JP5869882B2 - Insulin resistance prevention and / or improvement agent - Google Patents
Insulin resistance prevention and / or improvement agent Download PDFInfo
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- JP5869882B2 JP5869882B2 JP2011525308A JP2011525308A JP5869882B2 JP 5869882 B2 JP5869882 B2 JP 5869882B2 JP 2011525308 A JP2011525308 A JP 2011525308A JP 2011525308 A JP2011525308 A JP 2011525308A JP 5869882 B2 JP5869882 B2 JP 5869882B2
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- insulin resistance
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- trehalose
- mice
- fat
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Classifications
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Description
本発明は、ヒトを含む哺乳動物において、正常な状態と比べ、インスリンの感受性が低下し、より多くのインスリンが必要とされる状態(=インスリン抵抗性)となるのを予防及び/又は改善するための薬剤に関するものである。より詳細には、本発明は、α,α−トレハロースを有効成分として含んでなるインスリン抵抗性の予防及び/又は改善剤、とりわけ、高脂肪食品/飼料によりもたらされるインスリン抵抗性を予防及び/又は改善するための、α,α−トレハロースを有効成分として含んでなるインスリン抵抗性の予防及び/又は改善剤に関するものである。 The present invention prevents and / or improves that mammals including humans are less sensitive to insulin than normal, and require more insulin (= insulin resistance). For drugs. More specifically, the present invention provides an agent for preventing and / or improving insulin resistance comprising α, α-trehalose as an active ingredient, in particular, preventing and / or insulin resistance caused by high fat food / feed. The present invention relates to an agent for preventing and / or improving insulin resistance comprising α, α-trehalose as an active ingredient for improvement.
インスリン抵抗性という概念は、1936年、エイチ・ピー・ヒムスワース(HP.Himsworth)が提唱したもので、同氏によれば、インスリン抵抗性とは、「血中にインスリンが存在していても、標的組織である肝、筋肉、脂肪組織などにおいて十分な作用が発現できない状態」と定義されている。インスリンは、骨格筋や脂肪、肝臓で血液からの糖の吸収を促し、エネルギーを作ったり蓄えたりする働きをもつホルモンであるが、インスリン抵抗性が惹起されると、インスリンが十分存在しているにもかかわらず、その作用が鈍くなり、その結果、血糖値が下がりにくくなり、血糖値を正常に保つためにより多くのインスリンが必要となる。 The concept of insulin resistance was advocated by HP Himsworth in 1936 and, according to him, said that insulin resistance is the “target even if insulin is present in the blood. It is defined as “a state in which sufficient action cannot be expressed in the liver, muscle, adipose tissue, etc.”. Insulin is a hormone that stimulates the absorption of sugar from blood by skeletal muscle, fat, and liver, and creates and stores energy. However, when insulin resistance is induced, there is enough insulin. Nevertheless, the action becomes dull, and as a result, the blood sugar level is less likely to fall, and more insulin is needed to keep the blood sugar level normal.
インスリン抵抗性を惹起する最も重要な環境因子は脂肪摂取量であると言われる中、近年、食生活の欧米化に伴う変化(高脂肪食化)や交通手段の発達に伴う運動不足などにより過栄養状態となり、この状態が肥満をきたし、インスリン抵抗性を惹起している患者が急増している(『インスリン抵抗性』、松澤祐次等編集、株式会社医学書院発行、第1版第2刷、135〜150頁、2008年参照)。 It is said that fat intake is the most important environmental factor that induces insulin resistance. In recent years, it has been excessive due to changes in dietary habits due to westernization (high fat diet) and lack of exercise associated with the development of transportation methods. The number of patients who are in a nutritional state and suffer from obesity and causing insulin resistance is rapidly increasing ("Insulin Resistance", edited by Yuji Matsuzawa, etc., published by Medical School, 1st edition, 2nd edition, 135-150, 2008).
インスリン抵抗性の発現は、生体内の脂肪組織における脂肪細胞の肥大化と密接に関連している。脂肪細胞は、褐色脂肪細胞と白色脂肪細胞とに分類され、その内、後者の白色脂肪細胞は、下記メカニズムによりインスリン抵抗性を惹起すると言われている。すなわち、白色脂肪細胞は、過栄養や運動不足により中性脂肪の蓄積が進むと肥大化し、アディポネクチン(糖の取り込み、脂肪酸の燃焼亢進作用を有するホルモン)の産生量が低下し、インスリン受容体の機能を阻害するTNF−α、遊離脂肪酸(FFA)、及びレジスチンなどの分泌が増加し、さらに、白色脂肪細胞は、中性脂肪蓄積の亢進に伴って肥大化し、インスリン抵抗性が引き起こされる(『ニュー・フード・インダストリー(New Food Industry)』、第48巻、第11号、1〜14頁、2006年参照)。また、前記刊行物には、インスリン抵抗性と、メタボリックシンドローム、癌、睡眠時無呼吸症候群、糖尿病、多のう胞性卵巣症候群、アルツハイマーなどの種々の疾患の発症との関連性が述べられている。 The development of insulin resistance is closely related to adipocyte hypertrophy in adipose tissue in vivo. Adipocytes are classified into brown fat cells and white fat cells, and the latter white fat cells are said to cause insulin resistance by the following mechanism. In other words, white adipocytes become hypertrophic as neutral fat accumulates due to overnutrition and lack of exercise, resulting in a decrease in the production of adiponectin (a hormone that has a sugar uptake and fatty acid combustion enhancing action) Secretion of TNF-α, free fatty acid (FFA), resistin, and the like, which inhibit function, increases, and white adipocytes become hypertrophic with increased triglyceride accumulation, causing insulin resistance (“ New Food Industry, Vol. 48, No. 11, pp. 1-14, 2006). The publication also describes the relationship between insulin resistance and the onset of various diseases such as metabolic syndrome, cancer, sleep apnea syndrome, diabetes, polycystic ovary syndrome, and Alzheimer.
このような状況下、従来、インスリン抵抗性を改善する目的で、特定のジグリセリド及び/又はモノグリセリドを含有する油脂からなるインスリン抵抗性改善剤(特開2001−247473号公報参照)、レモン果実由来の親水性成分(ポリフェノール)を有効成分とするインスリン抵抗性改善剤(特開2007−63221号公報参照)、γ−アミノ酪酸を有効成分とするインスリン抵抗性改善剤(特開2008−74734号公報参照)、或いは、カルボン酸誘導体またはその塩を含有してなるインスリン抵抗性改善剤(特許第4484427号公報参照)など種々の報告がなされている。 Under such circumstances, conventionally, for the purpose of improving insulin resistance, an insulin resistance improving agent comprising fats and oils containing a specific diglyceride and / or monoglyceride (see JP 2001-247473 A), derived from lemon fruit Insulin resistance improving agent comprising a hydrophilic component (polyphenol) as an active ingredient (see JP 2007-63221 A), insulin resistance improving agent comprising γ-aminobutyric acid as an active ingredient (see JP 2008-74734 A) ), Or various reports such as an insulin resistance improving agent comprising a carboxylic acid derivative or a salt thereof (see Japanese Patent No. 4484427).
しかしながら、上記特開2001−247473号公報、特開2007−63221号公報、及び特開2008−74734号公報に記載されたインスリン抵抗性改善剤は、特定の油脂、ポリフェノール、又はγ−アミノ酪酸を有効成分とするもので、それら有効成分の入手性、取扱性には難点があった。一方、上記特許第4484427号公報に記載されたインスリン抵抗性改善剤は、カルボン酸誘導体またはその塩を有効成分とするインスリン抵抗性改善剤であって、ヒト成人(体重50kg)に経口投与する場合、当該有効成分の投与量は、1回投与量として約0.001〜500mgを1日1回〜3回投与することが規定された薬剤であり、ヒトを含む哺乳類に日常的に容易、安全かつ手軽に摂取させるか投与し得るものとは言い難いものであった。 However, the insulin resistance improving agent described in JP-A-2001-247473, JP-A-2007-63221, and JP-A-2008-74734 contains a specific fat, polyphenol, or γ-aminobutyric acid. The active ingredients are difficult to obtain and handle. On the other hand, the insulin resistance improving agent described in the above-mentioned Japanese Patent No. 4484427 is an insulin resistance improving agent containing a carboxylic acid derivative or a salt thereof as an active ingredient and is orally administered to a human adult (body weight 50 kg). The dose of the active ingredient is a drug prescribed to administer about 0.001 to 500 mg as a single dose once to three times a day. It is easy and safe for mammals including humans on a daily basis. And it was difficult to say that it was easy to ingest or administer.
