JP3506737B2 - Antidiabetic agent - Google Patents
Antidiabetic agentInfo
- Publication number
- JP3506737B2 JP3506737B2 JP22010793A JP22010793A JP3506737B2 JP 3506737 B2 JP3506737 B2 JP 3506737B2 JP 22010793 A JP22010793 A JP 22010793A JP 22010793 A JP22010793 A JP 22010793A JP 3506737 B2 JP3506737 B2 JP 3506737B2
- Authority
- JP
- Japan
- Prior art keywords
- antidiabetic agent
- ari
- diabetes
- acid
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【発明の詳細な説明】
【０００１】
【産業上の利用分野】この発明は、糖尿病の治療や予防
に利用される抗糖尿病剤に関するものである。
【０００２】
【従来の技術】アルドースリダクターゼ（ＥＣ１．１．
１．２１）はニコチンアミドアデニンジヌクレオチドリ
ン酸（ＮＡＤＰＨ）依存性の糖代謝に関与する酵素であ
り、糖尿病の合併症、特に末梢神経障害、網膜症、白内
障、腎障害などの発症に深く係わっている。すなわち、
糖尿病時のグルコース代謝はアルドースリダクターゼ
（以下、ＡＲという）により、グルコースからソルビト
ールへの変換が活発になる。しかも、ソルビトールは細
胞膜透過性が低く細胞内部に貯溜され、***されにくく
なる。そのため、浸透圧亢進、細胞の膨張化などが起こ
り、先に述べた糖尿病の合併症が引き起こされる。
【０００３】そのポリオール代謝経路の異常が糖尿病の
発症に深い関連があることから、最近多くのアルドース
リダクターゼ阻害剤（以下、ＡＲＩという）が開発され
（代謝Ｖｏｌ．２６、Ｎｏ２７、６２９頁、１９８９
年）、一般名Ｅｐａｌｒｅｓｔａｔのみが世界に先駆け
て、日本で医療用医薬品として１９９２年に市販されて
いる。この阻害剤は、現在糖尿病の合併症治療剤に適切
な医薬品がないことも相まって、一般に使用されるよう
になっている。
【０００４】元来、自然界に存在する草木の葉、樹脂な
どに広く存在するフラボノイド類にＡＲＩ作用のあるこ
とは広く知られているが、食品の中にフラボノイド類以
外のＡＲＩが存在するという報告は皆無である。
【０００５】ところで、生理活性物質の宝庫ともいわれ
るローヤルゼリーについては、特開平４−２７９５９７
号公報に開示されているように、多岐にわたる作用が報
告されている。
【０００６】
【発明が解決しようとする課題】ところが、ローヤルゼ
リーによる作用の発揮される物質が特定されているもの
は少ない。ローヤルゼリーの有する抗糖尿病作用につい
ては、ＫｒａｍｅｒらがＪ．Ｉｎｓｅｃｔ Ｐｈｙｓｉ
ｏｌ．，Ｖｏｌ．２３，２９３〜２９５頁、１９７７年
において、インスリン様ペプチドをローヤルゼリー中に
確認したとされている。
【０００７】しかし、その量が微量であることと、ロー
ヤルゼリーが経口投与であることのため、従来いわれて
いる抗糖尿病作用を説明するものとはいえなかった。一
方、臨床的に有効であったという報告は、国内、国外で
なされているが、ローヤルゼリー中のどのような物質が
抗糖尿病作用を発現するのかは解明されていない。
【０００８】この発明は上記のような従来の問題に着目
してなされたものである。その目的とするところは、特
に糖尿病の合併症を効果的に治療したり、予防したりす
ることのできる抗糖尿病剤を提供することにある。
【０００９】
【課題を解決するための手段】上記目的を達成するため
に、請求項１に記載の抗糖尿病剤の発明では、１０−ヒ
ドロキシデセン酸を含有することを特徴とするものであ
る。
【００１０】
