JP6241000B2 - Glucose tolerance improving agent - Google Patents
Glucose tolerance improving agent Download PDFInfo
- Publication number
- JP6241000B2 JP6241000B2 JP2013261692A JP2013261692A JP6241000B2 JP 6241000 B2 JP6241000 B2 JP 6241000B2 JP 2013261692 A JP2013261692 A JP 2013261692A JP 2013261692 A JP2013261692 A JP 2013261692A JP 6241000 B2 JP6241000 B2 JP 6241000B2
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- JP
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- Prior art keywords
- glucose tolerance
- mass
- alkylresorcinol
- carbon atoms
- general formula
- Prior art date
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- Fodder In General (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、人又は動物の血糖値上昇の抑制に効果的で、高血糖等の耐糖能異常の予防・治療に有効な耐糖能異常改善剤に関する。耐糖能異常は、空腹時血糖が正常値に比べて高い値を示す現象であり、糖尿病と診断された人や動物のみならず、糖尿病とまでは診断されていない人や動物（糖尿病の予備軍）にも見られる現象である。 The present invention relates to an agent for improving glucose tolerance that is effective in suppressing an increase in blood glucose level in humans or animals and is effective in preventing or treating glucose tolerance abnormalities such as hyperglycemia. Glucose intolerance is a phenomenon in which fasting blood glucose levels are higher than normal, and not only people and animals diagnosed with diabetes but also people and animals that have not been diagnosed with diabetes. ).
近年、食生活の欧米化、慢性的な運動不足等のため、糖尿病やその予備軍である耐糖能異常を示す者が増加している。糖尿病は、しびれ、痛み等の糖尿病性神経障害、白内障、糖尿病性網膜症、動脈硬化症、糖尿病性腎症、糖尿病性壊疽等の合併症を引き起こし、最終的には死に至るケースもみられることから、その予防・治療は極めて重要である。糖尿病（耐糖能異常）を予防又は治療するには、生活習慣の改善が望ましいが、容易に行い得るものではない。また、糖尿病に対する治療としては、インスリン注射や血糖降下剤の経口投与によって血中のインスリン量を調節する方法等があるが、これらの方法には副作用が伴うし、また、食事療法や運動療法では、患者に順守させるのが困難という問題がある。また、糖尿病や耐糖能異常は人に限ったものではなく、近年は動物、特にイヌやネコなどの愛玩動物でも同様な問題が生じている。 In recent years, due to westernization of eating habits, chronic lack of exercise, etc., an increasing number of people show diabetes and abnormal glucose tolerance as a reserve army. Diabetes causes complications such as diabetic neuropathy such as numbness and pain, cataracts, diabetic retinopathy, arteriosclerosis, diabetic nephropathy, diabetic gangrene, and may eventually lead to death. The prevention and treatment is extremely important. In order to prevent or treat diabetes (abnormal glucose tolerance), it is desirable to improve lifestyle habits, but it cannot be easily performed. In addition, as a treatment for diabetes, there are methods of adjusting the amount of insulin in the blood by insulin injection or oral administration of a hypoglycemic agent, etc., but these methods have side effects, and in diet therapy and exercise therapy, There is a problem that it is difficult for patients to comply with. Diabetes and impaired glucose tolerance are not limited to humans. In recent years, similar problems have arisen in animals, particularly pets such as dogs and cats.
このような中で、多彩な作用を有し、長期に服用しても、副作用等のおそれがない天然由来の成分を用いて、糖尿病（耐糖能異常）を予防・治療することが試みられている。例えば特許文献１には、小麦由来のアミラーゼ阻害物質が、血糖値上昇の抑制やインスリン分泌の調節に有効である旨記載されている。また特許文献２には、ペルオキシソーム増殖剤応答性受容体リガンド剤（ＰＰＡＲ）を有効成分として含有し、高脂血症、糖尿病、肥満、高血圧等の予防・改善剤として、イネ科植物の抽出物を有効成分とするＰＰＡＲを有効成分として含有するものが記載されている。 Under such circumstances, attempts have been made to prevent and treat diabetes (abnormal glucose tolerance) using naturally-occurring ingredients that have a variety of actions and do not cause side effects even if taken for a long time. Yes. For example, Patent Document 1 describes that an amylase inhibitor derived from wheat is effective for suppressing an increase in blood glucose level and regulating insulin secretion. Patent Document 2 contains a peroxisome proliferator-responsive receptor ligand agent (PPAR) as an active ingredient, and is an extract of a gramineous plant as a prophylactic / ameliorating agent for hyperlipidemia, diabetes, obesity, hypertension and the like. A substance containing PPAR as an active ingredient is described.
また、合成されたアルキルレゾルシノール及びその誘導体や、小麦、ライ麦等の穀類の種皮やカシューナッツ等のナッツ類の種皮から抽出されたアルキルレゾルシノール含有抽出物が、抗肥満作用、抗糖尿病作用等を有することが知られている。例えば特許文献３には、肥満防止剤として、アルキル基の炭素数が１４〜１６の範囲にある５−アルキルレゾルシノールを有効成分として含有するグリセロリン酸脱水素酵素阻害剤が記載されている。また特許文献４には、特定のコア部分を有するオレフィン置換化合物が、糖尿病の治療に有効である旨記載されており（特許文献４の請求項１２の記載参照）、また、このコア部分の一例としてレゾルシノールが挙げられている（特許文献４の第８頁の記載参照）。また特許文献５には、アディポサイトカイン（脂肪組織由来生理活性物質）の一種であるアディポネクチンの分泌を誘導することが動脈硬化、肥満、糖尿病等の予防・治療に有効であること、及び、特定の植物から抽出された特定成分がアディポネクチンの分泌を誘導することが記載されており、該特定成分として、レゾルシノール誘導体を含有するものが記載されている。 In addition, synthesized alkylresorcinol and derivatives thereof, and alkylresorcinol-containing extracts extracted from the seed coats of cereals such as wheat and rye and nuts such as cashew nuts have anti-obesity action, anti-diabetic action, etc. It has been known. For example, Patent Document 3 describes a glycerophosphate dehydrogenase inhibitor containing, as an active ingredient, a 5-alkylresorcinol having an alkyl group having 14 to 16 carbon atoms as an anti-obesity agent. Patent Document 4 describes that an olefin-substituted compound having a specific core portion is effective for the treatment of diabetes (see the description of claim 12 of Patent Document 4), and an example of this core portion. Resorcinol is mentioned (see the description on page 8 of Patent Document 4). Patent Document 5 discloses that inducing secretion of adiponectin, which is a kind of adipocytokine (adipose tissue-derived physiologically active substance), is effective in preventing and treating arteriosclerosis, obesity, diabetes, and the like. It is described that a specific component extracted from a plant induces secretion of adiponectin, and as the specific component, one containing a resorcinol derivative is described.
特許文献１〜５に記載の技術は、血糖値上昇の抑制に一定の効果はあるものの、耐糖能異常の予防・治療についてはより効果的な剤が望まれている。 Although the techniques described in Patent Documents 1 to 5 have a certain effect in suppressing an increase in blood glucose level, a more effective agent is desired for the prevention and treatment of abnormal glucose tolerance.
本発明の目的は、糖尿病若しくはその予備軍である人又は動物の耐糖能異常を効果的に予防・治療し得る耐糖能異常改善剤を提供することである。 An object of the present invention is to provide an agent for improving glucose tolerance that can effectively prevent or treat diabetes tolerance or abnormal glucose tolerance of a person or animal who is a reserve army thereof.
本発明者等は、鋭意検討した結果、イネ科植物種子のアルコール抽出物の分配クロマトグラフィーのピーク成分に、特定のアルキルレゾルシノールを複数種含む混合物が含有されており、この混合物（後述する特定アルキルレゾルシノール混合物）が耐糖能異常の予防・治療に有効であることを知見した。 As a result of intensive studies, the present inventors have included a mixture containing a plurality of specific alkylresorcinols in the peak component of the partition chromatography of the alcoholic extract of the gramineous plant seed. It was found that resorcinol mixture) is effective for prevention and treatment of impaired glucose tolerance.
本発明は、上記知見に基づいてなされたもので、イネ科植物種子のアルコール抽出物の分配クロマトグラフィーのピーク成分を有効成分として含有する耐糖能異常改善剤及びこれを配合した耐糖能異常改善用飲食品を提供するものである。 The present invention has been made on the basis of the above-mentioned findings, and is a glucose tolerance abnormality improving agent containing as an active ingredient a peak component of partition chromatography of an alcoholic extract of a gramineous plant seed, and a glucose tolerance abnormality improving composition containing the same. It provides food and drinks.