このような状況下、ヒトを含む哺乳類に日常的に容易、安全かつ手軽に摂取させるか投与することのできるインスリン抵抗性の予防及び/又は改善剤、とりわけ、高脂肪食品/飼料によりもたらされるインスリン抵抗性を予防及び/又は改善するための新たなインスリン抵抗性の予防及び/又は改善剤が鶴首されていた。 Under such circumstances, an insulin resistance preventing and / or ameliorating agent that can be easily or safely ingested or administered to mammals including humans on a daily basis, especially insulin provided by high-fat food / feed A new agent for preventing and / or improving insulin resistance for preventing and / or improving resistance has been crushed.
なお、『ニュー・フード・インダストリー(New Food Industry)』、第48巻、第11号、1〜14頁、2006年に示されるとおり、糖尿病は、1型糖尿病(インスリン依存性糖尿病)と2型糖尿病(インスリン非依存性糖尿病)とに分類され、更に、2型糖尿病は、インスリン分泌低下が原因となる糖尿病と、インスリンは分泌され、その濃度も十分高いにも拘わらず、インスリン感受性の低下が原因となって血糖値が下がらない糖尿病とに分けられており、後者の糖尿病がインスリン抵抗性と関連性を有すると言われている。 As shown in “New Food Industry”, Vol. 48, No. 11, pp. 1-14, 2006, diabetes is type 1 diabetes (insulin-dependent diabetes) and type 2 It is classified as diabetes (non-insulin dependent diabetes), and type 2 diabetes is diabetic due to low insulin secretion, and insulin is secreted and its insulin sensitivity is reduced despite its high concentration. It is divided into diabetes that does not cause a decrease in blood sugar level, and it is said that the latter diabetes is related to insulin resistance.
ちなみに、本願と同じ出願人は、α,α−トレハロースの薬理作用について研究する中、特開平11−158075号公報において、1型糖尿病を誘発する薬剤であるストレプトゾトシン(STZ)を用いる動物実験において、α,α−トレハロースに膵機能調節作用、とりわけ、糖尿病を予防する作用があることを報告した。特開平11−158075号公報で報告された内容は、1型糖尿病とα,α−トレハロースとの関連性についてのものであって、α,α−トレハロースと2型糖尿病、とりわけ、血中にインスリンが存在していても、骨格筋や脂肪、肝臓で血液からの糖の吸収が十分に行われない状態、つまり、インスリン抵抗性との関連性について報告したものではない。また、本出願人と同じ出願人は、特開2000−7570号公報において、糖尿病を緩和する作用を有する、有効成分としてα,α−トレハロースを含んでなる抗内分泌障害剤を報告しているものの、これは、特開平11−158075号公報と同様、1型糖尿病を誘発する薬剤であるストレプトゾトシン(STZ)を用いる動物実験において、α,α−トレハロースが、STZによるランゲルハンス氏島β細胞の減少及び核濃縮並びにβ細胞そのものの萎縮を抑制する作用を有することに基づいて、α,α−トレハロースには、抗内分泌障害作用があることを報告したものである。したがって、特開2000−7570号公報は、α,α−トレハロースと、ランゲルハンス氏島β細胞とは因果関係のないインスリン抵抗性との関連性について開示するものではない。更に、本願と同じ出願人は、特許第3877589号公報において、α,α−トレハロースをエネルギー用糖源として用いることを開示しているものの、その内容は、α,α−トレハロース自体が生体のエネルギー用糖源として利用されることについてのものであって、α,α−トレハロースとインスリン抵抗性との関連性について開示するものではない。 Incidentally, the same applicant as the present application, while studying the pharmacological action of α, α-trehalose, in an animal experiment using streptozotocin (STZ), which is a drug that induces type 1 diabetes, in Japanese Patent Application Laid-Open No. 11-158075, It has been reported that α, α-trehalose has an effect of regulating pancreatic function, in particular, preventing diabetes. The content reported in Japanese Patent Application Laid-Open No. 11-158075 relates to the relationship between type 1 diabetes and α, α-trehalose, and α, α-trehalose and type 2 diabetes, especially insulin in the blood. However, there is no report on the relationship between insulin resistance and skeletal muscle, fat, or liver that does not sufficiently absorb sugar from blood. Further, the same applicant as the present applicant has reported an anti-endocrine disorder agent comprising α, α-trehalose as an active ingredient having an action of alleviating diabetes in JP-A-2000-7570. This is similar to JP-A-11-158075. In animal experiments using streptozotocin (STZ), which is a drug that induces type 1 diabetes, α, α-trehalose is decreased in Langerhans Islet β cells by STZ and It is reported that α, α-trehalose has an anti-endocrine disorder action based on its activity of suppressing nuclear concentration and atrophy of β cells themselves. Therefore, JP 2000-7570 A does not disclose the relationship between α, α-trehalose and insulin resistance that is not causally related to Langerhans Islet β cells. Furthermore, although the same applicant as the present application discloses that α, α-trehalose is used as an energy sugar source in Japanese Patent No. 3877589, the content thereof is that α, α-trehalose itself is the energy of the living body. However, it does not disclose the relationship between α, α-trehalose and insulin resistance.
本発明は、インスリン抵抗性を予防及び/又は改善するためのインスリン抵抗性の予防及び/又は改善剤、とりわけ、高脂肪食品/飼料によりもたらされるインスリン抵抗性を予防及び/又は改善するための、インスリン抵抗性の予防及び/又は改善剤とその用途を提供することを課題とする。 The present invention relates to an agent for preventing and / or improving insulin resistance for preventing and / or improving insulin resistance, especially for preventing and / or improving insulin resistance caused by high fat food / feed. It is an object to provide an agent for preventing and / or improving insulin resistance and its use.
本発明者等は、ヒトを含む哺乳類に日常的に容易かつ安全に摂取させるか投与することのできるインスリン抵抗性の予防及び/又は改善剤、とりわけ、高脂肪食品/飼料によりもたらされるインスリン抵抗性の予防及び/又は改善剤を確立することを目的とし、各種糖質の利用に着目し、鋭意研究を続けてきた。その結果、本発明者等は、全く意外なことに、インスリン抵抗性が二糖類であるα,α−トレハロースにより有意に予防及び/又は改善されることを見出し、本発明を完成した。 The present inventors have developed a prophylactic and / or ameliorating agent for insulin resistance that can be easily and safely ingested or administered to mammals including humans on a daily basis, especially insulin resistance provided by high-fat foods / feeds. With the goal of establishing preventive and / or ameliorating agents, we have focused on the use of various carbohydrates and have been conducting intensive research. As a result, the present inventors have surprisingly found that insulin resistance is significantly prevented and / or improved by α, α-trehalose, which is a disaccharide, and completed the present invention.
α,α−トレハロースが、インスリン抵抗性、とりわけ、高脂肪食品/飼料によりもたらされるインスリン抵抗性を予防及び/又は改善する作用を有することを見出したのは、本発明をもって嚆矢とするものである。 It has been found in the present invention that α, α-trehalose has the effect of preventing and / or improving insulin resistance, especially insulin resistance caused by high fat food / feed. .
なお、特許第3877589号公報に示されるとおり、α,α−トレハロースは、自体、これを生体に摂取させるか投与すると、カロリー源として利用されるとともに、D−グルコースと同様、血糖値やインスリンの上昇をもたらす物質であることから、斯かるα,α−トレハロースが、インスリン抵抗性を予防及び/又は改善する作用を有することなど、本発明者等自身、全く予想外のことであった。 In addition, as shown in Japanese Patent No. 3877589, α, α-trehalose is used as a calorie source when it is ingested or administered to a living body, and as with D-glucose, blood glucose level and insulin Since it is a substance that causes an increase, the present inventors themselves were totally unexpected, such as that such α, α-trehalose has an action of preventing and / or improving insulin resistance.
すなわち、本発明は、高脂肪食品/飼料によりもたらされるインスリン抵抗性を予防及び/又は改善するための、α,α−トレハロースを有効成分として含んでなるインスリン抵抗性の予防及び/又は改善剤を提供するものである。 That is, the present invention provides an agent for preventing and / or improving insulin resistance comprising α, α-trehalose as an active ingredient for preventing and / or improving insulin resistance caused by high fat food / feed. It is to provide.