【作用】この発明の１０−ヒドロキシデセン酸は、アル
ドースリダクターゼ阻害機能を有している。そのため、
グルコース代謝において、グルコースからソルビトール
への変換が抑制されることから、糖尿病の予防や治療が
効果的に行われる。
【００１１】
【実施例】以下に実施例をあげてこの発明をさらに具体
的に説明する。
（実施例１）この実施例ではＡＲの調製法及び活性測定
法を示す。
【００１２】新鮮な牛水晶体を、１ｍＭメルカプトエタ
ノールを含む９倍量の生理食塩水に加えてホモジネート
し、３０００回転で１０分間の遠心分離操作にて硫安分
画を行い、蒸留水に対して透析を行った。そして、ＤＥ
ＡＥセルロースカラムクロマトグラフィーにより、塩化
ナトリウムのリニアグラジエント溶出を行い、ＡＲ画分
を集めた。また、同様にして、人胎盤由来のＡＲ画分を
集めた。
【００１３】これらの画分を用いて補酵素のＮＡＤＰＨ
を用い、酵素活性を測定し、ＡＲＩの酵素阻害作用を測
定した。
（実施例２）この実施例ではＡＲＩの精製法及びＡＲ阻
害活性について説明する。なお、この精製法や同定法自
体は周知のものである。
【００１４】新鮮な生ローヤルゼリーに等量のエチルア
ルコールを加え、攪拌後上清を分取し、減圧濃縮後、逆
相ＨＰＬＣを用い、アセトニトリルと水の溶出溶媒でＡ
ＲＩ作用の強い画分を分取した。さらに、再クロマトを
実施し、シリカゲルカラムクロマト（クロロホルム：メ
タノール＝４：１）で溶出した。単離したＡＲＩは、Ｎ
ＭＲ、質量分析（ＭＳ）で同定した。同定されたＡＲＩ
は、１０−ヒドロキシデセン酸、１０−ヒドロキシデカ
ン酸及び３，１０−ジヒドロキシデカン酸であった。
【００１５】また、ＡＲＩの阻害試験を行い、前記牛水
晶体由来ＡＲ及び人胎盤由来のＡＲに対する５０％阻害
率のときの試料濃度、すなわちＩＣ50を測定した。な
お、ＡＲ阻害活性は、Biochem. Pharm.,20,p1637〜1648
(1971)及び Anal.Biochem.,84,p361〜369(1978) に準じ
た周知の方法により、吸光度３４０ｎｍの変化率に基づ
いて測定した。その結果を表１に示す。また、対照例と
してフラボノール誘導体であるケルセチンのＩＣ50を示
した。
【００１６】
【表１】
【００１７】表１に示したように、実施例１〜３の３つ
の脂肪酸は、ＩＣ50の値が相当小さく、牛水晶体由来Ａ
Ｒに対するＩＣ50は特に実施例２及び３の脂肪酸が対照
例１のケルセチンとほぼ同等である。また、人胎盤由来
ＡＲに対するＩＣ50は実施例１〜３の脂肪酸がいずれも
ケルセチンのＩＣ50よりも小さい。そのため、これらの
脂肪酸はＡＲＩの酵素阻害効果に優れていることがわか
る。従って、これらの脂肪酸は、糖尿病による末梢神経
障害、網膜症、白内障、腎障害などの合併症を効果的に
治療したり、予防したりすることができる。
【００１８】なお、この発明は上記実施例に限定される
ものではなく、発明の趣旨から逸脱しない範囲で例えば
以下のように構成を変更して具体化してもよい。
（１）１０−ヒドロキシデセン酸、１０−ヒドロキシデ
カン酸及び３，１０−ジヒドロキシデカン酸のうちの２
種以上の成分を組合せて含有するように構成すること。
（２）この発明の抗糖尿病剤を経口摂食組成物として用
いること。
（３）ローヤルゼリー中又は健康食品などの他の食品に
１０−ヒドロキシデセン酸、１０−ヒドロキシデカン酸
又は３，１０−ジヒドロキシデカン酸を配合して抗糖尿
病剤とすること。
【００１９】
【発明の効果】以上詳述したように、この発明の抗糖尿
病剤によれば、特に糖尿病の合併症を効果的に治療した
り、予防したりすることができるという優れた効果を奏
する。Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antidiabetic agent used for treating and preventing diabetes. [0002] Aldose reductase (EC 1.1.