本発明の耐糖能異常改善剤は、糖尿病若しくはその予備軍である人又は動物の耐糖能異常を効果的に予防し、また、これを治療することができる。さらに、本発明の耐糖能異常改善剤の有効成分（アルキルレゾルシノール）は、植物由来、特に食経験が豊富なイネ科植物種子由来のものであるため、安全性が高く、副作用のおそれが少ないばかりでなく、優れた耐糖能異常改善効果を有するので、本発明の耐糖能異常改善剤は、極めて有利である。 The glucose tolerance ameliorating agent of the present invention can effectively prevent and treat diabetes tolerance or abnormal glucose tolerance in people or animals who are reserves thereof. Furthermore, since the active ingredient (alkylresorcinol) of the glucose tolerance ameliorating agent of the present invention is derived from a plant, particularly a gramineous plant seed with abundant dietary experience, it is highly safe and has a low risk of side effects. In addition, since it has an excellent glucose tolerance abnormality improving effect, the glucose tolerance abnormality improving agent of the present invention is extremely advantageous.
本発明の耐糖能異常改善剤は、イネ科植物種子のアルコール抽出物の分配クロマトグラフィーのピーク成分を有効成分として含有する。このピーク成分（本発明の耐糖能異常改善剤の有効成分）には、好ましくは、下記一般式（Ｉ）で表されるアルキルレゾルシノールを複数種含む、特定アルキルレゾルシノール混合物が含有されている。この特定アルキルレゾルシノール混合物は、血糖値の上昇を抑制し、糖尿病を含む耐糖能異常を改善する作用を有する。 The abnormal glucose tolerance improving agent of the present invention contains, as an active ingredient, a peak component of partition chromatography of an alcohol extract of a grass plant seed. This peak component (an active ingredient of the glucose tolerance abnormality improving agent of the present invention) preferably contains a specific alkyl resorcinol mixture containing a plurality of alkyl resorcinols represented by the following general formula (I). This specific alkyl resorcinol mixture has an action of suppressing an increase in blood glucose level and improving abnormal glucose tolerance including diabetes.
アルキルレゾルシノールは、天然の非イソテルぺノイド系フェノール性両親媒性化合物であるレゾルシノール脂質として、種々の植物に含まれていることが知られており、アルキルレゾルシノールの給源としては、イネ科植物以外にも、例えば、ウルシ科、イチョウ科、ヤマモガシ科、ヤブコウジ科、サクラソウ科、ニクズク科、アヤメ科、サトイモ科、キク科のヨモギ、マメ科等が知られている。これらの植物の中でも、イネ科植物は、可食性有効成分としてのアルキルレゾルシノールの研究が進んでいること等から、本発明においては、アルキルレゾルシノールの給源として、イネ科植物を採用している。 Alkylresorcinol is known to be contained in various plants as a resorcinol lipid, which is a natural non-isoterpenoid phenolic amphiphilic compound. In addition, for example, Urushiaceae, Ginkgoaceae, Porcupineaceae, Yabukodiidae, Primulaceae, Stigmaceae, Iridaceae, Araceae, Artemisia, Asteraceae, Legume, and the like are known. Among these plants, since gramineous plants have been studied for alkylresorcinol as an edible active ingredient, in the present invention, gramineous plants are employed as a source of alkylresorcinol.
アルキルレゾルシノールの給源として利用可能なイネ科植物としては、特に制限されないが、例えば、小麦、デュラム小麦、ライ麦、ライ小麦、大麦、オーツ麦、はと麦、トウモロコシ、イネ、ヒエ、アワ、キビ等の穀類が挙げられ、これら１種を単独で又は２種以上を組み合わせて用いることができる。これらの穀類の中でも、高い活性が得られる点から、特に小麦、デュラム小麦等のコムギ属の植物が好ましく、小麦が更に好ましい。イネ科植物種子としては、任意の形態のイネ科植物種子で良く、例えば、イネ科植物種子（好ましくは種子外皮；糟糠類）そのもの；当該イネ科植物種子を切断、粉砕若しくは粉末化したもの；当該イネ科植物種子を乾燥したもの；当該イネ科植物種子を乾燥後粉砕若しくは粉末化したもの等でも良い。イネ科植物種子外皮を含む好適な例としては、ふすま、末粉、籾殻、ぬか等が挙げられる他、外皮を伴った種子も挙げられる。 Examples of grasses that can be used as a source of alkylresorcinol are not particularly limited. For example, wheat, durum wheat, rye, rye wheat, barley, oats, potato, corn, rice, millet, millet, millet, etc. These cereals can be mentioned, and one of these can be used alone or in combination of two or more. Among these cereals, wheat plants such as wheat and durum wheat are particularly preferable, and wheat is more preferable because high activity is obtained. The gramineous plant seed may be any form of gramineous plant seed, for example, gramineous plant seed (preferably seed hull; moss) itself; a product obtained by cutting, crushing or pulverizing the gramineous plant seed; It may be a product obtained by drying the grass plant seed; a product obtained by drying or crushing or powdering the grass seed. Preferable examples including grass seed hulls include bran, powder, rice husk, bran and the like, and seeds with hulls.
イネ科植物種子のアルコールによる抽出方法は特に制限されないが、例えば、上記各種形態のイネ科植物種子をアルコール中に浸漬、攪拌又は還流する方法の他、超臨界流体抽出法等が挙げられる。前者の方法の場合、抽出温度は２〜１００℃が好ましく、抽出時間は３０分〜７２時間が好ましく、アルコール使用量は、イネ科植物種子１００質量部に対し５０〜２０００質量部が好ましい。 The method of extracting grass seeds with alcohol is not particularly limited, and examples thereof include a supercritical fluid extraction method and the like in addition to a method of immersing, stirring, or refluxing various kinds of grass seeds in the above-mentioned various forms. In the former method, the extraction temperature is preferably 2 to 100 ° C., the extraction time is preferably 30 minutes to 72 hours, and the amount of alcohol used is preferably 50 to 2000 parts by mass with respect to 100 parts by mass of the grass seed.
イネ科植物種子の抽出に用いられるアルコールとしては、例えば、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール等の１価の低級アルコール（好ましくは炭素原子数１〜４のもの）、及び１，３−ブチレングリコール、プロピレングリコール、グリセリン等の多価アルコール等の室温（２５℃）で液体であるアルコールが挙げられる。これらのアルコールの中でも、操作性や環境性の点から、エタノールが好ましい。尚、イネ科植物種子の抽出に用いられるアルコールとしては、アルコール以外の水性成分（水、純水、蒸留水、水道水、酸性水、アルカリ水、中性水等）が含まれている含水エタノールを用いることもできる。含水アルコール中のアルコール含有量は、通常７０体積％以上、好ましくは８０体積％以上、より好ましくは９０体積％以上である。 Examples of the alcohol used for the extraction of grass seeds include monovalent lower alcohols (preferably those having 1 to 4 carbon atoms) such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, and 1 , 3-butylene glycol, propylene glycol, polyhydric alcohols such as glycerin, and the like, which are liquids at room temperature (25 ° C.). Among these alcohols, ethanol is preferable from the viewpoint of operability and environmental properties. In addition, as alcohol used for the extraction of gramineous plant seeds, water-containing ethanol containing aqueous components (water, pure water, distilled water, tap water, acidic water, alkaline water, neutral water, etc.) other than alcohol Can also be used. The alcohol content in the hydrous alcohol is usually 70% by volume or more, preferably 80% by volume or more, more preferably 90% by volume or more.
本発明において、イネ科植物種子のアルコール抽出物は、そのまままたは濃縮、乾燥して耐糖能異常改善剤とすることができるが、公知の方法、例えば分配クロマトグラフィーで精製してもよい。イネ科植物種子のアルコール抽出物の精製に用いられる分配クロマトグラフィーは、本発明の耐糖能異常改善剤の有効成分（特定アルキルレゾルシノール混合物）が得られる手法であればその種類は問わないが、移動相として非水系溶媒を用いる順相クロマトグラフィー法が好ましく、オープンカラム法、中圧カラム法、高速液体クロマトグラフィー等の公知の方法を適宜選択することができる。 In the present invention, the alcoholic extract of the grass plant seed can be used as it is or after being concentrated and dried to obtain a glucose tolerance abnormality improving agent, but may be purified by a known method such as partition chromatography. The partition chromatography used for the purification of the alcoholic extract of the grass seeds is not limited as long as it is a technique that can obtain the active ingredient (specific alkylresorcinol mixture) of the glucose tolerance ameliorating agent of the present invention. A normal phase chromatography method using a non-aqueous solvent as a phase is preferable, and a known method such as an open column method, a medium pressure column method, or a high performance liquid chromatography can be appropriately selected.