また、本発明は、インスリン抵抗性の指標であるHOMA−IR値を有意に低下させる作用を有するインスリン抵抗性の予防及び/又は改善剤を提供するものである。 The present invention also provides an agent for preventing and / or improving insulin resistance having an action of significantly reducing the HOMA-IR value, which is an index of insulin resistance.
さらに、本発明は、α,α−トレハロースを無水物換算で1乃至20g含んでなる単位投与形態にあるインスリン抵抗性の予防及び/又は改善剤を提供するものである。 Furthermore, the present invention provides an agent for preventing and / or improving insulin resistance in a unit dosage form comprising 1 to 20 g of α, α-trehalose in terms of anhydride.
さらに、本発明は、α,α−トレハロースと、医薬許容性担体とからなる、インスリン抵抗性の予防及び/又は改善剤を提供するものである。 Furthermore, the present invention provides an agent for preventing and / or improving insulin resistance comprising α, α-trehalose and a pharmaceutically acceptable carrier.
さらに、本発明は、腸管膜脂肪細胞(「白色脂肪細胞」に分類される脂肪細胞)の肥大化を抑制する作用を有するインスリン抵抗性の予防及び/又は改善剤を提供するものである。 Furthermore, the present invention provides an agent for preventing and / or improving insulin resistance having an action of suppressing the enlargement of mesenteric fat cells (adipocytes classified as “white fat cells”).
本発明で言うインスリン抵抗性の予防及び/又は改善剤とは、ヒトを含む哺乳動物に高脂肪食品/飼料を日常的に摂取させるか投与する場合にもたらされるインスリン抵抗性を予防及び/又は改善することのできる薬剤を意味する。斯かる本発明のインスリン抵抗性の予防及び/又は改善剤が有効成分とするα,α−トレハロースは、本発明の目的を逸脱しない限り、その製法、給源、由来は特に限定されることなく用いることができる。例えば、従来公知の製造方法によって得られるα,α−トレハロースは言うに及ばず、現在、市販されている、粉末状、粒状、シラップ状などの形態を有するα,α−トレハロース製品をそのまま、あるいは、それらを公知の1種又は2種以上の糖質の精製方法を適宜適用して、所望の純度にまで高めたものを適宜用いることができる。また、本発明のインスリン抵抗性の予防及び/又は改善剤が有効成分とするα,α−トレハロースの純度は、その使用形態にもよるが、本発明の目的を逸脱しない限り、純度99質量%(以下、特に断りがない限り、「質量%」を単に「%」と略記する。)以上もの高純度のものに限定されない。なお、高純度のα,α−トレハロースとしては、α,α−トレハロース二含水結晶やα,α−トレハロース無水結晶などの結晶性α,α−トレハロースを例示できる。 The agent for preventing and / or improving insulin resistance referred to in the present invention means preventing and / or improving insulin resistance caused when a high-fat food / feed is ingested or administered daily to mammals including humans. Means a drug that can do. The α, α-trehalose used as an active ingredient in the agent for preventing and / or improving insulin resistance of the present invention is used without any particular limitation as long as it does not depart from the object of the present invention. be able to. For example, let alone α, α-trehalose obtained by a conventionally known production method, an α, α-trehalose product currently in the form of powder, granule, syrup or the like is commercially available These can be used as appropriate by appropriately applying one or more known methods for purifying one or more carbohydrates to the desired purity. Further, the purity of α, α-trehalose as an active ingredient of the agent for preventing and / or improving insulin resistance of the present invention depends on the use form, but the purity is 99% by mass unless departing from the object of the present invention. (Hereinafter, “% by mass” is simply abbreviated as “%” unless otherwise specified.) The present invention is not limited to those having a high purity. Examples of high-purity α, α-trehalose include crystalline α, α-trehalose such as α, α-trehalose dihydrate crystals and α, α-trehalose anhydrous crystals.
本発明のインスリン抵抗性の予防及び/又は改善剤は、実質的にα,α−トレハロースのみからなるものであっても、あるいは、α,α−トレハロースと1種又は2種以上の他の医薬許容性の担体、例えば、水、水性媒体、着色料、着香料、糊料、増量剤、pH調整剤、賦形剤、結合剤、崩壊剤、滑沢剤、安定化剤、矯味矯臭剤、希釈剤、及び注射剤用溶剤などの担体を含む組成物であってもよい。 The agent for preventing and / or improving insulin resistance of the present invention may consist essentially of α, α-trehalose, or α, α-trehalose and one or more other pharmaceutical agents. Acceptable carriers such as water, aqueous media, colorants, flavorings, pastes, extenders, pH adjusters, excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, It may be a composition containing a diluent and a carrier such as a solvent for injection.
また、本発明のインスリン抵抗性の予防及び/又は改善剤に配合し得るα,α−トレハロース以外の他の成分としては、例えば、α,α−トレハロースの製造方法に起因して共存するα,α−トレハロース以外の他の糖類、さらには、蛋白質、ペプチド(グレリンなど)、アミノ酸、糖類、ポリフェノール(フラボノイド、タンニンなど)、ビタミン、ミネラル、抗菌物質、酵素、ホルモン(レプチン、レジスチン、GLP−1、インスリンなど)、サイトカイン(アディポネクチン、TNF−αなど)、難消化性の多糖類(プルラン、エルシナン、カラギ−ナン、セルロース、及びそれらの誘導体など)、及び高甘味度甘味料(スクラロース、アスパルテーム、サッカリン、ステビオサイドなど)などを例示できる。上記α,α−トレハロース以外の他の成分は、その1種又は2種以上を必要に応じて適宜組み合わせて、本発明のインスリン抵抗性の予防及び/又は改善剤当たり、合計で、通常、0.01%以上99%未満、好適には、0.1%以上98%未満、より好適には、0.1%以上90%未満、より更に好適には、0.1%以上80%未満用いることができる。 Moreover, as other components other than α, α-trehalose that can be blended in the agent for preventing and / or improving insulin resistance of the present invention, for example, α, coexisting due to the production method of α, α-trehalose Saccharides other than α-trehalose, proteins, peptides (such as ghrelin), amino acids, saccharides, polyphenols (such as flavonoids and tannins), vitamins, minerals, antibacterial substances, enzymes, hormones (leptin, resistin, GLP-1) , Insulin, etc.), cytokines (such as adiponectin, TNF-α), indigestible polysaccharides (such as pullulan, erucinan, carrageenan, cellulose, and derivatives thereof), and high-intensity sweeteners (sucralose, aspartame, Saccharin, stevioside, etc.). In addition to the above α, α-trehalose, one or two or more of these components are appropriately combined as necessary, and the total is usually 0 per agent for preventing and / or improving insulin resistance of the present invention. 0.01% or more and less than 99%, preferably 0.1% or more and less than 98%, more preferably 0.1% or more and less than 90%, and even more preferably 0.1% or more and less than 80%. be able to.
なお、上記組み合わせの内、インスリン抵抗性改善作用を有するα,α−トレハロースと、インスリン抵抗性の程度を増大させる中性脂肪を低減する作用を有することが知られているポリフェノールとの併用は、本発明において特に好ましい組み合わせである。上記ポリフェノールの内、ナリンジン、ヘスペリジン、ルチンなどのフラボノイド、大豆イソフラボン、茶カテキン、及びそれらの酵素処理物又はグリコシル誘導体は、本発明においてはより好適に用いることができる。 Of the above combinations, the combined use of α, α-trehalose having an insulin resistance improving action and polyphenols known to have an action of reducing neutral fat that increases the degree of insulin resistance, This is a particularly preferred combination in the present invention. Of the above polyphenols, flavonoids such as naringin, hesperidin, rutin, soy isoflavones, tea catechins, and their enzyme-treated products or glycosyl derivatives can be more suitably used in the present invention.
