Insulin analog

Overview
An insulin analog is an altered insulin, different from the insulin secreted by the human pancreas, but still available to the human body for performing the same action as human insulin. 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.

These modifications have been used to create two types of insulin analogs: those that are more readily absorbed from the injection site and are therefore acting faster than natural insulin, 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.

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 with approximately the same strength. 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 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.

Non hexameric insulins
Unmodified human and porcine insulins tend to complex with zinc in the blood, forming hexamers. 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 to replace the injection of normal unmodified insulin before a meal.

Lispro insulin
Lilly 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 receptor binding, but blocked the formation of insulin dimers and hexamers. This allowed larger amounts of active monomeric insulin to be available for postprandial (after meal) injections.

Aspart insulin
Novo Nordisk created "aspart" and marketed it as NovoLog®/NovoRapid (UK) 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. Can be used in CSII pumps and Flexpen, Novopen delivery devices for subcutaneous injection.

Glulisine insulin
Glulisine is a newer rapid acting insulin analog from sanofi-aventis, approved for use in an insulin pump or the Opticlik Pen. 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.

Shifted isoelectric point insulins
Normal unmodified insulin is soluble at physiological pH. Analogues have been created that have a shifted isoelectric point so that they exist in a solubility equilibrium in which most precipitates out but slowly dissolves in the bloodstream is eventually excreted by the kidneys. These insulin analogues are used to replace the basal level of insulin, and are effective over a period of about 24 hours.

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 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 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 slower than NPH human insulin. It is clear solution.

Detemir insulin
Novo Nordisk created insulin detemir and markets it under the trade name Levemir® as a long-lasting insulin analogue for maintaining the basal level of insulin.

Criticism
A meta-analysis of 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 1".

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 in USA
 * 2006 Novo Nordisk's "Detemir" approved in USA