1.21) is an enzyme involved in nicotinamide adenine dinucleotide phosphate (NADPH) -dependent sugar metabolism and is deeply involved in the development of diabetes complications, particularly peripheral neuropathy, retinopathy, cataract, renal disorder, and the like. ing. That is,
In the metabolism of glucose during diabetes, conversion of glucose to sorbitol is activated by aldose reductase (hereinafter, referred to as AR). In addition, sorbitol has a low cell membrane permeability and is stored inside the cells, making it difficult to excrete. As a result, osmotic pressure increases, cell swelling and the like occur, and the above-mentioned complications of diabetes are caused. Since the abnormality of the polyol metabolic pathway is closely related to the onset of diabetes, many aldose reductase inhibitors (hereinafter referred to as ARI) have been developed recently (Metabolism Vol. 26, No. 27, p. 629, 1989).
), Only the generic name Epalrestat was marketed in Japan in 1992 as a prescription drug in Japan, ahead of the rest of the world. This inhibitor has become commonly used, in combination with the lack of suitable pharmaceuticals for the treatment of complications of diabetes at present. Originally, it is widely known that flavonoids widely present in leaves and resins of plants and the like existing in nature have an ARI action. However, there is a report that ARI other than flavonoids is present in foods. There is nothing. [0005] By the way, royal jelly, which is also said to be a treasure trove of physiologically active substances, is disclosed in Japanese Patent Application Laid-Open No. 4-279597.
A wide variety of effects have been reported, as disclosed in US Pat. [0006] However, few substances have been identified which exert the action of royal jelly. Regarding the antidiabetic effect of royal jelly, Kramer et al. Insect Physi
ol. , Vol. 23, 293-295, 1977, allegedly identified an insulin-like peptide in royal jelly. [0007] However, since the amount is very small and royal jelly is administered orally, it cannot be said that it explains the anti-diabetic action conventionally known. On the other hand, although it has been reported in Japan and abroad that it was clinically effective, it has not been clarified which substance in royal jelly exerts an antidiabetic effect. The present invention has been made in view of the above-mentioned conventional problems. It is an object of the present invention to provide an antidiabetic agent capable of effectively treating or preventing diabetes complications. [0009] In order to achieve the above object, the invention of an antidiabetic agent according to claim 1 is characterized by containing 10-hydroxydecenoic acid . The 10-hydroxydecenoic acid of the present invention has an aldose reductase inhibitory function. for that reason,
In glucose metabolism, the conversion of glucose to sorbitol is suppressed, so that the prevention and treatment of diabetes are effectively performed. The present invention will be described more specifically with reference to the following examples. (Example 1) This example shows a method for preparing AR and a method for measuring activity. A fresh bovine lens is added to a 9-fold amount of physiological saline containing 1 mM mercaptoethanol, homogenized, and subjected to centrifugation at 3000 rpm for 10 minutes to perform ammonium sulfate fractionation, and dialyzed against distilled water. Was done. And DE
Linear gradient elution of sodium chloride was performed by AE cellulose column chromatography, and the AR fraction was collected. Similarly, AR fractions derived from human placenta were collected. Using these fractions, the coenzyme NADPH
Was used to measure the enzyme activity, and the enzyme inhibitory action of ARI was measured. (Example 2) In this example, a method for purifying ARI and AR inhibitory activity will be described. The purification method and the identification method are well known. To a fresh raw royal jelly, an equal volume of ethyl alcohol is added. After stirring, the supernatant is separated, concentrated under reduced pressure, and subjected to reverse phase HPLC.
Fractions with strong RI action were collected. Further, rechromatography was performed, and elution was performed with silica gel column chromatography (chloroform: methanol = 4: 1). The isolated ARI is N
It was identified by MR and mass spectrometry (MS). ARI identified
Was 10-hydroxydecenoic acid, 10-hydroxydecanoic acid and 3,10-dihydroxydecanoic acid. In addition, an ARI inhibition test was carried out, and the sample concentration at a 50% inhibition rate against the AR derived from the bovine lens and the AR derived from the human placenta, ie, the IC 50 was measured. The AR inhibitory activity was determined according to Biochem. Pharm., 20, p1637-1648.