本発明のインスリン抵抗性の予防及び/又は改善剤の形態としては、例えば、錠剤、カプセル剤、トローチ剤、舌下剤、シロップ剤、液剤、顆粒剤、散剤、粉剤、乳剤、噴霧剤、座剤、注射剤、軟膏、テープ剤、パップ剤などを例示することができる。本発明のインスリン抵抗性の予防及び/又は改善剤の形態が、シロップ剤、液剤などの液状である場合、当該インスリン抵抗性の予防及び/又は改善剤のpHは、通常、3乃至9、好適には、6乃至8の範囲とする。 Examples of the form of the agent for preventing and / or improving insulin resistance of the present invention include tablets, capsules, troches, sublinguals, syrups, solutions, granules, powders, powders, emulsions, sprays, suppositories. , Injections, ointments, tapes, poultices and the like. When the form of the agent for preventing and / or improving insulin resistance of the present invention is a liquid such as a syrup or liquid, the pH of the agent for preventing and / or improving insulin resistance is usually 3 to 9, preferably Is in the range of 6 to 8.
当該インスリン抵抗性の予防及び/又は改善剤の摂取量又は投与量に関し、当該インスリン抵抗性の予防及び/又は改善剤を、例えば、ヒトに適用する場合、後述する実験1乃至6の結果から判断して、当該インスリン抵抗性の予防及び/又は改善剤が有効成分とするα,α−トレハロースを、無水物換算で、ヒト成人(体重60kg)一日当たり、通常、1乃至20g、好適には、3乃至18g、より好適には、5乃至16gの範囲で摂取させるか投与する。なお、上記範囲の下限を下回る場合には、本発明の所期の作用効果が著しく低減するか発揮されなくなる。また、上記範囲の上限を上回る場合には、本発明の所期の作用効果がさほど変わらないか、むしろ、α,α−トレハロースによる好ましくない血糖値の上昇や血中インスリン濃度の上昇を招く恐れがあることから推奨されない。 Regarding the intake or dose of the insulin resistance prevention and / or amelioration agent, when the insulin resistance prevention and / or amelioration agent is applied to, for example, humans, it is judged from the results of Experiments 1 to 6 described later. Then, α, α-trehalose as an active ingredient of the agent for preventing and / or improving insulin resistance is usually 1 to 20 g, preferably 1 to 20 g per day, in terms of anhydride, for a human adult (weight 60 kg). Ingest or administer in the range of 3 to 18 g, more preferably 5 to 16 g. In addition, when less than the lower limit of the said range, the effect of the effect of this invention will reduce remarkably or will not be exhibited. In addition, when the upper limit of the above range is exceeded, the intended effect of the present invention does not change so much, or rather, an undesirable increase in blood glucose level or blood insulin concentration may occur due to α, α-trehalose. Not recommended because of
本発明のインスリン抵抗性の予防及び/又は改善剤は、その所望量をヒトを含む哺乳類(犬、猫、ウサギ、マウス、ラット、ハムスター、リスなどの愛玩動物、馬、牛、豚、羊、山羊、鶏などの家畜・家禽、更には類人猿などへ、経口的又は非経口的に摂取させるか投与することにより、インスリン抵抗性、とりわけ、高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。 The agent for preventing and / or improving insulin resistance of the present invention contains a desired amount of mammals including humans (dogs, cats, rabbits, mice, rats, hamsters, squirrels and other pets, horses, cows, pigs, sheep, Insulin resistance, especially insulin resistance provided by high-fat foods / feeds, is effective by ingesting or administering orally or parenterally to goats, poultry and other livestock and poultry, and even apes Can be prevented and / or improved.
また、本発明のインスリン抵抗性の予防及び/又は改善剤を高脂肪食品/飼料によりもたらされるインスリン抵抗性を予防及び/又は改善するために用いる場合には、当該インスリン抵抗性の予防及び/又は改善剤の有効成分であるα,α−トレハロースを無水物換算で、当該高脂肪食品/飼料中に含まれる脂肪酸総質量に対し、通常、1乃至50質量%、好適には、5乃至40質量%、より好適には、5乃至30質量%、更に好適には、5乃至20質量%、より更に好適には、5乃至15質量%の割合となるように、ヒトを含む哺乳動物に摂取させるか投与することにより、当該高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。 In addition, when the agent for preventing and / or improving insulin resistance of the present invention is used for preventing and / or improving insulin resistance caused by high-fat food / feed, the insulin resistance can be prevented and / or Α, α-trehalose, which is an active ingredient of the improver, is usually 1 to 50% by mass, preferably 5 to 40% by mass, based on the total mass of fatty acids contained in the high-fat food / feed, in terms of anhydride. %, More preferably 5 to 30% by mass, more preferably 5 to 20% by mass, and even more preferably 5 to 15% by mass, ingested by mammals including humans In other words, insulin resistance caused by the high-fat food / feed can be effectively prevented and / or improved.
本発明で言う高脂肪食品とは、所謂、脂肪・油脂を比較的多く含む食品全般を意味し、それら各食品当たり、脂肪酸を合計で、通常、5%以上100%未満、狭義には、10%以上100%未満、より狭義には、15%以上100%未満、更に狭義には、20%以上100%未満、より更に狭義には、30%以上100%未満含む食品を意味する。本発明で言う脂肪酸とは、飽和脂肪酸、不飽和一価脂肪酸、及び不飽和多価脂肪酸を意味し、その具体例としては、ミリスチン酸、ミリストレイン酸、ペンタデカン酸、パルミチン酸、パルミトレイン酸、ヘプタデカン酸、ヘプタデセン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸、アラキジン酸、イコセン酸、ベヘン酸、ドコサヘキサエン酸などを例示できる。上記脂肪酸の中でも、パルミチン酸、ステアリン酸、オレイン酸、及びリノール酸は、高脂肪食品/飼料中に、通常、他の脂肪酸と比べより多く含まれている。殊に、脂肪酸組成で、パルミチン酸、ステアリン酸、オレイン酸、及びリノール酸含有量の高い高脂肪食品/飼料によりもたらされるインスリン抵抗性は、本発明のインスリン抵抗性の予防及び/又は改善剤によれば効果的に改善される。なお、上記脂肪酸は、斯界において公知の方法により定量することができる。その代表的な定量方法としては、例えば、『栄養表示基準(平成8年5月厚生省告示第146号)』における栄養成分等の分析方法等(栄養表示基準別第1の第3欄に掲げる方法)に添付された別添資料の6〜9頁に記載された方法を例示できる。 The high-fat food referred to in the present invention means so-called foods that contain a relatively large amount of fats and oils, and the total amount of fatty acids for each of these foods is usually 5% or more and less than 100%. % Or more, less than 100%, more narrowly, 15% or more and less than 100%, more narrowly, 20% or more and less than 100%, and more narrowly, a food containing 30% or more and less than 100%. The fatty acid referred to in the present invention means a saturated fatty acid, an unsaturated monovalent fatty acid, and an unsaturated polyvalent fatty acid. Specific examples thereof include myristic acid, myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, heptadecane. Examples include acid, heptadecenoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, icosenic acid, behenic acid, docosahexaenoic acid, and the like. Among the above fatty acids, palmitic acid, stearic acid, oleic acid, and linoleic acid are usually more contained in high fat foods / feeds compared to other fatty acids. In particular, the insulin resistance provided by high fat foods / feeds having a fatty acid composition and a high content of palmitic acid, stearic acid, oleic acid, and linoleic acid is an agent for preventing and / or improving insulin resistance according to the present invention. According to the effective improvement. The fatty acid can be quantified by a method known in the art. As a typical quantification method, for example, an analysis method of nutritional components, etc. in “Nutrition Labeling Standards (May 1996 Ministry of Health and Welfare Notification No. 146)” (methods listed in the first column of the third by nutrition labeling standard) The method described on pages 6 to 9 of the attached document attached to the above can be illustrated.
