Insulin analog
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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.
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.
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[edit] 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 calcitonin 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.
[edit] 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.
[edit] 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.
[edit] Lispro insulin
Lilly had the first insulin analogue with "lyspro" 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.
[edit] 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.
[edit] 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.
[edit] 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.
[edit] 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.
[edit] External links
[edit] 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 [1]
- 2006 Novo Nordisk "detemir" up for approval in USA