分配クロマトグラフィーにおける移動相としては、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール等の１価の低級アルコール（好ましくは炭素原子数１〜４のもの）、及び１，３−ブチレングリコール、プロピレングリコール、グリセリン等の多価アルコール等の室温（２５℃）で液体であるアルコール；ジエチルエーテル、プロピルエーテル等のエーテル；酢酸ブチル、酢酸エチル等のエステル；アセトン、エチルメチルケトン等のケトン；ヘキサン；塩化メチレン；アセトニトリル；並びにクロロホルム等が挙げられ、これら溶媒の１種を単独で又は２種以上を組み合わせて用いることができる。複数の溶媒を組み合わせて移動相とする場合、分配クロマトグラフィーの実施中（イネ科植物種子のアルコール抽出物の精製中）において、複数の溶媒の混合比を一定にするイソクラクティックモードでも良く、あるいは該混合比を変化させるグラジエントモードでも良い。 As a mobile phase in partition chromatography, monovalent lower alcohols (preferably having 1 to 4 carbon atoms) such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and 1,3-butylene glycol, Alcohols that are liquid at room temperature (25 ° C.) such as polyhydric alcohols such as propylene glycol and glycerine; ethers such as diethyl ether and propyl ether; esters such as butyl acetate and ethyl acetate; ketones such as acetone and ethyl methyl ketone; hexane Methylene chloride; acetonitrile; and chloroform and the like. One of these solvents can be used alone, or two or more can be used in combination. When a plurality of solvents are combined into a mobile phase, an isocratic mode in which the mixing ratio of the plurality of solvents is constant during partition chromatography (purification of the alcoholic extract of the grass seed) may be used. Alternatively, a gradient mode in which the mixing ratio is changed may be used.
分配クロマトグラフィーにおける担体としては、目的とする有効成分を担持−放出できる担体であればいずれも用いることができるが、一般的にはシリカゲル、ポリアクリルアミドゲル、デキストランゲル等を挙げることができる。 Any carrier can be used as the carrier in the partition chromatography as long as it can carry and release the target active ingredient, and generally includes silica gel, polyacrylamide gel, dextran gel and the like.
イネ科植物種子のアルコール抽出物の分配クロマトグラフィーにおける検出波長は、１７０〜３２０ｎｍであれば良く、好ましくは１９０〜２８０ｎｍである。 The detection wavelength in the partition chromatography of the alcoholic extract of the grass plant seed may be 170 to 320 nm, preferably 190 to 280 nm.
イネ科植物種子（好ましくはコムギ属の植物）のアルコール抽出物（好ましくはエタノール抽出物）の精製に好適な分配クロマトグラフィーの例として、下記分配クロマトグラフィーＡ及びＢが挙げられる。
・分配クロマトグラフィーＡ：担体としてシリカゲル及び移動相としてヘキサン−酢酸エチル混合溶媒を用いた中圧カラム法（中圧クロマトグラフィー）を用い、且つその分配クロマトグラフィーの実施中に、移動相を「ヘキサン−酢酸エチル混合溶媒においてヘキサンの含有割合が相対的に高いもの」から「ヘキサン−酢酸エチル混合溶媒においてヘキサンの含有割合が相対的に低いもの」へと変化させ（即ち、「ヘキサン大−少」へのグラジエントモードで用い）、且つ検出波長２５４ｎｍでのピーク成分を分取する。
・分配クロマトグラフィーＢ：担体としてシリカゲル及び移動相としてメタノールを用いた高速液体クロマトグラフィー（ＨＰＬＣ）を用い、且つ検出波長２１５ｎｍでのピーク成分を分取する。
Examples of partition chromatography suitable for purification of an alcohol extract (preferably an ethanol extract) of a grass seed (preferably a plant of the genus Wheat) include the following partition chromatography A and B.
Partition chromatography A: using a medium pressure column method (medium pressure chromatography) using silica gel as a carrier and a hexane-ethyl acetate mixed solvent as a mobile phase, and during the execution of the partition chromatography, -Changed from "relatively high hexane content in ethyl acetate mixed solvent" to "relatively low hexane content in hexane-ethyl acetate mixed solvent" And a peak component at a detection wavelength of 254 nm is fractionated.
Partition chromatography B: Using high performance liquid chromatography (HPLC) using silica gel as a carrier and methanol as a mobile phase, a peak component at a detection wavelength of 215 nm is fractionated.
本発明の耐糖能異常改善剤における有効成分の含有量、即ち、イネ科植物種子のアルコール抽出物の分配クロマトグラフィーのピーク成分（特定アルキルレゾルシノール混合物）の含有量は、耐糖能異常の予防・治療効果が奏されれば特に限定はされないが、耐糖能異常の予防・治療効果をより確実に奏させるようにする観点から、本発明の耐糖能異常改善剤中、５０質量％以上、好ましくは７０質量％以上、更に好ましくは７５質量％以上とするのが好適である。上記有効成分（特定アルキルレゾルシノール混合物）の含有量は１００質量％、即ち、本発明の耐糖能異常改善剤は上記有効成分（特定アルキルレゾルシノール混合物）のみから構成されていても良い。 The content of the active ingredient in the glucose tolerance ameliorating agent of the present invention, that is, the content of the peak component (specific alkylresorcinol mixture) in the distribution chromatography of the alcoholic extract of the gramineous plant seed is used for the prevention and treatment of abnormal glucose tolerance. The effect is not particularly limited as long as the effect is exerted, but from the viewpoint of ensuring the effect of preventing / treating impaired glucose tolerance more reliably, the agent for improving impaired glucose tolerance of the present invention is 50% by mass or more, preferably 70%. It is suitable that the content is not less than mass%, more preferably not less than 75 mass%. Content of the said active ingredient (specific alkyl resorcinol mixture) is 100 mass%, ie, the glucose tolerance abnormality improving agent of this invention may be comprised only from the said active ingredient (specific alkyl resorcinol mixture).
本発明の耐糖能異常改善剤の有効成分であり、イネ科植物種子のアルコール抽出物の分配クロマトグラフィーのピーク成分に好ましくは含有されている、特定アルキルレゾルシノール混合物について説明すると、特定アルキルレゾルシノール混合物は、上記一般式（Ｉ）で表されるアルキルレゾルシノールを複数種含む。 The specific alkyl resorcinol mixture, which is an active ingredient of the glucose tolerance ameliorating agent of the present invention and is preferably contained in the peak component of the partition chromatography of the alcohol extract of the grass seed, will be described. And a plurality of alkylresorcinols represented by the above general formula (I).
上記一般式（Ｉ）におけるＲ1に関し、炭素原子数１５〜２５の飽和アルキル基としては、代表例として、ｎ−ペンタデシル、ｎ−ヘプタデシル、ｎ−ノナデシル、ｎ−ヘンイコシル、ｎ−トリコシル、ｎ−ペンタコシル、ｎ−ヘプタコシル等の直鎖状のものが挙げられ、これらの他に、分岐状又は環状のものでも良い。これらの中でも、炭素原子数１５〜２３の飽和アルキル基が好ましい。 Regarding R 1 in the above general formula (I), typical examples of the saturated alkyl group having 15 to 25 carbon atoms include n-pentadecyl, n-heptadecyl, n-nonadecyl, n-henicosyl, n-tricosyl, n- Examples include linear ones such as pentacosyl and n-heptacosyl, and besides these, branched or cyclic ones may be used. Among these, a saturated alkyl group having 15 to 23 carbon atoms is preferable.
また、上記一般式（Ｉ）におけるＲ1に関し、炭素原子数１５〜２５の不飽和アルキル基としては、上記の炭素原子数１５〜２５の飽和アルキル基に対応するものが挙げられる。不飽和アルキル基に含まれる不飽和結合の数及び位置に特に制限はない。 Moreover, regarding R 1 in the general formula (I), examples of the unsaturated alkyl group having 15 to 25 carbon atoms include those corresponding to the saturated alkyl group having 15 to 25 carbon atoms. There is no restriction | limiting in particular in the number and position of the unsaturated bond contained in an unsaturated alkyl group.