本発明で言う高脂肪食品の具体例としては、自体、加工食品材料として用いられる、牛肉、豚肉、馬肉、羊肉、鶏肉、魚肉、魚卵(タラコ、数の子、ブリ、イクラ)、魚油(イワシ油、ニシン油、マグロ油、カツオ油、サンマ油、メンハーデン油など)、肝油、魚油、魚粕、骨油、牛脂、豚脂、馬脂、シア脂、魚油エキス、家禽卵(鶏卵、鶉卵など)、牛乳、アボカド油、あまに油、オリーブ油、カカオ脂、からし油、きり油、こめ油、サフラワー油、大豆油、とうもろこし油、菜種油、パーム油、パーム核油、ひまし油、ぶどう種子油、ホホバ油、綿実油、やし油、落花生油、カポック油、ごま油、けし油、ひまわり油など、さらには、上記加工食品材料を用いて製造される加工食品、例えば、畜肉・魚肉加工品(ハム、ソーセージ、ベーコン、フライドチキンなど)、乳製品(ヨーグルトなどの発酵乳製品を含む)、パン、ケーキ、菓子類(チョコレート、クッキー、クラッカー、ドーナツなど)、ハンバーグ、ハンバーガー、バター、マーガリン、マヨネーズ、ドレッシング、アイスクリーム、油脂粉乳、中華料理、ラーメン、即席麺(即席ラーメンなど)、スープ、天ぷら、フライ、油揚げなどの食品を例示できる。なお、上記高脂肪食品の内、パルミチン酸、ステアリン酸、オレイン酸、及びリノール酸を合計で、当該高脂肪食品当たり、通常、5%以上100%未満、厳密には、10%以上100%未満、より厳密には、15%以上100%未満、更に厳密には、20%以上100%未満、より更に厳密には、30%以上100%未満含む高脂肪食品は、本発明のインスリン抵抗性の予防及び/又は改善剤により、それら食品によりもたらされるインスリン抵抗性が効果的に予防及び/又は改善剤される食品である。上記高脂肪食品をヒトが摂取する前、後、及び/又は、摂取中に本発明のインスリン抵抗性の予防及び/又は改善剤の所定量をヒトに摂取させる場合には、上記高脂肪食品を比較的多量、日常的に摂取する場合であっても、上記高脂肪食品によりもたらされるインスリン抵抗性を一層効果的に予防及び/又は改善することができる。また、本発明で言う高脂肪飼料とは、上記した高脂肪食品と同様、高脂肪飼料当たり、脂肪酸を合計で、通常、5%以上100%未満、厳密には、10%以上100%未満、より厳密には、15%以上100%未満、更に厳密には、20%以上100%未満、より更に厳密には、30%以上100%未満含む高脂肪飼料を意味する。 Specific examples of the high-fat food according to the present invention include beef, pork, horse meat, mutton, chicken, fish, fish eggs (tarako, number child, yellowtail, salmon roe), fish oil (sardine oil), which are themselves used as processed food materials. , Herring oil, tuna oil, bonito oil, saury oil, menhaden oil, etc.), liver oil, fish oil, fish carp, bone oil, beef tallow, pork fat, horse fat, shea fat, fish oil extract, poultry eggs (chicken eggs, eggs etc.) ), Milk, avocado oil, sesame oil, olive oil, cocoa butter, mustard oil, potato oil, rice bran oil, safflower oil, soybean oil, corn oil, rapeseed oil, palm oil, palm kernel oil, castor oil, grape seed oil , Jojoba oil, cottonseed oil, palm oil, peanut oil, kapok oil, sesame oil, poppy oil, sunflower oil, and other processed foods produced using the above processed food materials such as processed meat and fish meat products (ham) , Sausage, ba , Fried chicken, etc.), dairy products (including fermented dairy products such as yogurt), bread, cakes, confectionery (chocolate, cookies, crackers, donuts, etc.), hamburger, hamburger, butter, margarine, mayonnaise, dressing, ice Examples thereof include foods such as cream, oil and fat powdered milk, Chinese food, ramen, instant noodles (instant noodles, etc.), soup, tempura, fried food, fried chicken. Of the high-fat foods, palmitic acid, stearic acid, oleic acid, and linoleic acid in total are usually 5% or more and less than 100%, strictly, 10% or more and less than 100% per the high-fat food. More specifically, the high-fat food containing 15% or more and less than 100%, more strictly 20% or more and less than 100%, and more strictly 30% or more and less than 100%, By the preventive and / or ameliorating agent, the insulin resistance caused by the food is effectively prevented and / or ameliorated. When the human is to take a predetermined amount of the agent for preventing and / or improving insulin resistance of the present invention before, after and / or during the intake of the high fat food, Even when a relatively large amount is taken daily, the insulin resistance caused by the high-fat food can be more effectively prevented and / or improved. Further, the high-fat feed referred to in the present invention is the same as the high-fat food described above, and the total fatty acids per high-fat feed is usually 5% or more and less than 100%, strictly 10% or more and less than 100%, More strictly, it means a high-fat feed containing 15% or more and less than 100%, more strictly 20% or more and less than 100%, and even more strictly 30% or more and less than 100%.
本発明のインスリン抵抗性の予防及び/又は改善剤の流通形態として、例えば、インスリン抵抗性を改善するために用いられる趣旨の表示を付した容器又は包装体内に収容されるか、インスリン抵抗性を予防及び/又は改善するとともに、腸間膜脂肪細胞の肥大化を抑制し、及び/又は、インスリン抵抗性により引き起こされる耐糖能(=負荷したD−グルコースに対して生体が示す代謝能力を指す。)の低下を改善するために用いられる趣旨の表示を付した容器又は包装体内に収容されたものを例示できる。 As a distribution form of the agent for preventing and / or improving insulin resistance according to the present invention, for example, the insulin resistance is contained in a container or a package with a sign indicating that it is used to improve insulin resistance, or insulin resistance is increased. Glucose tolerance (= metabolic ability exhibited by the living body against loaded D-glucose) is indicated by preventing and / or improving, suppressing mesenteric adipocyte hypertrophy, and / or causing insulin resistance. ) Can be exemplified by those contained in containers or packages with an indication to the effect that is used to improve the decrease in
このように、本発明のインスリン抵抗性の予防及び/又は改善剤によれば、インスリン抵抗性、とりわけ、高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善できる。また、本発明のインスリン抵抗性の予防及び/又は改善剤によれば、インスリン抵抗性を効果的に予防及び/又は改善できることから、インスリン抵抗性と関連性を有する、例えば、メタボリックシンドローム、癌、睡眠時無呼吸症候群、多のう胞性卵巣症候群、アルツハイマーなどの疾患を改善することができるのではないかと考えられる。 Thus, according to the agent for preventing and / or improving insulin resistance of the present invention, it is possible to effectively prevent and / or improve insulin resistance, particularly insulin resistance caused by high fat food / feed. In addition, according to the agent for preventing and / or improving insulin resistance of the present invention, since insulin resistance can be effectively prevented and / or improved, it has a relationship with insulin resistance, for example, metabolic syndrome, cancer, It may be possible to ameliorate diseases such as sleep apnea syndrome, multiple cystic ovary syndrome, and Alzheimer's.
以下、実験に基づいて本発明をより詳細に説明する。 Hereinafter, the present invention will be described in more detail based on experiments.
