-approved label states that it differs from regular human insulin by its rapid onset and shorter duration of action.
so that they exist in a solubility equilibrium in which most precipitates out but slowly dissolves in the bloodstream and is eventually excreted by the kidneys. These insulin analogues are used to replace the basal level of insulin, and may be effective over a period of up to 24 hours. However, some insulin analogues, such as insulin detemir, bind to albumin rather than fat like earlier insulin varieties, and results from long-term usage (e.g. more than 10 years) have never been released.
developed glargine as a longer lasting insulin analogue, and markets it under the trade name Lantus. It was created by modifying three amino acids. Two positively charged arginine
molecules were added to the C-terminus of the B-chain, and they shift the isoelectric point from 5.4 to 6.7, making glargine more soluble at a slightly acidic pH
and less soluble at a physiological pH. Replacing the acid-sensitive asparagine
at position 21 in the A-chain by glycine
is needed to avoid deamination and dimerization of the arginine residue. These three structural changes and formulation with zinc result in a prolonged action when compared with biosynthetic human insulin. When the pH 4.0 solution is injected, most of the material precipitates and is not bioavailable. A small amount is immediately available for use, and the remainder is sequestered in subcutaneous tissue. As the glargine is used, small amounts of the precipitated material will move into solution in the bloodstream, and the basal level of insulin will be maintained up to 24 hours. The onset of action of subcutaneous insulin glargine is somewhat slower than NPH human insulin. It is clear solution as there is no zinc in formula.
created insulin detemir and markets it under the trade name Levemir as a long-lasting insulin analogue for maintaining the basal level of insulin. The basal level of insulin may be maintained for up to 20 hours, but the time is clearly affected by the size of the injected dose.
This insulin has a high affinty for serum albumin, increasing its duration of action.
pathways, which can cause abnormal cell growth and tumorigenesis. Modifications to insulin always carry the risk of unintentionally enhancing IGF signalling in addition to the desired pharmacological properties.
of numerous randomized controlled trials by the international Cochrane Collaboration
found "only a minor clinical benefit of treatment with long-acting insulin analogues (including two studies of insulin detemir) for patients with diabetes mellitus type 2" while others have examined the same issue in type 1 diabetes. Subsequent meta-analyses undertaken in a number of countries and continents have confirmed Cochrane's findings.
In July 2007, Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector (IQWiG) reached a strikingly similar conclusion. In its report, IQWiG concluded that there is currently "no evidence" available of the superiority of rapid-acting insulin analogs over synthetic human insulins in the treatment of adult patients with type 1 diabetes. Many of the studies reviewed by IQWiG were either too small to be considered statistically reliable and, perhaps most significantly, none of the studies included in their widespread review were blinded, the gold-standard methodology for conducting clinical research. However, IQWiG's terms of reference explicitly disregard any issues which cannot be tested in double-blind studies, for example a comparison of radically different treatment regimes. IQWiG is regarded with skepticism by some doctors in Germany, being seen merely as a mechanism to reduce costs. But the lack of study blinding does increase the risk of bias in these studies. The reason this is important is because patients, if they know they are using a different type of insulin, might behave differently (such as testing blood glucose levels more frequently, for example), which leads to bias in the study results, rendering the results inapplicable to the diabetes population at large. Numerous studies have concluded that any increase in testing of blood glucose levels is likely to yield improvements in glycemic control, which raises questions as to whether any improvements observed in the clinical trials for insulin analogues were the result of more frequent testing or due the drug undergoing trials.
More recently, the Canadian Agency for Drugs and Technology in Health (CADTH) found in its 2008 comparison of the effects of insulin analogues and biosynthetic human insulin that insulin analogues failed to show any clinically relevant differences, both in terms of glycemic control and adverse reaction profile.
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....
, 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. Through genetic engineering
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...
of the underlying DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, the amino acid sequence of insulin can be changed to alter its ADME
ADME
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
(absorption, distribution, metabolism, and excretion) characteristics. Officially, 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...
