Novo Nordisk's NovoLog® substituting a single amino acid prevents hexamers from forming and allows a quicker onset

Aventis's Lantus® substituting a single amino acid and adding two extra amino acids to the c-terminus of the b-chain shifts the isoelectric point so that less of the analogue is soluble in the blood to prevent spiking

Sanofi-Aventis's Apidra® substitutes two amino acids

Glargine versus NPH insulin in duration

Through genetic engineering of the underlying DNA, the primary amino acid sequence of insulin can be changed to alter its ADME characteristics. These characteristics are its absorption, distribution, metabolism, and excretion. Image File history File linksMetadata Aspart_01. ... Image File history File linksMetadata Aspart_01. ... Novo Nordisk (NYSE: NVO) manufactures and markets pharmaceutical products and services. ... Image File history File linksMetadata Glargine_01. ... Image File history File linksMetadata Glargine_01. ... Aventis was formed in 1999 when Rhône-Poulenc S.A. merged with Hoechst AG. The merged company was based in Strasbourg, France. ... Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Sanofi-aventis (Euronext: SAN, NYSE: SNY), headquartered in Paris, France, is one of the 3 largest pharmaceutical companies in the world, along with Pfizer,GlaxoSmithKline. ... Image File history File linksMetadata Glargine_02. ... Image File history File linksMetadata Glargine_02. ... Hans Christian Hagedorn (1888-1971) Neutral Protamine Hagedorn was created in 1946 when Nordisk formulated isophane porcine insulin by adding Neutral Protamine Hagedorn or NPH. History Hans Christian Hagedorn (1888-1971) and August Krogh (1874-1949) obtained the rights for insulin from Banting and Best in Toronto. ... Insulin (from Latin insula, island, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. ... ADME is an acronym in pharmacokinetics and pharmacology for Absorption, Distribution, Metabolism, and Excretion, and describes the disposition of a pharmaceutical compound within an animal or human body. ...

The modifications have been used to create two types of insulin. One that is faster acting and more bioavailable than natural insulin, to supply the level of insulin needed after a meal. The second is one that needs to be less bioavailable, and released more slowly over a 24-hour period to supply the basal level of insulin for the day.

Animal insulins

The amino acid sequence for insulin is highly conserved in mammals. Porcine 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 and are roughly equipotent. For instance salmon [[

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[[[Link title]]is more potent on the human receptor than human calcitonin is. Non human insulins can cause allergic reactions in some people, and human insulin replaced animal analogues.

Chemically and enzymatically modified insulins

Before human recombinant analogues were available, porcine insulin was chemically converted into human insulin. Chemical modifications of amino acid side chains, and the N-terminus and C-terminus to alter the ADME characteristics of the analogue were employed. 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. ADME is an acronym in pharmacokinetics and pharmacology for Absorption, Distribution, Metabolism, and Excretion, and describes the disposition of a pharmaceutical compound within an animal or human body. ... Novo Nordisk (NYSE: NVO) manufactures and markets pharmaceutical products and services. ...

Non hexameric insulins

Unmodified human and porcine insulin tend to form hexamers in contact with zinc in the bloodstream. 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 is not readily available for the body when insulin is needed in large doses, such as after a meal. 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 replace the injection of normal unmodified insulin that comes after a meal. General Name, Symbol, Number zinc, Zn, 30 Chemical series transition metals Group, Period, Block 12, 4, d Appearance bluish pale gray Atomic mass 65. ...

Lispro insulin

Lilly had the first insulin analogue with "lispro" as a rapid acting insulin analogue. It was 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 receptor binding, but blocked the formation of insulin dimers and hexamers. This allowed larger amounts of active monomeric insulin to be available for postprandial, or after meal, injections. Eli Lilly and Company (NYSE: LLY) is a global pharmaceutical company and one of the worlds largest corporations. ... Recombinant deoxyribonucleic acid(rDNA) is an artificial DNA sequence resulting from the combining of two other DNA sequences in a plasmid. ...