また、上記一般式（Ｉ）におけるＲ2は水素原子であることが好ましく、また、Ｒ1はＲ2に対してパラ位に結合していることが好ましい。 In the general formula (I), R 2 is preferably a hydrogen atom, and R 1 is preferably bonded to R 2 at the para position.
上記特定アルキルレゾルシノール混合物に含まれ得るアルキルレゾルシノールの具体例としては、以下のものが挙げられる。
１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）
１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）
１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）
１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）
１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）
１，３−ジヒドロキシ−５−ｎ−ペンタコシルベンゼン（Ｃ２５：０）
Specific examples of the alkyl resorcinol that can be contained in the specific alkyl resorcinol mixture include the following.
1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0)
1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0)
1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0)
1,3-dihydroxy-5-n-henicosylbenzene (C21: 0)
1,3-dihydroxy-5-n-tricosylbenzene (C23: 0)
1,3-dihydroxy-5-n-pentacosylbenzene (C25: 0)
上記特定アルキルレゾルシノール混合物の好ましい一例として、下記６種類のアルキルレゾルシノールを含有するものが挙げられる。本発明者らの知見によれば、下記６種類のアルキルレゾルシノールは、血糖値の上昇抑制作用に特に優れ、耐糖能異常の予防・治療に有効である。
１）上記一般式（Ｉ）におけるＲ1が炭素原子数１５の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ１５ともいう）。
２）上記一般式（Ｉ）におけるＲ1が炭素原子数１７の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ１７ともいう）。
３）上記一般式（Ｉ）におけるＲ1が炭素原子数１９の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ１９ともいう）。
４）上記一般式（Ｉ）におけるＲ1が炭素原子数２１の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ２１ともいう）。
５）上記一般式（Ｉ）におけるＲ1が炭素原子数２３の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ２３ともいう）。
６）上記一般式（Ｉ）におけるＲ1が炭素原子数２５の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ２５ともいう）。
A preferable example of the specific alkyl resorcinol mixture is one containing the following six types of alkyl resorcinol. According to the knowledge of the present inventors, the following 6 types of alkylresorcinol are particularly excellent in the action of suppressing the increase in blood glucose level and are effective in the prevention and treatment of impaired glucose tolerance.
1) Alkyl resorcinol (hereinafter, also referred to as AR15) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 15 carbon atoms.
2) Alkyl resorcinol (hereinafter, also referred to as AR17) in which R 1 in the above general formula (I) is a saturated or unsaturated alkyl group having 17 carbon atoms.
3) Alkyl resorcinol (hereinafter, also referred to as AR19) in which R 1 in the above general formula (I) is a saturated or unsaturated alkyl group having 19 carbon atoms.
4) Alkyl resorcinol (hereinafter, also referred to as AR21) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 21 carbon atoms.
5) Alkyl resorcinol (hereinafter, also referred to as AR23) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 23 carbon atoms.
6) Alkyl resorcinol (hereinafter, also referred to as AR25) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 25 carbon atoms.
ＡＲ１５として特に好ましいものは、Ｒ1が炭素原子数１５の飽和アルキル基、Ｒ2が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）が挙げられる。
ＡＲ１７として特に好ましいものは、Ｒ1が炭素原子数１７の飽和アルキル基、Ｒ2が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）が挙げられる。
ＡＲ１９として特に好ましいものは、Ｒ1が炭素原子数１９の飽和アルキル基、Ｒ2が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）が挙げられる。
ＡＲ２１として特に好ましいものは、Ｒ1が炭素原子数２１の飽和アルキル基、Ｒ2が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）が挙げられる。
ＡＲ２３として特に好ましいものは、Ｒ1が炭素原子数２３の飽和アルキル基、Ｒ2が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）が挙げられる。
ＡＲ２５として特に好ましいものは、Ｒ1が炭素原子数２５飽和アルキル基、Ｒ2が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ペンタコシルベンゼン（Ｃ２５：０）が挙げられる。
Particularly preferred as AR15 is one in which R 1 is a saturated alkyl group having 15 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-pentadecylbenzene (C15 : 0).
Particularly preferred as AR17 is one in which R 1 is a saturated alkyl group having 17 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-heptadecylbenzene (C17 : 0).
Particularly preferred as AR19 is one in which R 1 is a saturated alkyl group having 19 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-nonadecylbenzene (C19 : 0).
Particularly preferred as AR21 is one in which R 1 is a saturated alkyl group having 21 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-henecosylbenzene ( C21: 0).
Particularly preferred as AR23 is one in which R 1 is a saturated alkyl group having 23 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-tricosylbenzene (C23 : 0).
Particularly preferred as AR25 is one in which R 1 is a saturated alkyl group having 25 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-pentacosylbenzene (C25 : 0).
ＡＲ１５、ＡＲ１７、ＡＲ１９、ＡＲ２１、ＡＲ２３及びＡＲ２５の含有量は、耐糖能異常を効果的に予防・治療する観点から、それぞれ、下記範囲内にあることが好ましい。
ＡＲ１５の含有量は、上記特定アルキルレゾルシノール混合物中、好ましくは０．１〜１０．０質量％、更に好ましくは０．１〜５．０質量％、特に好ましくは０．５〜１．５質量％である。
ＡＲ１７の含有量は、上記特定アルキルレゾルシノール混合物中、好ましくは１．０〜２０．０質量％、更に好ましくは５．０〜１５．０質量％、特に好ましくは８．０〜１２．０質量％である。
ＡＲ１９の含有量は、上記特定アルキルレゾルシノール混合物中、好ましくは２５．０〜４０．０質量％、更に好ましくは２７．５〜３７．５質量％、特に好ましくは３０．０〜３５．０質量％である。
ＡＲ２１の含有量は、上記特定アルキルレゾルシノール混合物中、好ましくは４０．０〜５５．０質量％、更に好ましくは４２．５〜５２．５質量％、特に好ましくは４５．０〜５０．０質量％である。
ＡＲ２３の含有量は、上記特定アルキルレゾルシノール混合物中、好ましくは１．０〜１５．０質量％、更に好ましくは２．５〜１２．５質量％、特に好ましくは５．０〜１０．０質量％である。
ＡＲ２５の含有量は、上記特定アルキルレゾルシノール混合物中、好ましくは０〜５．０質量％、更に好ましくは０〜２．０質量％、特に好ましくは０〜１．５質量％である。
The contents of AR15, AR17, AR19, AR21, AR23, and AR25 are each preferably within the following ranges from the viewpoint of effectively preventing and treating impaired glucose tolerance.
The content of AR15 is preferably 0.1 to 10.0% by mass, more preferably 0.1 to 5.0% by mass, and particularly preferably 0.5 to 1.5% by mass in the specific alkylresorcinol mixture. It is.
The content of AR17 is preferably 1.0 to 20.0% by mass, more preferably 5.0 to 15.0% by mass, and particularly preferably 8.0 to 12.0% by mass in the specific alkylresorcinol mixture. It is.
The content of AR19 is preferably 25.0 to 40.0% by mass, more preferably 27.5 to 37.5% by mass, and particularly preferably 30.0 to 35.0% by mass in the specific alkylresorcinol mixture. It is.
The content of AR21 is preferably 40.0 to 55.0% by mass, more preferably 42.5 to 52.5% by mass, and particularly preferably 45.0 to 50.0% by mass in the specific alkylresorcinol mixture. It is.
The content of AR23 is preferably 1.0 to 15.0% by mass, more preferably 2.5 to 12.5% by mass, and particularly preferably 5.0 to 10.0% by mass in the specific alkylresorcinol mixture. It is.
The content of AR25 is preferably 0 to 5.0% by mass, more preferably 0 to 2.0% by mass, and particularly preferably 0 to 1.5% by mass in the specific alkylresorcinol mixture.
上記特定アルキルレゾルシノール混合物は、ＡＲ１５、ＡＲ１７、ＡＲ１９、ＡＲ２１、ＡＲ２３及びＡＲ２５以外の他のアルキルレゾルシノールの１種以上を含有していても良い。この他のアルキルレゾルシノールとしては、例えば、上記一般式（Ｉ）におけるＲ1が炭素原子数２７の飽和又は不飽和のアルキル基であるアルキルレゾルシノール（以下、ＡＲ２７ともいう）が挙げられる。ＡＲ２７として特に好ましいものは、Ｒ1が炭素原子数２７の飽和アルキル基、Ｒ2が水素原子であるものであり、具体的には、１，３−ジヒドロキシ−５−ｎ−ヘプタコシルベンゼン（Ｃ２７：０）が挙げられる。 The specific alkyl resorcinol mixture may contain one or more alkyl resorcinols other than AR15, AR17, AR19, AR21, AR23 and AR25. Examples of the other alkylresorcinol include alkylresorcinol (hereinafter, also referred to as AR27) in which R 1 in the general formula (I) is a saturated or unsaturated alkyl group having 27 carbon atoms. Particularly preferred as AR27 is one in which R 1 is a saturated alkyl group having 27 carbon atoms and R 2 is a hydrogen atom. Specifically, 1,3-dihydroxy-5-n-heptacosylbenzene ( C27: 0).