(FDA) refers to these as "insulin receptor ligands", although they are more commonly referred to as insulin analogs.
These modifications have been used to create two types of insulin analogs: those that are more readily absorbed from the injection site and therefore act faster than natural insulin injected subcutaneously, intended to supply the bolus level of insulin needed after a meal; and those that are released slowly over a period of between 8 and 24 hours, intended to supply the basal level of insulin for the day. Insulin analog was first manufactured by 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...
.
Animal insulin
The amino acid sequence for insulin is almost the same in different mammals. PorcPORC
PORC may refer to:* Porcelain* Porcupine, see also Porcupine * Postoperative Residual Curarization, see Neuromuscular-blocking drugs...
ine insulin has only a single amino acid variation from the human variety, and bovine
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
insulin varies by three amino acids. Both are active on the human receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
with approximately the same strength. Prior to the introduction of biosynthetic human insulin, insulin derived from sharks was widely used in Japan. Even insulin from some species of fish may be effective in humans. Non-human insulins can cause allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
reactions in a tiny number of people, as can genetically engineered "human" insulin. This is usually caused by the preservatives used in the insulin rather than the insulin molecule itself. Biosynthetic "human" insulin has largely replaced animal insulin. With the advent of high-pressure liquid chromatography (HPLC) equipment, the level of purification of animal-sourced insulins has reached as high as 99%, whereas the purity level of synthetic human insulins made via recombinant DNA has only attained a maximum purity level of 97%, which raises questions about the claim of synthetic insulin's purity relative to animal-sourced insulin varieties.
Chemically and enzymatically modified insulins
Before biosynthetic human recombinantRecombinant 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...
analogues were available, porcine insulin was chemically converted into human insulin. Chemical modifications of the amino acid side chains at the N-terminus and/or the C-terminus were made in order to alter the ADME
ADME
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
characteristics of the analogue. 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;...
was able to enzymatically convert porcine insulin into 'human' insulin by removing the single amino acid that varies from the human variety, and chemically adding the correct one.
Non hexameric analogs
Unmodified human and porcine insulins tend to complexComplex (chemistry)
In chemistry, a coordination complex or metal complex, is an atom or ion , bonded to a surrounding array of molecules or anions, that are in turn known as ligands or complexing agents...
with zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
in the blood, forming 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. Insulin in the form of a hexamer will not bind to its receptors, so the hexamer has to slowly equilibrate back into its monomers to be biologically useful. Hexameric insulin delivered subcutaneously is not readily available for the body when insulin is needed in larger doses, such as after a meal (although this is more a function of subcutaneously administered insulin, as intravenously dosed insulin is distributed rapidly to the cell receptors, and therefore, avoids this problem). Zinc combinations of insulin are used for slow release of basal insulin. Basal insulin is the amount the body needs through the day excluding the amount needed after meals. Non hexameric insulins were developed to be faster acting and to replace the injection of normal unmodified insulin before a meal.
NPH
NPH insulin; also known as Humulin N, Novolin N, Novolin NPH, NPH Iletin II, and isophane insulin, marketed by Eli Lilly and Company under the name Humulin N, is an intermediate-acting insulin given to help manage the blood sugar level of those with diabetes. Many people reported problems following being switched to these insulins in the 80s, from porcine/bovine insulins. Problems included mood/character changes, memory problems,and hypo-unawareness.Lispro
Eli Lilly and CompanyEli 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...
had the first insulin analogue with "lispro" as a rapid acting insulin analogue. It is marketed under the trade name Humalog. It was engineered through 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 so that the penultimate lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
and proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
residues on the C-terminal end of the B-chain were reversed. This modification did not alter the insulin receptor binding, but blocked the formation of insulin dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s and hexamers. This allowed larger amounts of active monomeric insulin to be available for postprandial
Postprandial
Postprandial means after eating a meal while preprandial is before a meal.-Usages of the term:This term is used in many contexts but also in relation to blood sugar levels, which are normally measured 2 hours after and before eating in a postprandial glucose test...