(1971) and Anal. Biochem., 84, pp. 361-369 (1978), and the absorbance was measured based on the rate of change at 340 nm. Table 1 shows the results. As a control, the IC 50 of quercetin, which is a flavonol derivative, is shown. [Table 1] As shown in Table 1, the three fatty acids of Examples 1 to 3 have considerably smaller IC 50 values, and the A 50 originated from bovine lens.
The IC 50 for R is particularly similar for the fatty acids of Examples 2 and 3 to quercetin of Control Example 1. Further, IC 50 is less than the IC 50 of either the fatty acid of Examples 1 to 3 quercetin to human placenta-derived AR. Therefore, it is understood that these fatty acids are excellent in the enzyme inhibitory effect of ARI. Therefore, these fatty acids can effectively treat or prevent complications such as peripheral neuropathy, retinopathy, cataract, and renal disorder due to diabetes. The present invention is not limited to the above-described embodiment, but may be embodied by, for example, changing the configuration as follows without departing from the spirit of the invention. (1) Two of 10-hydroxydecenoic acid, 10-hydroxydecanoic acid and 3,10-dihydroxydecanoic acid
To be configured to contain a combination of two or more components. (2) Use of the antidiabetic agent of the present invention as an oral feeding composition. (3) Mixing 10-hydroxydecenoic acid, 10-hydroxydecanoic acid or 3,10-dihydroxydecanoic acid in royal jelly or other foods such as health foods to obtain an antidiabetic agent. As described above in detail, the antidiabetic agent of the present invention has an excellent effect that, in particular, it can effectively treat or prevent diabetes complications. Play.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 野々垣 孝 岐阜市加納桜田町１丁目１番地 アピ 株式会社 内 (56)参考文献 特開 平３−58953（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/201 A61P 3/10 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ) ＭＥＤＬＩＮＥ（ＳＴＮ) ＢＩＯＳＩＳ（ＳＴＮ) ＥＭＢＡＳＥ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Takashi Nonogaki 1-1-1, Kano Sakuradacho, Gifu City Within Api Co., Ltd. (56) References JP-A-3-58953 (JP, A) (58) Fields investigated ( Int.Cl. 7 , DB name) A61K 31/201 A61P 3/10 CA (STN) REGISTRY (STN) MEDLINE (STN) BIOSIS (STN) EMBASE (STN)
Claims (1)
とを特徴とする抗糖尿病剤。(57) [Claim 1] An antidiabetic agent comprising 10-hydroxydecenoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22010793A JP3506737B2 (en) | 1993-09-03 | 1993-09-03 | Antidiabetic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22010793A JP3506737B2 (en) | 1993-09-03 | 1993-09-03 | Antidiabetic agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0769879A JPH0769879A (en) | 1995-03-14 |
| JP3506737B2 true JP3506737B2 (en) | 2004-03-15 |
Family
ID=16746026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22010793A Expired - Fee Related JP3506737B2 (en) | 1993-09-03 | 1993-09-03 | Antidiabetic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3506737B2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10114652A (en) * | 1996-10-15 | 1998-05-06 | Dokutaazu Kosumeteikusu:Kk | Improver for aqueous body fluid and composition for oral administration comprising the same |
| JP4579620B2 (en) * | 2004-08-25 | 2010-11-10 | アピ株式会社 | Estrogen-like agent, method for producing the same, osteoporosis preventive agent and osteoporosis therapeutic agent |
| JP2007091614A (en) * | 2005-09-27 | 2007-04-12 | Noevir Co Ltd | Blood glucose level elevation inhibitor |
| JP2009051732A (en) * | 2005-12-13 | 2009-03-12 | Meiji Seika Kaisha Ltd | Composition having ppar ligand activity |
| JPWO2009014105A1 (en) | 2007-07-20 | 2010-10-07 | 株式会社山田養蜂場本社 | NOVEL CARBOXYLIC ACID AND ANTI-DEPRESSION COMPOSITION CONTAINING THE SAME |
| JP2011037732A (en) * | 2009-08-07 | 2011-02-24 | Chube Univ | Amp kinase activating agent and use thereof |
-
1993
- 1993-09-03 JP JP22010793A patent/JP3506737B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0769879A (en) | 1995-03-14 |
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