また、上記特定アルキルレゾルシノール混合物は、アルキルレゾルシノール以外の他の成分を含んでいても良く、このアルキルレゾルシノール以外の他の成分の含有量は、上記特定アルキルレゾルシノール混合物中、好ましくは３０質量％以下である。 The specific alkyl resorcinol mixture may contain other components other than the alkyl resorcinol, and the content of other components other than the alkyl resorcinol is preferably 30% by mass or less in the specific alkyl resorcinol mixture. is there.
上記特定アルキルレゾルシノール混合物の好ましい一例として、次の組成を有するものが挙げられる。即ち、ＡＲ１５として１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）を１．２質量％、ＡＲ１７として１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）を１０．９質量％、ＡＲ１９として１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）を３３．９質量％、ＡＲ２１として１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）を４６．４質量％、ＡＲ２３として１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）を７．５質量％、及びＡＲ２５として１，３−ジヒドロキシ−５−ｎ−ペンタコシルベンゼン（Ｃ２５：０）を０．１質量％含有する特定アルキルレゾルシノール混合物である。 A preferable example of the specific alkyl resorcinol mixture is one having the following composition. That is, 1.2% by mass of 1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0) as AR15 and 1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0) as AR17 10.9% by mass, AR19 as 1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0) 33.9% by mass, AR21 as 1,3-dihydroxy-5-n-heneicosylbenzene ( C21: 0) 46.4% by weight, AR23 as 1,3-dihydroxy-5-n-tricosylbenzene (C23: 0) as 7.5% by weight, and AR25 as 1,3-dihydroxy-5-n -A specific alkyl resorcinol mixture containing 0.1% by mass of pentacosylbenzene (C25: 0).
本発明の耐糖能異常改善剤は、イネ科植物種子のアルコール抽出物の分配クロマトグラフィーのピーク成分（上記特定アルキルレゾルシノール混合物）、並びに必要に応じて薬学的又はサプリメント等の保健用食品において許容される種々の担体、賦形剤、その他の添加剤、その他の成分を含有するものである。本発明の耐糖能異常改善剤は、常法により製剤化することができ、その場合、本発明の耐糖能異常改善剤の剤型は、錠剤、散剤、液剤、シロップ剤、顆粒剤、カプセル剤等の経口剤である。また、本発明の耐糖能異常改善剤に含有可能な「その他の成分」としては、その他の薬効作用を有する成分や健康食品素材（例えば血糖値の上昇抑制作用を有する成分や素材）、各種ビタミン類、生薬、ミネラル類等が挙げられる。 The agent for improving impaired glucose tolerance of the present invention is acceptable in the peak component (particular mixture of the above-mentioned specific alkyl resorcinol) of the alcoholic extract of grass plant seeds, and in health foods such as pharmaceuticals or supplements as necessary. Containing various carriers, excipients, other additives, and other components. The glucose tolerance improving agent of the present invention can be formulated by a conventional method. In that case, the dosage form of the glucose tolerance improving agent of the present invention is a tablet, powder, liquid, syrup, granule, capsule. Orally. The “other ingredients” that can be contained in the glucose tolerance ameliorating agent of the present invention include other ingredients having a medicinal effect, health food materials (for example, ingredients and materials having an inhibitory effect on the increase in blood glucose level), various vitamins. , Herbal medicine, minerals and the like.
本発明の耐糖能異常改善剤中の有効成分（特定アルキルレゾルシノール混合物）の含有量は、耐糖能異常改善剤の剤型、投与又は摂取する者の症状や年齢性別等によって適宜変化させることができ、人を対象とする場合、通常、本発明の耐糖能異常改善剤の有効成分の投与量又は摂取量が１人（６０ｋｇ換算で）１日当たり０．５〜５０００ｍｇ、好ましくは１０〜４５００ｍｇ、より好ましくは４２〜４２００ｍｇとなるように含有させることが好適である。また、本発明の耐糖能異常改善剤をイヌやネコ等の愛玩動物に投与又は摂取させる場合には、当該有効成分の１日の投与又は摂取量は、０．０１５〜１５０ｍｇ／体重１ｋｇ、好ましくは０．０５〜１５０ｍｇ／体重１ｋｇ、より好ましくは０．１３〜１３０ｍｇ／体重１ｋｇとなるように含有させることが好適である。 The content of the active ingredient (specific alkyl resorcinol mixture) in the glucose tolerance ameliorating agent of the present invention can be appropriately changed depending on the dosage form of the glucose tolerance ameliorating agent, the symptoms or age and sex of the person to be administered or ingested, etc. When the subject is a human, the dosage or intake of the active ingredient of the glucose tolerance ameliorating agent of the present invention is usually 0.5 to 5000 mg per person (in terms of 60 kg), preferably 10 to 4500 mg per day. Preferably it is contained so as to be 42 to 4200 mg. When the glucose tolerance improving agent of the present invention is administered or ingested to a companion animal such as a dog or cat, the daily administration or intake of the active ingredient is 0.015 to 150 mg / kg of body weight, preferably Is preferably contained in an amount of 0.05 to 150 mg / kg of body weight, more preferably 0.13 to 130 mg / kg of body weight.
本発明の耐糖能異常改善剤は、前述のように医薬又は保健用食品として、人又は動物に直接投与若しくは摂取させても良いが、飲食品又はペットフード等の動物用飼料に添加・配合して摂取させても良い。この場合、耐糖能異常改善剤を添加・配合する飲食品としては特に限定されないが、例えばパン類、ご飯類、麺類、タブレット、キャンディー等の菓子類、清涼飲料、ジュース、栄養ドリンク等の飲料等が挙げられる。また、ペットフードとしてはドライタイプ、セミドライ・セミモイストタイプ、モイストタイプの何れでも良いが、これらに限定されるものではなく、また、耐糖能異常改善剤の飲食品又は動物用飼料への添加・配合方法も、特に制限されるものではなく、飲食品又は動物用飼料の製造前に原料・素材に直接配合しても良く、該製造工程中に添加しても良く、製造された飲食品又は動物用飼料に添加しても良い。また、本発明の耐糖能異常改善剤を飲食品や動物用飼料に配合して摂取させる場合、本発明における特定アルキルレゾルシノール混合物に富む食品素材、例えば小麦ふすまや小麦やライ麦等の全粒粉と組み合わせても良い。このとき、飲食品や動物用飼料中の特定アルキルレゾルシノール混合物の量が前述の摂取量になるようにそれぞれの配合量を調整すれば良い。 As described above, the glucose tolerance ameliorating agent of the present invention may be directly administered or ingested to humans or animals as a pharmaceutical or health food, but is added to and mixed with animal feed such as food and drink or pet food. May be consumed. In this case, the food / beverage products to which the glucose tolerance improving agent is added / blended are not particularly limited. For example, confectionery such as breads, rice, noodles, tablets, and candy, beverages such as soft drinks, juices, and energy drinks Is mentioned. In addition, the pet food may be any of dry type, semi-dry semi-moist type, and moist type, but is not limited to these, and addition of a glucose tolerance improving agent to foods and drinks or animal feeds The blending method is not particularly limited, and may be blended directly into the raw material / material before the production of the food / drink or animal feed, or may be added during the production process. It may be added to animal feed. In addition, when the glucose tolerance ameliorating agent of the present invention is incorporated in food and drink or animal feed, the food material rich in the specific alkylresorcinol mixture in the present invention, for example, wheat bran, wheat, rye, etc. Also good. At this time, what is necessary is just to adjust each compounding quantity so that the quantity of the specific alkyl resorcinol mixture in food-drinks and animal feed may become the above-mentioned intake.