(after meal) injections.
Aspart
Novo NordiskNovo 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;...
created "aspart" and marketed it as NovoLog/NovoRapid (UK-CAN) as a rapid acting insulin analogue. It was created through 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 so that the amino acid, B28, which is normally proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
, is substituted with an aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
residue. The sequence was inserted into the 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...
genome, and the yeast expressed the insulin analogue, which was then harvested from a bioreactor
Bioreactor
A bioreactor may refer to any manufactured or engineered device or system that supports a biologically active environment. In one case, a bioreactor is a vessel in which a chemical process is carried out which involves organisms or biochemically active substances derived from such organisms. This...
. This analogue also prevents the formation of hexamers, to create a faster acting insulin. It is approved for use in CSII pumps and Flexpen, Novopen delivery devices for subcutaneous injection.
Glulisine
Glulisine is a newer rapid acting insulin analog from Sanofi-AventisSanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
, approved for use with a regular syringe, in 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 the Opticlik Pen http://opticlik.com/home.do. Standard syringe delivery is also an option. It is sold under the name Apidra. The FDA-approved label states that it differs from regular human insulin by its rapid onset and shorter duration of action.
Shifted isoelectric point insulins
Normal unmodified insulin is soluble at physiological pH. Analogues have been created that have a shifted isoelectric pointIsoelectric point
The isoelectric point , sometimes abbreviated to IEP, is the pH at which a particular molecule or surface carries no net electrical charge....
so that they exist in a solubility equilibrium in which most precipitates out but slowly dissolves in the bloodstream and is eventually excreted by the kidneys. These insulin analogues are used to replace the basal level of insulin, and may be effective over a period of up to 24 hours. However, some insulin analogues, such as insulin detemir, bind to albumin rather than fat like earlier insulin varieties, and results from long-term usage (e.g. more than 10 years) have never been released.
Glargine insulin
Sanofi-AventisAventis
Aventis was a pharmaceutical and lab assay testing company. It was formed in 1999 when Rhône-Poulenc S.A. merged with Hoechst AG. The merged company was based in Strasbourg, France. With its headquarters in Strasbourg, Aventis was the product of the first transnational merger to combine large...
developed glargine as a longer lasting insulin analogue, and markets it under the trade name Lantus. It was created by modifying three amino acids. Two positively charged arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
molecules were added to the C-terminus of the B-chain, and they shift the isoelectric point from 5.4 to 6.7, making glargine more soluble at a slightly acidic pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
and less soluble at a physiological pH. Replacing the acid-sensitive asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
at position 21 in the A-chain by glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
is needed to avoid deamination and dimerization of the arginine residue. These three structural changes and formulation with zinc result in a prolonged action when compared with biosynthetic human insulin. When the pH 4.0 solution is injected, most of the material precipitates and is not bioavailable. A small amount is immediately available for use, and the remainder is sequestered in subcutaneous tissue. As the glargine is used, small amounts of the precipitated material will move into solution in the bloodstream, and the basal level of insulin will be maintained up to 24 hours. The onset of action of subcutaneous insulin glargine is somewhat slower than NPH human insulin. It is clear solution as there is no zinc in formula.
Detemir insulin
Novo NordiskNovo 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;...
created insulin detemir and markets it under the trade name Levemir as a long-lasting insulin analogue for maintaining the basal level of insulin. The basal level of insulin may be maintained for up to 20 hours, but the time is clearly affected by the size of the injected dose.
This insulin has a high affinty for serum albumin, increasing its duration of action.
Carcinogenicity
All insulin analogs must be tested for carcinogenicity, as insulin engages in cross-talk with IGFInsulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
pathways, which can cause abnormal cell growth and tumorigenesis. Modifications to insulin always carry the risk of unintentionally enhancing IGF signalling in addition to the desired pharmacological properties.