実験1
<高脂肪飼料摂取試験>
A.試験方法
C57BL/6N雌マウス(7週齢:日本チャールス・リバー株式会社から購入)50匹を無作為に一群8匹からなるA乃至E群、及び一群5匹からなるF群及びG群に分けた。A乃至E群のマウスは、飼育飼料として、糖尿病・肥満研究用高脂肪飼料(『High Fat Diet 32(HFD32)』、日本クレア株式会社製)(以下、単に、「高脂肪飼料」と言う。)[一般成分値、配合組成、及び脂肪酸含量は、下記(1)参照]を用いて飼育するとともに、飲用水として、A群のマウスにはD−グルコース(純度98%、和光純薬工業株式会社製)を、B群のマウスにはα,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)を、C群のマウスにはマルトース(純度97%、三和澱粉工業株式会社製)、D群のマウスには、異性化糖(商品名『ハイフラクトM75』、フラクトース含量約60%、D−グルコース含量約40%、日本コーンスターチ株式会社製)を、また、E群のマウスにはフラクトース(純度98%、株式会社林原製)をそれぞれ蒸留水に無水物換算で、濃度2.5%(w/v)含むように溶解した糖質含有水溶液[下記(2)参照]を用いて飼育した。なお、対照1(F群)として、飲用水として、糖質含有水溶液に代えて蒸留水を用いた以外は、A乃至E群のマウスと同様にして飼育する群を設けた。また、対照2(G群)として、飼育飼料として、高脂肪飼料に代えて標準飼料(商品名『NMF』、オリエンタル酵母工業株式会社製)(以下、単に、「標準飼料」と言う。)[一般成分値は、下記(3)参照]を用い、飲用水として、前記糖質含有水溶液に代えて蒸留水を用いた以外は、A乃至E群のマウスと同様にして飼育する群を設けた。飼育試験期間中、定期的に各群マウスの体重、摂餌量、及び飲水量を測定した。飼育試験開始後、7週間目に耐糖能を評価するためのD−グルコース負荷試験(糖負荷試験)[下記(4)参照]を行い、各群マウスの血糖値、インスリン濃度、及び空腹時の血糖値とインスリン濃度に基づいて算出されるインスリン抵抗性の指標である、HOMA−IR(「HOMA−R」とも言う。)(Homeostasis Model Assessment − Insulin Resistance)値(={[空腹時の血糖値(mg/dl)]×[空腹時のインスリン濃度(μU/ml)]/405}の計算式により算出される。)を常法により調べた。なお、HOMA−IR値は、インスリン抵抗性が高いほど高値を示す。ちなみに、ヒトにおいて、正常者のHOMA−IR値は1.6以下は正常、2.5以上のときインスリン抵抗性ありとされている(『糖尿病学 基礎と臨床』、門脇孝等編集、西村書店出版、初版、427〜430頁、2007年参照)。また、A乃至G群のマウスについてそれぞれ、飼育試験開始後、8週間目にエーテル麻酔下で腹部大静脈から全採血するとともに、腸間膜脂肪組織を採取し、その一部を後述する実験3で行う腸間膜脂肪細胞の遺伝子解析用試料として、試験に供するまで−80℃で凍結保存した。一方、採取した残りの腸間膜脂肪組織の一部を常法にしたがってホルマリン固定し、ヘマトキシリン・エオジン(HE)標本を作成した。HE標本それぞれにつき、光学顕微鏡(倍率200倍)を用いて、無作為に5視野の写真を撮影し、0.267mm2(1視野の面積)当たりの腸間膜脂肪細胞数をカウントし、その面積を細胞数で除した数値を腸間膜脂肪細胞面積とした。Experiment 1
<High fat feed intake test>
A. Test method 50 C57BL / 6N female mice (7 weeks old: purchased from Nippon Charles River Co., Ltd.) were randomly divided into groups A to E consisting of 8 animals per group, and groups F and G consisting of 5 animals per group. It was. The mice in groups A to E are referred to as “high fat diet” (hereinafter simply referred to as “high fat diet”) as a dietary feed for high fat diet for diabetes and obesity research (“High Fat Diet 32 (HFD32)” manufactured by CLEA Japan, Inc.). ) [General component values, composition, and fatty acid content are as follows (see (1) below)], and as drinking water, D-glucose (purity 98%, Wako Pure Chemical Industries, Ltd.) Company), α, α-trehalose (purity 99% or higher, Hayashibara Biochemical Laboratories) for group B mice, and maltose (purity 97%, Sanwa Starch Co., Ltd.) for group C mice. Company), Group D mice are isomerized sugar (trade name “Hyfract M75”, fructose content: about 60%, D-glucose content: about 40%, manufactured by Nippon Corn Starch Co., Ltd.), and Group E mice In Using a saccharide-containing aqueous solution [see (2) below] in which fructose (purity 98%, manufactured by Hayashibara Co., Ltd.) was dissolved in distilled water so as to contain 2.5% (w / v) in terms of anhydride. Raised. In addition, as a control 1 (Group F), there was provided a group reared in the same manner as the mice in Groups A to E except that distilled water was used instead of the saccharide-containing aqueous solution as drinking water. Moreover, as control 2 (group G), instead of high-fat feed as a breeding feed, a standard feed (trade name “NMF”, manufactured by Oriental Yeast Co., Ltd.) (hereinafter simply referred to as “standard feed”) [ For general component values, see the following (3)], and provided drinking groups in the same manner as the mice in groups A to E, except that distilled water was used instead of the saccharide-containing aqueous solution as drinking water. . During the breeding test period, the weight, food intake, and water consumption of each group of mice were measured periodically. D-glucose tolerance test (glucose tolerance test) [see (4) below] for evaluating glucose tolerance at the 7th week after the start of the breeding test, blood glucose level, insulin concentration, and fasting of each group of mice HOMA-IR (also referred to as “HOMA-R”) (Homeostasis Model Assessment-Insulin Resistance) value (= {[Fasting blood glucose level], which is an index of insulin resistance calculated based on blood glucose level and insulin concentration (Mg / dl)] × [fasting insulin concentration (μU / ml)] / 405}. In addition, a HOMA-IR value shows a high value, so that insulin resistance is high. By the way, in humans, the normal HOMA-IR value of 1.6 or less is normal, and when it is 2.5 or more, it is considered to have insulin resistance ("Diabetics Basic and Clinical", edited by Takashi Kadowaki, Nishimura Shoten) Publication, first edition, pages 427-430, 2007). In addition, for mice in groups A to G, blood was collected from the abdominal vena cava under ether anesthesia 8 weeks after the start of the breeding test, and mesenteric adipose tissue was collected. As a sample for gene analysis of mesenteric adipocytes performed in step 1, the sample was stored frozen at −80 ° C. until the test. On the other hand, a part of the remaining collected mesenteric adipose tissue was fixed in formalin according to a conventional method to prepare a hematoxylin-eosin (HE) specimen. For each HE specimen, photographs of 5 fields of view were randomly taken using an optical microscope (200 times magnification), and the number of mesenteric fat cells per 0.267 mm 2 (area of 1 field of view) was counted. The value obtained by dividing the area by the number of cells was defined as the mesenteric adipocyte area.
高脂肪飼料の一般成分値、配合組成、及び脂肪酸含量: General component values, composition, and fatty acid content of high-fat feed:
(2)糖質含有水溶液の調製:
既述のD−グルコース、α,α−トレハロース、マルトース、異性化糖又はフラクトースを無水物換算で濃度2.5%(w/v)含むように蒸留水に溶解して調製した。(2) Preparation of carbohydrate-containing aqueous solution:
It was prepared by dissolving the aforementioned D-glucose, α, α-trehalose, maltose, isomerized sugar or fructose in distilled water so as to contain a concentration of 2.5% (w / v) in terms of anhydride.
(3)標準飼料の一般成分値: (3) Standard component values of standard feed:
(4)D−グルコース負荷試験(糖負荷試験):
1.糖負荷試験前日の夕方から絶食させ、蒸留水だけを摂取させる。
2.空腹時の血糖値を調べるために、糖負荷前に眼底静脈から採血する。
3.投与量が2g/kgマウス体重となるように、D−グルコース溶液(濃度0.4g/ml)を胃ゾンデを用いて経口投与する。
4.D−グルコース投与後、30、60及び120分間経過後に眼底静脈からヘマトクリット管で採血し、採血チューブに血液を移し採り、血清を分離するまで氷冷しておく。
5.血液を4℃で遠心分離(10,000rpm)し、得られた血清の血糖値を『グルコースCIIテストワコー』(和光純薬工業株式会社製)にて測定する。(4) D-glucose tolerance test (sugar tolerance test):
1. Fast from the evening before the glucose tolerance test and consume only distilled water.
2. Blood samples are collected from the fundus vein before glucose loading to check for fasting blood glucose levels.
3. A D-glucose solution (concentration 0.4 g / ml) is orally administered using a stomach tube so that the dose is 2 g / kg mouse body weight.
4). After 30, 60, and 120 minutes after administration of D-glucose, blood is collected from the fundus vein with a hematocrit tube, and the blood is transferred to a blood collection tube and cooled on ice until the serum is separated.
5. The blood is centrifuged (10,000 rpm) at 4 ° C., and the blood glucose level of the obtained serum is measured with “Glucose CII Test Wako” (manufactured by Wako Pure Chemical Industries, Ltd.).