本発明の耐糖能異常改善剤及び飲食品又は動物用飼料は、脂肪や糖類に富み、高カロリーな食事や飼料を摂取していても優れた耐糖能異常改善効果を奏するが、糖尿病の予防・治療のために推奨されている低カロリー食やペットフードと組み合わせても良い。この場合、インスリン注射や血糖降下剤を用いることなく、高い耐糖能異常改善効果を達成することができる。 Glucose tolerance improving agent and food or animal feed of the present invention is rich in fats and sugars, and exhibits excellent glucose tolerance improvement effect even when ingesting a high calorie meal or feed, It may be combined with a low-calorie diet or pet food recommended for treatment. In this case, a high glucose tolerance improvement effect can be achieved without using insulin injection or a hypoglycemic agent.
以下、実施例及び試験例を挙げて、本発明を更に詳細に説明するが、本発明はこれらの実施例及び試験例により制限されるものではない。 EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated further in detail, this invention is not restrict | limited by these Examples and a test example.
〔実施例〕
下記＜抽出精製法＞により、小麦ふすま（イネ科植物種子）から特定アルキルレゾルシノール混合物を得、これを耐糖能異常改善剤とした。小麦ふすまから得られた特定アルキルレゾルシノール混合物（実施例の耐糖能異常改善剤）の組成は次の通り。
・１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）１．２質量％。
・１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）１０．９質量％。
・１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）３３．９質量％。
・１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）４６．４質量％。
・１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）７．５質量％。
・１，３−ジヒドロキシ−５−ｎ−ペンタコシルベンゼン（Ｃ２５：０）０．１質量％。
〔Example〕
A specific alkylresorcinol mixture was obtained from wheat bran (Gramineae seed) by the following <Extraction and purification method>, and this was used as a glucose tolerance abnormality improving agent. The composition of the specific alkyl resorcinol mixture obtained from wheat bran (glucose tolerance abnormality improving agent in Examples) is as follows.
-1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0) 1.2 mass%.
-1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0) 10.9 mass%.
-1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0) 33.9 mass%.
-1,3-dihydroxy-5-n-henicosylbenzene (C21: 0) 46.4 mass%.
-7.5 mass% of 1, 3- dihydroxy-5-n-tricosyl benzene (C23: 0).
-1,3-dihydroxy-5-n-pentacosylbenzene (C25: 0) 0.1 mass%.
＜抽出精製法＞
小麦ふすまに５倍量のエタノールを添加して、６００ｒｐｍ、室温の条件で、１６時間撹拌抽出した。抽出物を濾過して不要物を除きエタノール抽出液を回収した後、エタノールを留去し、小麦ふすま（イネ科植物種子）のエタノール抽出物を得た。次いで、このエタノール抽出物を中圧クロマトグラフィーによって精製した。中圧クロマトグラフィー条件は下記の通りである。溶出開始後３１〜３６分に出現するピーク成分を回収して、溶媒留去し、目的とする特定アルキルレゾルシノール混合物を得た。
（中圧クロマトグラフィーの条件）
・カラム：シリカゲル（インジェクトカラム３Ｌ、ハイフラッシュカラム５Ｌ、６０Å、４０μｍ、山善株式会社製）
・移動相：ヘキサン／酢酸エチル混合溶媒（体積比）＝９０／１０にて９分、８０／２０にて１５分、６０／４０にて１６分
・検出波長：２５４ｎｍ
<Extraction purification method>
Five times the amount of ethanol was added to wheat bran, and the mixture was extracted with stirring at 600 rpm and room temperature for 16 hours. The extract was filtered to remove unnecessary substances and an ethanol extract was collected, and then the ethanol was distilled off to obtain an ethanol extract of wheat bran (Poaceae seed). The ethanol extract was then purified by medium pressure chromatography. Medium pressure chromatography conditions are as follows. The peak component appearing 31 to 36 minutes after the start of elution was collected, and the solvent was distilled off to obtain the desired specific alkylresorcinol mixture.
(Medium pressure chromatography conditions)
Column: silica gel (injection column 3 L,
・ Mobile phase: Hexane / ethyl acetate mixed solvent (volume ratio) = 9/10 at 90/10, 15 minutes at 80/20, 16 minutes at 60/40 ・ Detection wavelength: 254 nm
尚、上記＜抽出精製法＞におけるエタノール抽出物の精製は、中圧クロマトグラフィーに代えて、ＨＰＬＣによって行うこともできる。その場合、エタノール抽出物にメタノールを添加して該エタノール抽出物の濃度が２００ｕｇ／ｍＬのメタノール添加液を調製し、該メタノール添加液を、孔径０．４５μｍのフィルターを通過させ、その通過分を、ＨＰＬＣの試料とする。ＨＰＬＣの条件は下記の通り。
（ＨＰＬＣの条件）
・カラム：シリカゲル（ＯＤＳ−８０Ａ、５μｍ、４．６×２５０ｍｍ、ジーエルサイエンス株式会社製）
・ガードカラム：ＯＤＳ−８０Ａ、５μｍ、４．６×５０ｍｍ、
・カラム温度：３０℃
・移動相：メタノール１００％
・検出波長：２１５ｎｍ
The purification of the ethanol extract in <Extraction and purification method> can also be performed by HPLC instead of medium pressure chromatography. In that case, methanol is added to the ethanol extract to prepare a methanol addition solution having a concentration of 200 ug / mL, and the methanol addition solution is passed through a filter having a pore size of 0.45 μm. , HPLC sample. HPLC conditions are as follows.
(HPLC conditions)
Column: silica gel (ODS-80A, 5 μm, 4.6 × 250 mm, manufactured by GL Sciences Inc.)
Guard column: ODS-80A, 5 μm, 4.6 × 50 mm,
-Column temperature: 30 ° C
-Mobile phase: 100% methanol
・ Detection wavelength: 215 nm
〔試験例１〕
実施例の耐糖能異常改善剤について、下記試験により、高脂肪高ショ糖食負荷マウスの耐糖能への影響を調べた。その結果を図１〜図３に示す。図１〜図３中、ＮＤは、普通食を摂餌したマウス群、ＨＦＨＳＤは、高脂肪高ショ糖食を摂餌したマウス群、ＨＦＨＳＤＡＲは、実施例の耐糖能異常改善剤（特定アルキルレゾルシノール混合物）が添加された高脂肪高ショ糖食を摂餌したマウス群である。また、図１〜図３において、＊（アスタリスクが１つ）は、ＮＤとＨＦＨＳＤ又はＨＦＨＳＤＡＲとの間における有意差が、有意水準ｐ＜０．０１で認められたことを示す。
[Test Example 1]
About the glucose tolerance abnormality improving agent of an Example, the influence on the glucose tolerance of a high fat high sucrose diet load mouse | mouth was investigated by the following test. The results are shown in FIGS. 1 to 3, ND is a group of mice fed a normal diet, HFHSD is a group of mice fed a high-fat high sucrose diet, and HFHSDAR is a glucose tolerance abnormality improving agent (specific alkylresorcinol in Examples). It is a group of mice fed a high fat high sucrose diet to which a mixture) was added. 1 to 3, * (one asterisk) indicates that a significant difference between ND and HFHSD or HFHSDAR was recognized at a significance level p <0.01.
＜血糖値低下作用確認試験（自由摂取による実施）＞
普通食（ＮＤ）として、ＡＩＮ９３Ｍ（ミルクカゼイン使用）（オリエンタル酵母工業株式会社製）、高脂肪高ショ糖食（ＨＦＨＳＤ）として、Ｆ２ＨＦＨＳＤ（オリエンタル酵母工業株式会社製）を用意し、また別途、ＨＦＨＳＤに実施例の耐糖能異常改善剤（特定アルキルレゾルシノール混合物）を０．５質量％添加したもの（ＨＦＨＳＤＡＲ）を用意した。C57BL/6JJmsSlc系統のマウス（４週齢の雄性、日本エスエルシー株式会社）を明期１２時間、暗期１２時間の明暗サイクル下（0:00点灯、12:00消灯）で２週間馴化飼育した後、これらのマウスを、ＮＤ摂餌群（９ケージ）と、ＨＦＨＳＤ摂餌群（９ケージ）と、ＨＦＨＳＤＡＲ摂餌群（９ケージ）との３群に分け、馴化期間と同じ明暗サイクル下で６週間自由摂食させた。その自由摂食期間中、随時、マウス尾部より微量採血を行い、血糖値測定器（アキュチェックコンフォート：ロシュ・ダイアグノスティックス株式会社）を用いて血糖値を測定し、それらの平均値を算出した。その結果を図１に示す。
<Confirmation of blood glucose level lowering effect (implemented by free intake)>
As a normal diet (ND), AIN93M (using milk casein) (made by Oriental Yeast Co., Ltd.) and F2HFHSD (made by Oriental Yeast Industry Co., Ltd.) as a high fat high sucrose diet (HFHSD) are prepared. To which 0.5% by mass of the glucose tolerance abnormality improving agent (specific alkyl resorcinol mixture) of Example was added was prepared (HFHSDAR). C57BL / 6JJmsSlc strain mice (4-week-old male, Japan SLC Co., Ltd.) were bred for 2 weeks under a light-dark cycle of 12 hours light and 12 hours dark (lights on at 0:00, lights off at 12:00). Later, these mice were divided into 3 groups: ND feeding group (9 cages), HFHSD feeding group (9 cages), and HFHSDAR feeding group (9 cages), and under the same light-dark cycle as the habituation period. Ad libitum for 6 weeks. During the free feeding period, a small amount of blood is collected from the tail of the mouse at any time, and the blood glucose level is measured using a blood glucose level measuring instrument (Accucheck Comfort: Roche Diagnostics Inc.), and the average value is calculated. did. The result is shown in FIG.