Criticism
A meta-analysisMeta-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...
of numerous randomized controlled trials by the international 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...
found "only a minor clinical benefit of treatment with long-acting insulin analogues (including two studies of insulin detemir) for patients with diabetes mellitus type 2" while others have examined the same issue in type 1 diabetes. Subsequent meta-analyses undertaken in a number of countries and continents have confirmed Cochrane's findings.
In July 2007, Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector (IQWiG) reached a strikingly similar conclusion. In its report, IQWiG concluded that there is currently "no evidence" available of the superiority of rapid-acting insulin analogs over synthetic human insulins in the treatment of adult patients with type 1 diabetes. Many of the studies reviewed by IQWiG were either too small to be considered statistically reliable and, perhaps most significantly, none of the studies included in their widespread review were blinded, the gold-standard methodology for conducting clinical research. However, IQWiG's terms of reference explicitly disregard any issues which cannot be tested in double-blind studies, for example a comparison of radically different treatment regimes. IQWiG is regarded with skepticism by some doctors in Germany, being seen merely as a mechanism to reduce costs. But the lack of study blinding does increase the risk of bias in these studies. The reason this is important is because patients, if they know they are using a different type of insulin, might behave differently (such as testing blood glucose levels more frequently, for example), which leads to bias in the study results, rendering the results inapplicable to the diabetes population at large. Numerous studies have concluded that any increase in testing of blood glucose levels is likely to yield improvements in glycemic control, which raises questions as to whether any improvements observed in the clinical trials for insulin analogues were the result of more frequent testing or due the drug undergoing trials.
More recently, the Canadian Agency for Drugs and Technology in Health (CADTH) found in its 2008 comparison of the effects of insulin analogues and biosynthetic human insulin that insulin analogues failed to show any clinically relevant differences, both in terms of glycemic control and adverse reaction profile.
Timeline
- 1922 Banting and Best use bovine insulin extract on human
- 1923 Eli Lilly and CompanyEli Lilly and CompanyEli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
(Lilly) produces commercial quantities of bovine insulin - 1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark forerunner of Novo NordiskNovo NordiskNovo 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 NordiskNovo NordiskNovo 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 Danish charter to produce insulin as a non-profit - 1936 Canadians D.M. Scott and A.M. Fisher formulate 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 a.k.a. Neutral Protamine Hagedorn or NPH insulinNPH insulinNPH 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
- 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer-lasting insulin
- 1978 GenentechGenentechGenentech 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 synthetic 'human' insulin in Escheria coli bacteria using recombinant DNA technology - 1981 Novo Nordisk chemically and enzymatically converts porcine insulin to 'human' insulin
- 1982 GenentechGenentechGenentech 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 approved, largely thanks to its partnership with Eli Lilly and Company, who shepherded the product through the U.S. Food and Drug AdministrationFood and Drug AdministrationThe 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...
(FDA) approval process - 1983 Lilly produces synthetic, recombinant 'human' insulin, branded Humulin
- 1985 Axel UllrichAxel UllrichAxel 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 the human insulin receptor - 1988 Novo Nordisk produces synthetic, recombinant 'human' insulin
- 1996 Lilly Humalog "lispro" insulin analogue approved by the U.S. Food and Drug Administration
- 2003 AventisAventisAventis was a pharmaceutical and lab assay testing company. It was formed in 1999 when Rhône-Poulenc S.A. merged with Hoechst AG. The merged company was based in Strasbourg, France. With its headquarters in Strasbourg, Aventis was the product of the first transnational merger to combine large...
Lantus "glargine" insulin analogue approved in USA - 2004 Sanofi Aventis Apidra insulin "glulisine" analogue approved for clinical use in the USA.
- 2006 Novo Nordisk's Levemir "insulin detemir" analogue approved in USA