Insulin analog/ja

インスリンアナログ（also called an insulin analogue）は、インスリンというホルモンを変化させたものであり、自然界に存在するものとは異なるが、糖尿病における血糖値のコントロールという点ではヒトのインスリンと同じ作用を発揮するために人体で利用可能である。基礎となるDNAの遺伝子工学を通じて、インスリンのアミノ酸配列を変化させ、そのADME（吸収、分布、代謝、排泄）特性を変えることができる。 公式には、米国食品医薬品局（FDA）はこれらの薬物をインスリン受容体リガンド（インスリンそのものと同様に、インスリン受容体のリガンドであるため）と呼んでいるが、通常は単にインスリンアナログ、あるいは（緩やかではあるが一般的には）単にインスリンと呼ばれている（それ以上の指定はない）。

これらの改良は、2つのタイプのインスリンアナログを作成するために使用されてきた：注射部位から容易に吸収され、したがって、食事時に必要なインスリンのボーラスレベルを供給することを目的とした皮下注入された天然のインスリンよりも速く作用するもの（プランダイヤルインスリン）；および日中および特に夜間にインスリンの基礎レベルを供給することを目的とした8〜24時間の期間にわたってゆっくりと放出されるもの（基礎インスリン）。最初のインスリンアナログ（インスリンリスプロrDNA）は1996年にヒトの治療薬として承認され、Eli Lilly and Companyによって製造された。

Fast acting

Lispro

Main article: Insulin lispro

Eli Lilly and Company developed and marketed the first rapid-acting insulin analogue (insulin lispro rDNA) 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 the insulin 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

Main article: Insulin aspart

Novo Nordisk created "aspart" and marketed it as NovoLog/NovoRapid (UK-CAN) 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. It is approved for use in CSII pumps and Flexpen, Novopen delivery devices for subcutaneous injection.

Glulisine

Main article: Insulin glulisine

Glulisine is rapid acting insulin analog from Sanofi-Aventis, approved for use with a regular syringe, in an insulin pump. 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.

Long acting

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. The basal level of insulin may be maintained for up to 20 hours, but the time is affected by the size of the injected dose. This insulin has a high affinity for serum albumin, increasing its duration of action.

Degludec insulin

Main article: Insulin degludec

This is an ultralong-acting insulin analogue developed by Novo Nordisk, which markets it under the brand name Tresiba. It is administered once daily and has a duration of action that lasts up to 40 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir).

Glargine insulin

Main article: Insulin glargine

Sanofi-Aventis developed glargine as a longer-lasting insulin analogue, and sells it under the brand 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 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. The biosimilar insulin glargine-yfgn (Semglee) was approved for medical use in the United States in July 2021, and in the European Union in March 2018.

Comparison with other insulins

NPH

Main article: NPH insulin

NPH (Neutral Protamine Hagedorn) insulin is an intermediate-acting insulin with delayed absorption after subcutaneous injection, used for basal insulin support in diabetes type 1 and type 2. NPH insulins are suspensions that require shaking for reconstitution prior to injection. Many people reported problems when being switched to intermediate acting insulins in the 1980s, using NPH formulations of porcine/bovine insulins. Basal insulin analogs were subsequently developed and introduced into clinical practice to achieve more predictable absorption profiles and clinical efficacy.

Animal insulin

Ribbon diagram of a porcine insulin hexamer. Porcine insulin differs from human insulin by only one amino acid.

The amino acid sequence of animal insulins in different mammals may be similar to human insulin (insulin human INN), there is however considerable viability within vertebrate species. 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. Bovine insulin and porcine insulin may be considered as the first clinically used insulin analogs (naturally occurring, produced by extraction from animal pancreas), at the time when biosynthetic human insulin (insulin human rDNA) was not available. There are extensive reviews on structure-relationship of naturally occurring insulins (phylogenic relationship in animals) and structural modifications. Prior to the introduction of biosynthetic human insulin, insulin derived from sharks was widely used in Japan. Insulin from some species of fish may be also effective in humans. Non-human insulins have caused allergic reactions in some patients related to the extent of purification, formation of non-neutralising antibodies is rarely observed with recombinant human insulin (insulin human rDNA) but allergy may occur in some patients. This may be enhanced by the preservatives used in insulin preparations, or occur as a reaction to the preservative. Biosynthetic insulin (insulin human rDNA) has largely replaced animal insulin.

Modifications

Before biosynthetic 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. Semisynthetic insulins were clinically used for some time based on chemical modification of animal insulins, for example Novo Nordisk enzymatically converted porcine insulin into semisynthetic 'human' insulin by removing the single amino acid that varies from the human variety, and chemically adding the human amino acid.