B.試験結果
図1乃至3は、D−グルコース投与群(A群、n=8)、α,α−トレハロース投与群(B群、n=8)、マルトース投与群(C群、n=8)、異性化糖投与群(D群、n=8)、フラクトース投与群(E群、n=8)、蒸留水投与群(F群:対照1、n=5)、及び標準飼料飼育群(G群:対照2、n=5)のマウスの試験期間中における体重、摂餌量、及び飲水量変化(各群マウスの平均値)をそれぞれ示す。図1乃至3に示すとおり、試験期間中、A乃至F群のマウスにおいては、体重、摂餌量、飲水量変化に有意差は認められなかった。G群のマウスにおいては、A乃至F群のマウスと比べ、摂餌量に有意差は認められなかったが、飲水量は多く、体重増加は少なかった。なお、図2の結果から、A乃至F群のマウスは高脂肪飼料(脂肪酸総量31.9%)を約2乃至3g/日/匹摂取したことから、それらマウスは脂肪酸をその総量で約0.6乃至1g/日/匹、摂取したことがわかる。一方、図3の結果から、A乃至F群のマウスは水(D−グルコース、α,α−トレハロース、マルトース、異性化糖、又はフラクトース濃度2.5%(w/v))を約2乃至3g/日/匹、摂取したことから、それらマウスは、D−グルコース、α,α−トレハロース、マルトース、異性化糖、又はフラクトースを約0.05乃至0.08g/日/匹、摂取したことがわかる。つまり、D−グルコース、α,α−トレハロース、マルトース、異性化糖、又はフラクトースは、マウスが摂取した脂肪酸総量に対し、約5乃至13%投与されたことを意味する。B. Test results FIGS. 1 to 3 show a D-glucose administration group (Group A, n = 8), an α, α-trehalose administration group (Group B, n = 8), a maltose administration group (Group C, n = 8), Isomerized sugar administration group (group D, n = 8), fructose administration group (group E, n = 8), distilled water administration group (group F: control 1, n = 5), and standard feed breeding group (group G) : Control 2, n = 5) shows body weight, food intake, and drinking water change (average value of mice in each group) during the test period. As shown in FIGS. 1 to 3, no significant differences were observed in changes in body weight, food intake, and water consumption among the mice in groups A to F during the test period. In the group G mice, no significant difference was observed in the amount of food intake compared to the mice in the groups A to F, but the amount of drinking water was large and the body weight gain was small. From the results shown in FIG. 2, the mice in groups A to F ingested about 2 to 3 g / day / animal of a high fat diet (total amount of fatty acid 31.9%). 6 to 1 g / day / animal was found to have been ingested. On the other hand, from the results shown in FIG. 3, the mice in groups A to F receive about 2 to 2 water (D-glucose, α, α-trehalose, maltose, isomerized sugar, or fructose concentration 2.5% (w / v)). Since 3 g / day / animal was ingested, the mice ingested about 0.05 to 0.08 g / day / animal of D-glucose, α, α-trehalose, maltose, isomerized sugar, or fructose. I understand. That is, D-glucose, α, α-trehalose, maltose, isomerized sugar, or fructose means that about 5 to 13% of the total amount of fatty acid ingested by the mouse was administered.
図4は、飼育試験開始後、7週間目に耐糖能を評価するために行なったD−グルコース負荷試験(糖負荷試験)結果(各群マウスの平均値)を示す。図4に示すとおり、糖負荷試験開始直前(0分)の空腹時の血糖値は、高脂肪飼料で飼育したマウス[A乃至E群のマウス(各群n=8)及びF群のマウス(n=5)]、及び標準飼料で飼育した対照2のマウス[G群のマウス(n=5)]との間に差は認められなかったが、糖負荷試験開始後、120分間に亘り、高脂肪飼料で飼育したマウス(A乃至F群のマウス)の血糖値は、標準飼料で飼育した対照2(G群)のマウスと比べ高かった。また、A乃至F群のマウスにおいて、糖負荷試験開始後、30〜60分後には、幾分、血糖値に差を認めたものの、糖負荷試験開始後、120分後には、各群のマウスに有意差は認められなかった。 FIG. 4 shows the results of D-glucose tolerance test (glucose tolerance test) (average value of mice in each group) conducted to evaluate glucose tolerance 7 weeks after the start of the breeding test. As shown in FIG. 4, the fasting blood glucose level immediately before the start of the glucose tolerance test (0 minutes) was measured in mice [group A to E mice (each group n = 8) and group F mice (n = 8) and mice ( n = 5)], and control 2 mice [group G mice (n = 5)] bred on standard diet, but for 120 minutes after the start of the glucose tolerance test, The blood glucose level of mice bred with a high fat diet (groups A to F) was higher than that of control 2 (group G) bred with a standard diet. Further, in the mice of groups A to F, although some difference in blood glucose level was observed 30 to 60 minutes after the start of the glucose tolerance test, each group of mice was 120 minutes after the start of the glucose tolerance test. There was no significant difference.
図5は、インスリン濃度の測定結果(各群マウスの平均値)を示す。図5に示すとおり、高脂肪飼料で飼育したマウス[A乃至E群のマウス(各群n=8)及びF群のマウス(n=5)]のインスリン濃度は、標準飼料で飼育した対照2(G群、n=5)のマウスと比べ高かった。また、α,α−トレハロース投与群(B群)のマウスの空腹時インスリン濃度は、A群及びC群のマウスと比べ、有意に低い値を示した(p<0.05)。また、B群のマウスのインスリン濃度は、糖負荷試験開始後、0〜60分間に亘り、A群及びC乃至F群のいずれのマウスと比べても明らかに低い値を示した。 FIG. 5 shows the measurement results of insulin concentration (average value of each group of mice). As shown in FIG. 5, the insulin concentration of mice [A to E group mice (each group n = 8) and F group mice (n = 5)] bred with a high-fat diet was compared to Control 2 bred with a standard diet. It was higher than the mice of (G group, n = 5). In addition, the fasting insulin concentration of the mice in the α, α-trehalose administration group (Group B) was significantly lower than that of the mice in Group A and Group C (p <0.05). In addition, the insulin concentration in the mice in group B was clearly lower than that in any of the mice in groups A and C to F for 0 to 60 minutes after the start of the glucose tolerance test.
図6は、飼育試験開始後、7週間目に行なった、インスリン抵抗性の指標であるHOMA−IR値の測定結果(各群マウスの平均値)を示す。図6に示すとおり、α,α−トレハロース投与群(B群、n=8)のマウスのHOMA−IR値は、マルトース投与群(C群、n=8)のマウスと比べ有意に低い値を示し(p<0.05)、D−グルコース投与群(A群、n=8)のマウスに比べ低い傾向を示した(p=0.11)。また、α,α−トレハロース投与群(B群)のマウスのHOMA−IR値は、異性化糖投与群(D群、n=8)、フラクトース投与群(E群、n=8)、及び蒸留水投与群(F群:対照1、n=5)のいずれのマウスと比べても明らかに低い値を示した。 FIG. 6 shows the measurement results (average value of each group of mice) of the HOMA-IR value, which is an index of insulin resistance, 7 weeks after the start of the breeding test. As shown in FIG. 6, the HOMA-IR value of the mice in the α, α-trehalose administration group (Group B, n = 8) is significantly lower than that of the mice in the maltose administration group (Group C, n = 8). (P <0.05) and showed a tendency to be lower than that of the mice in the D-glucose administration group (Group A, n = 8) (p = 0.11). Moreover, the HOMA-IR values of the mice in the α, α-trehalose administration group (Group B) are the isomerized sugar administration group (Group D, n = 8), the fructose administration group (E group, n = 8), and the distillation. The value was clearly lower than that of any mouse in the water administration group (F group: control 1, n = 5).
図7は、腸間膜脂肪細胞面積の測定結果(各群マウスの平均値)を示す。図7に示すとおり、高脂肪飼料で飼育したマウス[A乃至E群のマウス(各群n=8)及びF群のマウス(n=5)]の腸間膜脂肪細胞面積は、標準飼料で飼育した対照2(G群、n=5)のマウスと比べ明らかに大きかった。しかしながら、α,α−トレハロース投与群(B群)のマウスの腸間膜脂肪細胞面積は、D−グルコース投与群(A群)、マルトース投与群(C群)、異性化糖投与群(D群)、及びフラクトース投与群(E群)のマウスと比べ有意に小さかった(p<0.05)。また、α,α−トレハロース投与群(B群)のマウスの腸間膜脂肪細胞面積は、蒸留水投与群(F群)のマウスと比べても明らかに小さかった。 FIG. 7 shows the measurement results of mesenteric adipocyte area (average value of each group of mice). As shown in FIG. 7, the mesenteric adipocyte area of mice [A to E group mice (each group n = 8) and F group mice (n = 5)] bred with a high-fat diet was the standard diet. It was clearly larger than the control 2 (G group, n = 5) mice reared. However, the mesenteric adipocyte area of the mice in the α, α-trehalose administration group (Group B) is as follows: D-glucose administration group (Group A), maltose administration group (Group C), isomerized sugar administration group (Group D). ) And the fructose-administered group (E group) mice were significantly smaller (p <0.05). In addition, the mesenteric adipocyte area of mice in the α, α-trehalose administration group (Group B) was clearly smaller than that of the mice in the distilled water administration group (Group F).
