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 engineeringof the underlying DNA, the amino acid sequenceof 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.
The amino acid sequence for insulin is almost the same in different 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. Prior to the introduction of biosynthetic human insulin, insulin derived from sharks was widely used in Japan. Even insulin from some species of fish may be effective in humans. Non-human insulins can cause 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 biosynthetic human
recombinantanalogues were available, porcine insulin was chemically converted into human insulin. Chemical modifications of the amino acid side chains at the N-terminusand/or the C-terminuswere made in order to alter the ADMEcharacteristics of the analogue. Novo Nordiskwas 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
Unmodified human and porcine insulins tend to complex with
zincin 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.
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 DNAtechnology so that the penultimate lysineand prolineresidues 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. [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= ]
Novo Nordiskcreated "aspart" and marketed it as NovoLog/NovoRapid (UK) as a rapid acting insulin analogue. It was created through recombinant DNAtechnology so that the amino acid, B28, which is normally proline, is substituted with an aspartic acidresidue. The sequence was inserted into the yeastgenome, 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. It is approved for use in CSII pumps and Flexpen, Novopen delivery devices for subcutaneous injection. [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= ]
Glulisine is a newer rapid acting insulin analog from
Sanofi-Aventis, approved for use in an insulin pumpor the Opticlik Pen [http://opticlik.com/home.do] . Standard syringe delivery is also an option. It is sold under the name Apidra. The FDA-approved label states that it differs from regular human insulin by its "rapid onset and shorter duration of action". [cite web |url=http://www.apidra.com/ |title=Apidra insulin glulisine (rDNA origin) injection |accessdate=2007-06-08 |format= |work= ]
hifted isoelectric point insulins
Normal unmodified insulin is soluble at physiological pH. Analogues have been created that have a shifted
isoelectric pointso 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. However, some insulin analogues such insulin detemir binds to albumin rather than fat like earlier insulin varieties, and results from long-term usage (e.g. more than 10 years) have never been released.
Aventisdeveloped 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 argininemolecules 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 pHand less soluble at a physiological pH. Replacing the acid-sensitive asparagineat position 21 in the A-chain by glycineis 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 biosynthetic 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. [cite web |url=http://www.lantus.com |title=Lantus insulin glargine (rDNA origin) injection |accessdate=2007-06-08|format= |work= ]
Novo Nordiskcreated insulin detemir and markets it under the trade name Levemir as a long-lasting insulin analogue for maintaining the basal level of insulin. [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= ] [cite web |url=http://www.lantus.com |title=Levemir insulin detemir (rDNA origin) injection |accessdate=2007-06-08 |format= |work= ] 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.
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.Fact|date=June 2007
meta-analysisof numerous randomized controlled trialsby the international Cochrane Collaborationfound "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".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] , while others have examined the same issue in type 1 diabetes. Subsequent meta-analyses undetaken in a number of different countries and continents have confirmed Cochrane's findings.
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 were blinded, the gold-standard methodology for conducting clinical research. 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. IQWiG is regarded with skepticism by some doctors in Germany, being seen merely as a mechanism to reduce costs. But the lack of study blinding does increase the risk of bias in these studies. The reason this is important is because patients, if they know they are using a different type of insulin, might behave differently (such as testing blood glucose levels more frequently, for example), which leads 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 of blood glucose levels is likely to yield improvements in glycemic control, which raises questions as to whether any improvements observed in the clinical trials for insulin analogues were the result of more frequent testing or due the drug undergoing trials.
More recently, the Canadian Agency for Drugs and Technology in Health (CADTH) also found in its 2007 comparison of the effects of insulin analogues and biosynthetic human insulin that insulin analogues failed to show any clinically relevant differences, both in terms of glycemic control and adverse reaction profile [ [http://www.cadth.ca/media/pdf/341A_Insulin_tr_e.pdf Banerjee S, Tran K, Li H, Cimon K, Daneman D, Simpson S, Campbell K. "Short-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost effectiveness" [Technology Report No 87] . Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007.] ] .
*1922 Banting and Best use bovine insulin extract on human
Eli Lilly and Company(Lilly) produces commercial quantities of bovine insulin
*1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark forerunner of
Nordiskreceives 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
*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
Genentechproduces synthetic 'human' insulin in "Escheria coli" bacteria using recombinant DNA technology
*1981 Novo Nordisk chemically and enzymatically converts porcine insulin to 'human' insulin
Genentechsynthetic 'human' insulin approved, largely thanks to its partnership with Lilly, who shepherded the product through the U.S. Food and Drug Administration(FDA) approval process
*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
AventisLantus "glargine" insulin analogue approved in USA [ [http://www.newsrx.com/newsletters/Obesity-and-Diabetes-Week/2003-06-02/0602200333315OD.html Glucose Control - Lantus receives FDA approval for flexible administration ] ]
Sanofi AventisApidra insulin "glulisine" analogue approved for clinical use in the USA.
*2006 Novo Nordisk's Levemir "insulin detemir" analogue approved in USA
* [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®]
Wikimedia Foundation. 2010.
Look at other dictionaries:
Insulin aspart — Clinical data AHFS/Drugs.com … Wikipedia
Insulin — This article is about the insulin protein. For uses of insulin in treating diabetes, see insulin therapy. Not to be confused with inulin. Insulin Computer generated image of six insulin molecules assembled in a hexamer, highlighting the threefold … Wikipedia
Insulin lispro — drugbox IUPAC name = CAS number = 133107 64 9 ATC prefix = A10 ATC suffix = AB04 PubChem = 16132438 DrugBank = BTD00065 chemical formula = C=257|H=389|N=65|O=77|S=6 molecular weight = 5813.63 g/mol bioavailability = protein bound = metabolism =… … Wikipedia
Insulin detemir — Clinical data AHFS/Drugs.com monograph MedlinePlus … Wikipedia
Insulin-Glargin — Wikipedia:Redaktion Chemie/ausgeblendete Strukturformel Allgemeines Freiname Insulin glargin Summenformel C267H404N72O78S6 CAS Nummer 160337 95 1 … Deutsch Wikipedia
NPH-Insulin — Für die Insulintherapie zur Behandlung des Diabetes beim Menschen stehen verschiedene Insulinpräparate zur Verfügung. Dieser Artikel beschreibt, wie die Insulinpräparate beschaffen sind, wie sie hergestellt werden und wie sie wirken. Über das… … Deutsch Wikipedia
Novo Nordisk — A/S Type Publicly traded Aktieselskab (OMX: NOVO B, NYSE: … Wikipedia
Diabetes management — Main article: Diabetes mellitus Diabetes is a chronic disease with no cure as of 2010[update] but a lot of research is underway. It is associated with an impaired glucose cycle, altering metabolism. Management of this disease may include… … Wikipedia
Intensive insulinotherapy — is a therapeutic regimen for diabetes mellitus treatment. This newer approach contrasts with conventional insulinotherapy. Rather than minimize the number of insulin injections per day (a technique which demands a rigid schedule for food and… … Wikipedia
Anti-diabetic drug — Anti diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral… … Wikipedia