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 and 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 up to 24 hours. However, some insulin analogues, such as insulin detemir, bind to albumin rather than fat like earlier insulin varieties, and results from long-term usage (e.g. more than 10 years) are currently not available but required for assessment of clinical benefit.

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 delivered subcutaneously is not readily available for the body when insulin is needed in larger doses, such as after a meal (although this is more a function of subcutaneously administered insulin, as intravenously dosed insulin is distributed rapidly to the cell receptors, and therefore, avoids this problem). Zinc combinations of insulin are used for slow release of basal insulin. Basal insulin support is required throughout the day representing about 50% of daily insulin requirement, the insulin amount needed at mealtime makes up for the remaining 50%. Non hexameric insulins (monomeric insulins) were developed to be faster acting and to replace the injection of normal unmodified insulin before a meal. There are phylogenetic examples for such monomeric insulins in animals.

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. There has been concern with the mitogenic activity and the potential for carcinogenicity of glargine. Several epidemiological studies have been performed to address these issues. Recent study result of the 6.5 years Origin study with glargine have been published.

Research on safety, efficacy, and comparative effectiveness

Main article: Comparative effectiveness research

A meta-analysis completed in 2007 and updated in 2020 of numerous randomized controlled trials by the international Cochrane Collaboration found that the effects on blood glucose and glycated haemoglobin A1c (HbA1c) were comparable, treatment with glargine and detemir resulted in fewer cases of hypoglycemia when compared to NPH insulin. Treatment with detrimir also reduced the frequency of serious hypoglycemia. This review did note limitations, such as low glucose and HbA1c targets, that could limit the applicability of these findings to daily clinical practice.

In 2007, Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector (IQWiG) report, 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 to the drug undergoing trials.

In 2008, the Canadian Agency for Drugs and Technologies in Health (CADTH) found, in its 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.

年表

• 1922年 バンティングとベストが牛インスリンエキスをヒトに使用する。
• 1923年 Eli Lilly and Company（Lilly）がウシインスリンを商業生産する。
• 1923年 ハゲドホーンがデンマークにNovo Nordiskの前進となるノルディスクインスリン研究所を設立する。
• 1926年 Nordiskがデンマークの非営利団体としてインスリン製造の認可を受ける。
• 1936年 カナダ人のD.M.スコットとA.M.フィッシャーが亜鉛インスリン混合製剤を調合し、Novoにライセンス供与する。
• 1936年 ハゲドホーンがインスリンにプロタミンを加えるとインスリンの効果が延長することを発見する。
• 1946年 Nordiskがイソフェン豚インスリン、別名NPHインスリンを製剤化する。
• 1946年 Nordiskがプロタミンとインスリンの混合物を結晶化させる。
• 1950年 NordiskがNPHインスリンを販売する。
• 1953年 Novoがインスリンを長持ちさせるために亜鉛を加えてレンテ豚と牛のインスリンを製剤化する。
• 1978年 Genentechが組換えDNA技術を用いて大腸菌で組換えヒトインスリンの生合成を開発する。
• 1981年 Novo Nordiskが豚のインスリンを化学的および酵素的に「ヒト」インスリンに変換する（アクトラピッドHM）。
• 1982年 GenentechがEli Lilly and Companyとの提携により、合成'ヒト'インスリンを承認し、米国食品医薬品局（FDA）の承認プロセスを通過させた。
• 1983年 Lillyが生合成組換え型「rDNAインスリンヒトINN」（Humulin）を製造する。
• 1985年 Axel Ullrich がヒトインスリンレセプターの配列を決定する。
• 1988年 Novo Nordiskが合成組換え型インスリン（「インスリンヒトINN」）を製造する。
• 1996年 リリー・ヒューマログ「インスリンリスプロINN」が米国食品医薬品局より承認される。
• 2003年 [[Wikipedia:Aventis|Aventis]］のランタス「グラルギン」インスリンアナログが米国で承認される
• 2004年 Sanofi Aventisのアピドラ "グラルギン "インスリンアナログ"が米国で承認される。
• 2006年 Novo Nordiskのレベミル「インスリンデテミルINN」アナログが米国で承認される。
• 2013年 Novo Nordiskのトレシーバ「インスリン デグルデクINN」アナログ製剤が欧州で承認される（EMAによる追加監視付き）

外部リンク

• Analog Insulin
• "Insulin Analogue Therapy for Diabetes Management". CADTH.ca.