図１から明らかなように、高脂肪高ショ糖食（ＨＦＨＳＤ）摂餌群は、普通食（ＮＤ）摂餌群に比べて、空腹時の血糖値が有意に増加しており、このことから、ＨＦＨＳＤの摂取が高血糖を引き起こす原因となることが明らかである。しかし、このような高血糖の原因となり得るＨＦＨＳＤに実施例の耐糖能異常改善剤を所定量添加した、ＨＦＨＳＤＡＲを摂餌した群は、ＨＦＨＳＤ摂餌群に比べて空腹時の血糖値が低くなっており、これにより、実施例の耐糖能異常改善剤による耐糖能異常の予防・治療効果が確認された。 As is clear from FIG. 1, the high-fat high-sucrose diet (HFHSD) feeding group has a significantly increased fasting blood glucose level compared to the normal diet (ND) feeding group. It is clear that intake of HFHSD causes hyperglycemia. However, the fasting blood glucose level of the group fed with HFHSDAR, in which a predetermined amount of the glucose tolerance improving agent of the example was added to HFHSD, which can cause such hyperglycemia, was lower than that of the HFHSD fed group. As a result, the effect of preventing or treating glucose tolerance by the glucose tolerance ameliorating agent of Examples was confirmed.
＜糖負荷試験＞
上記＜血糖値低下作用確認試験＞の実施後、マウスを４時間絶食させた後に、１ｇ／体重１ｋｇのグルコース溶液をマウスの腹腔内に投与し、糖負荷直前（０分）、糖負荷後１５分後、３０分後、６０分後、９０分後、１２０分後それぞれにおいて、上記＜血糖値低下作用確認試験＞と同様の方法により血糖値を測定した。AUC0-120min値は、Woleverらの方法（Wolever TM, Jenkins DJ, Jenkins AL, Josse RG: The glycemic index: methodology and clinical implications. Am J Clin Nutr 1991;54:846-854）に従って算出した。それらの結果を図２及び図３に示す。
<Glucose tolerance test>
After the above <blood glucose level lowering action confirmation test> was performed, the mice were fasted for 4 hours, and then a glucose solution of 1 g / kg body weight was administered into the abdominal cavity of the mice. After 30 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes, blood glucose levels were measured in the same manner as in the above <Blood glucose level lowering confirmation test>. The AUC 0-120 min value was calculated according to the method of Wolever et al. (Wolever ™, Jenkins DJ, Jenkins AL, Josse RG: The glycemic index: methodology and clinical implications. Am J Clin Nutr 1991; 54: 846-854). The results are shown in FIGS.
図２及び図３から明らかなように、高脂肪高ショ糖食（ＨＦＨＳＤ）摂餌群は、普通食（ＮＤ）摂餌群に比べて、血中血糖値（図２参照）及びAUC0-120min（図３参照）が有意に大きくなっており、このことから、ＨＦＨＳＤの摂取が高血糖を引き起こす原因となることが明らかである。しかし、このような高血糖の原因となり得るＨＦＨＳＤに実施例の耐糖能異常改善剤を所定量添加した、ＨＦＨＳＤＡＲを摂餌した群は、ＨＦＨＳＤ摂餌群に比べて血中血糖値及びAUC0-120minが小さくなっており、これにより、実施例の耐糖能異常改善剤による耐糖能異常の予防・治療効果が確認された。 As is clear from FIG. 2 and FIG. 3, the high-fat high-sucrose diet (HFHSD) feeding group has a blood glucose level (see FIG. 2) and AUC 0− 120 min (see FIG. 3) is significantly large, and it is clear from this that the intake of HFHSD causes hyperglycemia. However, the group fed with HFHSDAR in which a predetermined amount of the glucose tolerance ameliorating agent of Examples was added to HFHSD, which can cause such hyperglycemia, had a blood glucose level and AUC 0- 120 min was reduced, and this confirmed the effect of preventing and treating glucose tolerance abnormalities by the glucose tolerance abnormality improving agents of the Examples.
〔試験例２〕
実施例の耐糖能異常改善剤の投与方法について、下記試験により、高脂肪高ショ糖食負荷マウスの耐糖能への影響を調べた。その結果を図４〜図８に示す。図４〜図８中、ＨＦＨＳＤは、高脂肪高ショ糖食の摂餌期間中にブランクを強制的に経口投与したマウス群、ＨＦＨＳＤ＋ＡＲｓは、高脂肪高ショ糖食の摂餌期間中に実施例の耐糖能異常改善剤（特定アルキルレゾルシノール混合物）を強制的に経口投与したマウス群である。また、図６〜図８において、＊（アスタリスクが１つ）は、ＨＦＨＳＤとＨＦＨＳＤ＋ＡＲｓとの間における有意差が、有意水準ｐ＜０．０１で認められたことを示す。
[Test Example 2]
About the administration method of the glucose tolerance abnormality improving agent of an Example, the influence on the glucose tolerance of a high fat high sucrose diet load mouse | mouth was investigated by the following test. The results are shown in FIGS. 4 to 8, HFHSD is a group of mice forcibly orally administered blank during the feeding period of a high fat high sucrose diet, and HFHSD + ARs is an example during the feeding period of a high fat high sucrose diet. This is a group of mice forcibly orally administered with an agent for improving glucose tolerance abnormality (specific alkyl resorcinol mixture). 6 to 8, * (one asterisk) indicates that a significant difference between HFHSD and HFHSD + ARs was recognized at a significance level p <0.01.