Aspart insulin

Novo Nordisk created "aspart" and marketed it as NovoLog® 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. Novo Nordisk (NYSE: NVO) manufactures and markets pharmaceutical products and services. ... Recombinant deoxyribonucleic acid(rDNA) is an artificial DNA sequence resulting from the combining of two other DNA sequences in a plasmid. ... L-Proline is one of the twenty proteinogenic units which are used in living organisms as the building blocks of proteins. ... Aspartic acid (Asp), also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Typical divisions Ascomycota Saccharomycotina (true yeasts) Taphrinomycotina Schizosaccharomycetes (fission yeasts) Basidiomycota Basidiomycotina (club fungi) Urediniomycetes Sporidiales Yeasts are unicellular, eukaryotic microorganisms classified in the kingdom Fungi. ... A bioreactor may refer to any device or system that supports a biologically active environment. ...

Glulisine insulin

Glulisine is a newer rapid acting insulin analog from Sanofi-Aventis, approved for use in an insulin pump or the Opticlik Pen [1]. Standard syringe delivery is also an option. It is sold under the name Apidra®. It differs from regular human insulin by its rapid onset and shorter duration of action. Insulin glulisine is a rapid-acting insulin analogue that differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. ... Sanofi-aventis (Euronext: SAN, NYSE: SNY), headquartered in Paris, France, is one of the 3 largest pharmaceutical companies in the world, along with Pfizer,GlaxoSmithKline. ... Insulin Pump with an Infusion Set An insulin pump is a medical device used for administering insulin in the treatment of diabetes mellitus. ...

Shifted isoelectric point insulins

Normal unmodified insulin is soluble at physiological pH. Analogues have been created that have a shifted isoelectric point so that it exists in a solubility equilibrium in which most is precipitated in the bloodstream. More becomes soluble as the small amount dissolved in the bloodstream is excreted by the kidney. These insulin analogues are used to replace the basal level of insulin, and are effective over a period of 24 hours. The isoelectric point sucks (pI) is the pH at which a molecule carries no net electrical charge. ...

Glargine insulin

Aventis 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, or pI, 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 regular 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 the bloodstream. 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 over a 24 hour period. The onset of action of subcutaneous insulin glargine is slower than NPH human insulin. Aventis was formed in 1999 when Rhône-Poulenc S.A. merged with Hoechst AG. The merged company was based in Strasbourg, France. ... Insulin glargine, sold under the name Lantus, is a long-acting basal insulin analogue, usually given once or twice daily to help control the blood sugar level of those with diabetes. ... The isoelectric point sucks (pI) is the pH at which a molecule carries no net electrical charge. ... Asparagine is one of the 20 most common natural amino acids on Earth. ... Glycine (Gly, G) is a nonpolar amino acid. ...

Detemir insulin

Novo Nordisk created "detemir" and markets it under the trade name Levemir® as a long-lasting insulin analogue for maintaining the basal level of insulin. Novo Nordisk (NYSE: NVO) manufactures and markets pharmaceutical products and services. ...

External links

• Levemir®
• Lantus

Timeline

• 1922 Banting and Best use bovine insulin extract on human
• 1923 Lilly produces commercial quantities of bovine insulin
• 1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark forerunner of Novo Nordisk
• 1926 Nordisk 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 aka Neutral Protamine Hagedorn or NPH insulin
• 1946 Nordisk crystallizes a protamine and insulin mixture
• 1950 Nordisk markets NPH insulin
• 1953 Novo formulates Lente® porcine and bovine insulins by adding zinc for longer lasting insulin
• 1978 Genentech produces human insulin in Escheria coli bacteria using recombinant DNA
• 1981 Novo Nordisk chemically and enzymatically converts bovine to human insulin
• 1982 Genentech human insulin approved
• 1983 Lilly produces recombinant human insulin, Humulin®
• 1985 Axel Ullrich sequences the human insulin receptor
• 1988 Novo Nordisk produces recombinant human insulin
• 1996 Lilly Humalog® "lyspro" insulin analogue approved
• 2003 Aventis Lantus® "glargine" insulin analogue approved [2]
• 2006 Novo Nordisk "detemir" up for approval in USA