Insulin analog

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An insulin analog is an altered form of 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 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.

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 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.

Contents 1 Animal analog 2 Chemically and enzymatically modified insulins 3 Non hexameric insulin analogs 3.1 Lispro insulin 3.2 Aspart insulin 3.3 Glulisine insulin 4 Shifted isoelectric point insulins 4.1 Glargine insulin 4.2 Detemir insulin 5 Carcinogenicity 6 Criticism 7 Criticism of the criticism 8 Timeline 9 References 10 External links

[edit] Animal analog

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. Even insulin from some species of fish may be effective in humans. Non-human insulins can cause allergic reactions in an insignificant percentage of people, although synthetic "human" insulin has largely replaced animal analogs. With the advent of high-pressure liquid chromatography (HPLC) equipment, the level of purification of animal-sourced insulins ultimately 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.

[edit] 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.

[edit] Non hexameric insulin analogs

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 larger doses delivered subcutaneously (although this is more a function of subcutaneously administering insulin, as interveinously dosed insulin is distributed rapidly to the cell receptors and therefore does not generally encounter this problem), 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.

[edit] Lispro insulin

Main article: Insulin lispro

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. ^[1]

[edit] Aspart insulin

Main article: Insulin aspart

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. ^[2]

[edit] Glulisine insulin

Main article: Insulin glulisine

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. ^[3]

[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 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 may be effective over a period of about 24 hours.

[edit] Glargine insulin

Main article: Insulin glargine

Sanofi-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 somewhat slower than NPH human insulin. It is clear solution as there is no zinc in formula. ^[4]

[edit] Detemir insulin

Main article: Insulin detemir

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.^[5][6] The basal level of insulin may be maintained up to 20 hours, but the time is clearly affected by the size of the injected dose.

[edit] Carcinogenicity

All insulin analogs must be tested for carcinogenicity, as insulin engages in cross-talk with IGF 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.^{[citation needed]}

[edit] Criticism

A meta-analysis 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".^[7], while others have examined the same issue in type 1 diabetes. Subsequent meta-analyses have confirmed Cochrane's findings. For example, 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, and that many of the studies reviewed were either too small to be considered statistically reliable, and perhaps more significantly, none of the studies included in their widespread review was blinded. The lack of study blinding increases the risk of bias in these studies. The reason this is important is because patients, if they know their type of insulin, might behave differently (such as testing more frequently, for example), which would subsequently lead to bias in the study results, rendering the results inapplicable to the diabetes population at large. More recently, the Canadian Agency for Drugs and Technology in Health (CADTH) also found in its 2007 comparison of the effects of insulin analogs and plain synthetic human insulins that insulin analogs failed to show any clinically relevant differences, both in terms of glycemic control and adverse reaction profile^[8].

[edit] Criticism of the criticism

A blind comparison of the fast acting analogs with "human" insulin is impossible, or at least would be grossly irresponsible, since the two drugs act in such hugely different ways. "Human" insulin starts lowering the blood sugar around half an hour after injection, and carries on working for around 8 hours, whereas Lispro, perhaps the most popular of the fast acting analogs, starts working instantly, and its duration is restricted to about 2 hours. Thus when "human" insulin is injected before a meal, the user must wait over half an hour before eating, if this insulin is to available to process the food properly. By contrast, Humalog need only (indeed, must) be injected immediately before eating. It is obvious that the fast acting analogs are beneficial to diabetics whose mealtimes are unpredictable, or who don't know in advance how much carbohydrate they are about to eat.

[edit] Timeline

• 1922 Banting and Best use bovine insulin extract on human
• 1923 Eli Lilly and Company (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 a.k.a. 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 synthetic 'human' insulin in Escheria coli bacteria using recombinant DNA technology
• 1981 Novo Nordisk chemically and enzymatically converts porcine insulin to 'human' insulin
• 1982 Genentech synthetic 'human' insulin approved, largely thanks to its partnership with Lilly, who shepherded the product through the U.S. Food and Drug Administration (FDA)
• 1983 Lilly produces synthetic, recombinant 'human' insulin, branded Humulin
• 1985 Axel Ullrich sequences the human insulin receptor
• 1988 Novo Nordisk produces synthetic, recombinant 'human' insulin
• 1996 Lilly Humalog "lispro" insulin analogue approved
• 2003 Aventis Lantus "glargine" insulin analogue approved in USA ^[9]
• 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

[edit] References

[edit] External links

• Apidra®
• Humalog®
• Lantus
• Levemir®
• Novolog®

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