Insulin analog
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224116812
2008-07-07T11:35:49Z
AMackenzie
4544010
/* Criticism */ Add background information on IQWIG.
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.
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.
==Animal insulin==
The amino acid sequence for insulin is almost the same in different mammals. [[Porc]]ine insulin has only a single amino acid variation from the human variety, and [[cattle|bovine]] insulin varies by three amino acids. Both are active on the human [[Receptor (biochemistry)|receptor]] with approximately the same strength. Even insulin from some species of fish may be effective in humans. Non-human insulins can cause [[Allergy|allergic]] reactions in a tiny number of people, as can genetically engineered "human" insulin. Synthetic "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 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 insulin analogs==<!--This section is linked from [[Insulin pump]]-->
Unmodified human and porcine insulins tend to [[complex (chemistry)|complex]] 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 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.
===Lispro insulin===
{{main|Insulin lispro}}
[[Eli Lilly and Company|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 [[dimer]]s and hexamers. This allowed larger amounts of active monomeric insulin to be available for [[postprandial]] (after meal) injections. <ref>{{cite web |url=http://www.aafp.org/afp/980115ap/noble.html |title=Insulin Lispro:
A Fast-Acting Insulin Analog |accessdate=2007-06-08 |format= |work= }}</ref>
===Aspart insulin===
{{main|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. <ref>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a605013.html |title=Aspart insulin (rDNA origin) injection |accessdate=2007-06-08 |format= |work= }}</ref>
===Glulisine insulin===
{{main|Insulin glulisine}}
Glulisine is a newer rapid acting insulin analog from [[Sanofi-Aventis]], approved for use 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. It differs from regular human insulin by its ''rapid onset and shorter duration of action''. <ref>{{cite web |url=http://www.apidra.com/ |title=Apidra insulin glulisine (rDNA origin) injection |accessdate=2007-06-08 |format= |work= }}</ref>
==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.
===Glargine insulin===
{{main|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. <ref>{{cite web |url=http://www.lantus.com |title=Lantus insulin glargine (rDNA origin) injection |accessdate=2007-06-08|format= |work= }}</ref>
===Detemir insulin===
{{main|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.<ref>{{cite web |url=http://www.aafp.org/afp/980115ap/noble.html |title=Insulin Lispro:
A Fast-Acting Insulin Analog |accessdate=2007-06-08 |format= |work= }}</ref><ref>{{cite web |url=http://www.lantus.com |title=Levemir insulin detemir (rDNA origin) injection |accessdate=2007-06-08 |format= |work= }}</ref> 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.
==Carcinogenicity==
All insulin analogs must be tested for [[carcinogenicity]], as insulin engages in cross-talk with [[Insulin-like growth factor|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.{{Fact|date=June 2007}}
==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".<ref name="pmid17443605">{{cite journal |author=Horvath K, Jeitler K, Berghold A, Ebrahim Sh, Gratzer T, Plank J, Kaiser T, Pieber T, Siebenhofer A |title=Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus |journal=Cochrane database of systematic reviews (Online) |volume= |issue=2 |pages=CD005613 |year=2007 |pmid=17443605 |doi=10.1002/14651858.CD005613.pub3}}</ref>, 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 [http://www.iqwig.de/pdf.php?url=pdf.658.en.html 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 could be blinded, since rapid-acting insulin analogs work so differently from "human" insulin. 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, and in particular, a diabetic's quality of life. For this reason, IQWIG is regarded with contempt and disdain by doctors and patients in Germany, being widely seen merely as a mechanism to reduce costs. The impossibility of study blinding increases the risk of bias in these studies. The reason this is important is because patients, since they know whether they are using an analog or insulin, might behave differently (such as testing more frequently, for example), which may lead 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 is likely to yield improvements in glycemic control, therefore the impossibility of study blinding raises questions as to whether any improvements were the result of more frequent testing or the insulin analogues.
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<ref>[http://www.cadth.ca/index.php/en/compus/compus-communique/compus-communiqu-vol-3-no-12 CADTH: COMPUS Communiqué – Vol. 3, No. 12<!-- Bot generated title -->]</ref>.
==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 by the U.S. Food and Drug Administration
*2003 [[Aventis]] Lantus "glargine" insulin analogue approved in USA <ref>[http://www.newsrx.com/newsletters/Obesity-and-Diabetes-Week/2003-06-02/0602200333315OD.html Glucose Control - Lantus receives FDA approval for flexible administration<!-- Bot generated title -->]</ref>
* 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
==References==
{{reflist}}
==External links==
*[http://apidra.com/ Apidra®]
*[http://www.humalog.com/index.jsp Humalog®]
*[http://www.lantus.com Lantus]
*[http://www.levemir-us.com Levemir®]
*[http://www.novolog.com/ Novolog®]
{{Oral hypoglycemics and insulin analogs}}
[[Category:Insulin therapies]]
[[Category:Eli Lilly and Company]]
[[Category:Diabetes]]
[[de:Insulinpräparat]]
[[ja:インスリンアナログ]]
[[pl:Analogi insuliny]]