＜血糖値低下作用確認試験（強制経口投与による実施）＞
実施例の耐糖能異常改善剤（特定アルキルレゾルシノール混合物）にオリーブオイルとエタノールを加えて懸濁させた餌（耐糖能異常改善剤懸濁液）と、高脂肪高ショ糖食（ＨＦＨＳＤ）とを用意した。またブランクとして、オリーブオイルとエタノールとの懸濁液も用意した。C57BL/6J HamSlc ob/obのマウス（５週齢の雄性、日本エスエルシー株式会社）を明期１２時間、暗期１２時間の明暗サイクル下（0:00点灯、12:00消灯）で３週間馴化飼育した。３週間の馴化期間後、これらのマウスを、暗期の終期（ZT=23、点灯の１時間前）にブランクを投与する群と、暗期の初期（ZT=13、消灯から１時間経過後）にブランクを投与する群と、暗期の終期（ZT=23）に耐糖能異常改善剤懸濁液を投与する群と、暗期の初期（ZT=13）に耐糖能異常改善剤懸濁液を投与する群との４群に分けて、馴化期間と同じ明暗サイクル下で試験を実施した。マウスの活動期は、通常、暗期である。試験期間中、ブランク又は耐糖能異常改善剤懸濁液のマウスへの投与は、強制的な経口投与によって行い、また、４群の何れに対しても、４日間連続投与後、２日間投与を中止し、その後５日間連続投与した。耐糖能異常改善剤懸濁液の投与量は、アルキルレゾルシノールとして０．０２５ｇ／匹とした。３週間の馴化期間と試験期間とを通じて、マウスに対し高脂肪高ショ糖食（ＨＦＨＳＤ）の自由摂取を継続した。その自由摂取期間中、前記＜血糖値低下作用確認試験（自由摂取による実施）＞と同様の方法でマウスの血糖値を随時測定し、それらの平均値を算出した。その際、ブランクを投与したマウスの血糖値を１００％とし、それに対する耐糖能異常改善剤懸濁液を投与した群の血糖値の比率を図４〜図７に示した。図４及び図５は何れも、２日間の非投与期間前の４日間の連続投与期間（前期試験期間）後の測定結果を示すものであり、図４は、投与を暗期の終期に実施した場合、図５は、投与を暗期の初期に実施した場合である。また、図６及び図７は何れも、５日間の連続投与期間（後期試験期間）後、即ち合計９日間の投与期間経過後の測定結果を示すものであり、図６は、投与を暗期の終期に実施した場合、図７は、投与を暗期の初期に実施した場合である。
<Glucose level lowering confirmation test (implemented by gavage)>
A diet (glucose tolerance improving agent suspension) suspended by adding olive oil and ethanol to the glucose tolerance improving agent (specific alkylresorcinol mixture) of Example, and a high fat high sucrose diet (HFHSD) Prepared. As a blank, a suspension of olive oil and ethanol was also prepared. C57BL / 6J HamSlc ob / ob mice (5-week-old male, Japan SLC Co., Ltd.) under a light / dark cycle of 12 hours light and 12 hours dark (lights on at 0:00, lights off at 12:00) for 3 weeks Acclimatized. After a 3-week acclimatization period, these mice were given a blank group at the end of the dark period (ZT = 23, 1 hour before lighting), and the initial dark period (ZT = 13, 1 hour after extinction). ) In the blank group, the group in which the glucose tolerance improving agent suspension is administered at the end of the dark period (ZT = 23), and the glucose tolerance improving agent suspension in the early stage of the dark period (ZT = 13) The test was carried out under the same light-dark cycle as the acclimatization period, divided into 4 groups with the liquid administration group. The active period of the mouse is usually the dark period. During the test period, administration of a blank or a glucose tolerance improving agent suspension to mice is performed by forced oral administration, and for all four groups, administration is continued for 4 days followed by 2 days. The administration was discontinued, and administration was continued for 5 days thereafter. The dosage of the glucose tolerance improving agent suspension was 0.025 g / animal as alkylresorcinol. Mice were kept on a high-fat high-sucrose diet (HFHSD) ad libitum throughout the 3-week habituation period and test period. During the free intake period, the blood glucose levels of the mice were measured at any time in the same manner as in the above <Blood glucose level lowering action confirmation test (execution by free intake)>, and the average value thereof was calculated. At that time, the blood glucose level of the mouse administered with the blank was taken as 100%, and the ratio of the blood glucose level of the group administered with the glucose tolerance improving agent suspension was shown in FIGS. 4 and 5 both show the measurement results after the continuous administration period (preliminary test period) for 4 days before the non-administration period for 2 days. FIG. 4 shows the administration at the end of the dark period. In this case, FIG. 5 shows the case where the administration was performed at the beginning of the dark period. 6 and 7 both show the measurement results after a continuous administration period of 5 days (late test period), that is, after the administration period of 9 days in total, and FIG. FIG. 7 shows the case where the administration was performed at the beginning of the dark period.
ＨＦＨＳＤの摂取が高血糖を引き起こす原因となることは、試験例１の結果から明らかであり、試験例２のマウスは、高血糖の原因となりうる食生活を送っていたと言える。このようなマウスに対し、前期試験期間において活動期（暗期）の終期（ZT=23）に耐糖能異常改善剤を強制的に経口投与すると、空腹時の血糖が低くなる（図４参照）が、前期試験期間において活動期（暗期）の初期（ZT=13）に同様に投与しても、空腹時血糖の低下は認められなかった（図５参照）。しかし、全試験期間の終了後においては、活動期の終期（ZT=23）に耐糖能異常改善剤を投与した場合（図６参照）は勿論のこと、活動期の初期（ZT=13）に耐糖能異常改善剤を投与した場合（図７参照）も、空腹時血糖が有意に低くなった。 It is clear from the results of Test Example 1 that the intake of HFHSD causes hyperglycemia, and it can be said that the mouse of Test Example 2 was eating a diet that could cause hyperglycemia. When such a mouse is forcibly orally administered with a glucose tolerance ameliorating agent at the end of the active phase (dark phase) (ZT = 23) in the previous test period, the fasting blood glucose level is lowered (see FIG. 4). However, no decrease in fasting blood glucose was observed even when administered in the same way at the beginning of the active period (dark period) (ZT = 13) in the first test period (see FIG. 5). However, after the end of the whole test period, not only when the glucose tolerance improving agent is administered at the end of the active period (ZT = 23) (see FIG. 6), but also at the initial stage of the active period (ZT = 13). Also when the glucose tolerance improving agent was administered (see FIG. 7), fasting blood glucose was significantly reduced.
このように、実施例の耐糖能異常改善剤の強制経口投与を行うと、耐糖能異常の予防・治療効果が得られる。また、耐糖能異常改善剤の投与を活動期の初期に実施した場合、前期試験期間は目立った予防・治療効果が見られず（図５参照）、後期試験期間になって予防・治療効果が見られるようになったのに対し（図７参照）、耐糖能異常改善剤の投与を活動期の終期に実施した場合、前期試験期間から予防・治療効果が認められ（図４参照）、その予防・治療効果は後期試験期間も維持された（図６参照）。以上のことから、実施例の耐糖能異常改善剤の経口投与あるいは経口摂取は、耐糖能異常の予防・治療に有効であり、また、その投与あるいは摂取は、前期試験〜後期試験までのようにある程度の期間継続すれば投与・摂取時期に関係なく所望の効果が達成されるが、活動期（マウスであれば暗期）の終期（後半）に実施するのがより効果的である。 As described above, when the glucose tolerance ameliorating agent according to the examples is forcibly administered orally, an effect of preventing or treating glucose tolerance can be obtained. In addition, when the glucose tolerance ameliorating agent is administered at the beginning of the active period, no prominent preventive / therapeutic effect is seen in the first period (see Fig. 5), and the preventive / therapeutic effect is observed in the second period. In contrast, when the administration of the glucose tolerance ameliorating agent was carried out at the end of the active period, a prophylactic / therapeutic effect was observed from the first trial period (see FIG. 4). The preventive / therapeutic effect was maintained during the late test period (see FIG. 6). Based on the above, oral administration or ingestion of the glucose tolerance ameliorating agent of the examples is effective for the prevention and treatment of glucose tolerance abnormality, and the administration or ingestion is as from the first test to the second test. If it is continued for a certain period, the desired effect is achieved regardless of the administration / intake period, but it is more effective to carry out at the end (second half) of the active period (the dark period in the case of mice).
＜脂肪肝改善効果確認試験＞
上記＜血糖値低下作用確認試験（強制経口投与による実施）＞の実施後、マウスを解剖して肝臓中の中性脂肪量を測定した。その結果、活動期（暗期）の初期（ZT=13）に実施例の耐糖能異常改善剤を投与したマウスにおいては、肝臓中の中性脂肪量の減少はやや認められたのに対し、活動期（暗期）の終期（ZT=23）に実施例の耐糖能異常改善剤を投与したマウスは、肝臓中の中性脂肪が有意に減少した（図８参照）。以上のことから、本発明の耐糖能異常改善剤の経口投与あるいは経口摂取は、脂肪肝の予防・治療にも有効であり、また、その投与あるいは摂取は、前期試験〜後期試験までのようにある程度の期間継続すれば投与・摂取時期に関係なく所望の効果が達成されるが、活動期（マウスであれば暗期）の終期（後半）に実施するのがより効果的である。
<Fatty liver improvement effect confirmation test>
After performing the above <blood glucose level lowering action confirmation test (performed by forced oral administration)>, mice were dissected to measure the amount of neutral fat in the liver. As a result, in the mice administered with the glucose tolerance improving agent of the example in the early stage of the active period (dark period) (ZT = 13), a decrease in the amount of neutral fat in the liver was slightly observed, In the mice to which the glucose tolerance improving agent of the example was administered at the end of the active period (dark period) (ZT = 23), the neutral fat in the liver was significantly reduced (see FIG. 8). From the above, oral administration or ingestion of the glucose tolerance ameliorating agent of the present invention is also effective for the prevention and treatment of fatty liver, and the administration or ingestion is as in the first to second tests. If it is continued for a certain period, the desired effect is achieved regardless of the administration / intake period, but it is more effective to carry out at the end (second half) of the active period (the dark period in the case of mice).
Claims (6)
A food or drink for improving glucose tolerance abnormality or a feed for animals, comprising the glucose tolerance improving agent according to any one of claims 1 to 5.
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