図8は、腸間膜脂肪細胞の顕微鏡写真(各群マウスの代表例)である。図8に示すとおり、D−グルコース投与群(A群、n=8)、マルトース投与群(C群、n=8)、異性化糖投与群(D群、n=8)、フラクトース投与群(E群、n=8)、及び蒸留水投与群(F群:対照1、n=5)のマウスの腸間膜脂肪細胞は、対照2(G群、n=5)のマウスと比べ著しく肥大化していた。しかしながら、α,α−トレハロース投与群(B群)のマウスの腸間膜脂肪細胞は、対照2(G群)のマウスと比べると幾分肥大化は認められたものの、A群及びC乃至F群のマウスと比べ肥大化は著しく抑制されていた。 FIG. 8 is a photomicrograph of mesenteric adipocytes (representative example of each group of mice). As shown in FIG. 8, D-glucose administration group (A group, n = 8), maltose administration group (C group, n = 8), isomerized sugar administration group (D group, n = 8), fructose administration group ( Mesenteric adipocytes of mice in group E, n = 8) and distilled water administration group (F group: control 1, n = 5) are significantly enlarged compared to mice in control 2 (G group, n = 5) It was converted. However, although the mesenteric adipocytes of mice in the α, α-trehalose administration group (Group B) were somewhat enlarged compared to the mice in Control 2 (Group G), the A group and C to F Compared with the mice in the group, enlargement was remarkably suppressed.
本実験において、A群及びC乃至F群のマウスに見られるとおり、マウスを高脂肪飼料で飼育すると、糖負荷試験における血糖値及びインスリン濃度、及びHOMA−IR値が著しく上昇し、腸間膜脂肪細胞が著しく肥大化するのに対し、B群のマウスに見られるとおり、高脂肪飼料とともにα,α−トレハロースを投与したときには、糖負荷試験におけるインスリン濃度、及びHOMA−IR値の上昇が顕著に抑制されるとともに、腸間膜脂肪細胞の肥大化が顕著に抑制されることが判明した。殊に、図4及び図5に示すとおり、高脂肪飼料で飼育したマウスの血糖値とインスリン濃度は、標準飼料で飼育したマウスの血糖値とインスリン濃度と比べ高かった。これは、高脂肪飼料で飼育したマウスにおいては、標準飼料で飼育したマウスと比べ、高脂肪飼料によりもたらされる血糖値の上昇を低下させるために、より多くのインスリンが要求されていたことを示している。このような状況下、高脂肪飼料で飼育したマウスの内、α,α−トレハロースを投与したマウスにおいては、α,α−トレハロース以外の他の糖質を投与したマウスと比べ、インスリン濃度は、有意ないしは明らかに低い値を示したことから、α,α−トレハロースを投与したマウスにおいては、α,α−トレハロース以外の他の糖質を投与したマウスと比べ、血糖値を下げるために要求されるインスリンの量が少ない状態、つまり、インスリン感受性が高い状態にあったと判断される。本実験結果は、α,α−トレハロースがインスリン抵抗性を効果的に予防ないしは改善する作用を有することを示すものである。 In this experiment, as seen in the mice of group A and C to F, when the mice were bred with a high fat diet, the blood glucose level and insulin concentration in the glucose tolerance test and the HOMA-IR value were significantly increased. While the fat cells are significantly enlarged, when α, α-trehalose is administered together with the high fat diet as seen in the mice of group B, the increase in insulin concentration and HOMA-IR value in the glucose tolerance test is remarkable. It was found that hypertrophy of mesenteric adipocytes was significantly suppressed. In particular, as shown in FIGS. 4 and 5, the blood glucose level and the insulin concentration of the mice fed with the high fat diet were higher than those of the mice fed with the standard diet. This indicates that in mice fed on high fat diet, more insulin was required to reduce the increase in blood glucose levels caused by high fat diet compared to mice fed on standard diet. ing. Under such circumstances, among the mice bred with high-fat diet, in the mice administered with α, α-trehalose, compared to the mice administered with carbohydrates other than α, α-trehalose, the insulin concentration was Since the value was significantly or clearly low, mice administered with α, α-trehalose were required to lower blood glucose levels compared to mice administered with carbohydrates other than α, α-trehalose. It is determined that the amount of insulin to be consumed is low, that is, the insulin sensitivity is high. This experimental result indicates that α, α-trehalose has an action of effectively preventing or improving insulin resistance.
実験2
<高脂肪飼料摂取試験>
A.試験方法
実験1で行った高脂肪飼料摂取試験の期間を8週間から14週間に延長した以外は実験1と同様にして、D−グルコース投与群(A群、n=8)、α,α−トレハロース投与群(B群、n=8)、マルトース投与群(C群、n=8)、異性化糖投与群(D群、n=8)、フラクトース投与群(E群、n=8)、飲用水として糖質含有水溶液に代えて蒸留水を用いた以外は、A乃至E群のマウスと同様にして飼育する対照1(F群、n=5)、及び飼育飼料として、実験1で用いたと同じ標準飼料を用い、飲用水として、糖質含有水溶液に代えて蒸留水を用いた以外は、A乃至E群のマウスと同様にして飼育する対照2(G群、n=5)を設けた。飼育試験開始後、14週間目に、実験1と同様にして、耐糖能を評価するためのD−グルコース負荷試験を行った。なお、飼育試験期間中、定期的に各群マウスの体重、摂餌量、及び飲水量を測定した。Experiment 2
<High fat feed intake test>
A. Test Method D-glucose administration group (Group A, n = 8), α, α−, except that the period of the high fat feed intake test conducted in Experiment 1 was extended from 8 weeks to 14 weeks. Trehalose administration group (group B, n = 8), maltose administration group (group C, n = 8), isomerized sugar administration group (group D, n = 8), fructose administration group (group E, n = 8), Used in Experiment 1 as control 1 (F group, n = 5) reared in the same manner as the mice in groups A to E, except that distilled water was used instead of the sugar-containing aqueous solution as drinking water, and the rearing feed Control 2 (G group, n = 5) is provided in the same manner as mice in groups A to E, except that the same standard feed is used and distilled water is used as drinking water instead of the sugar-containing aqueous solution. It was. In the 14th week after the start of the breeding test, a D-glucose tolerance test for evaluating glucose tolerance was performed in the same manner as in Experiment 1. During the breeding test period, the body weight, food intake, and water consumption of each group of mice were measured periodically.
B.試験結果
図9乃至11は、D−グルコース投与群(A群、n=8)、α,α−トレハロース投与群(B群、n=8)、マルトース投与群(C群、n=8)、異性化糖投与群(D群、n=8)、フラクトース投与群(E群、n=8)、蒸留水投与群(F群:対照1、n=5)、及び標準飼料飼育群(G群:対照2、n=5)のマウスの試験期間中における体重、摂餌量、及び飲水量変化(各群マウスの平均値)をそれぞれ示す。図9乃至11に示されるとおり、試験期間中、A乃至E群のマウス間において、体重、摂餌量、及び飲水量変化に有意差は認められなかった。また、F群のマウスの摂餌量は、A乃至E群のマウスよりやや多く、飲水量はやや少なかった。G群のマウスにおいては、A乃至F群のマウスと比べ、摂餌量に有意差は認められなかったが、飲水量は多く、体重増加は少なかった。なお、図10の結果から、A乃至F群のマウスは高脂肪飼料(脂肪酸総量31.9%)を約2.2乃至3.2g/日/匹摂取したことから、それらマウスは脂肪酸をその総量で約0.7乃至1g/日/匹、摂取したことがわかる。一方、図12の結果から、A乃至F群のマウスは水(D−グルコース、α,α−トレハロース、マルトース、異性化糖、又はフラクトース濃度2.5%(w/v))を約1.5乃至3g/日/匹、摂取したことから、それらマウスは、D−グルコース、α,α−トレハロース、マルトース、異性化糖、又はフラクトースを約0.04乃至0.08g/日/匹、摂取したことがわかる。つまり、D−グルコース、α,α−トレハロース、マルトース、異性化糖、又はフラクトースは、マウスが摂取した脂肪酸総量に対し、約5乃至11%投与されたことを意味する。B. Test results FIGS. 9 to 11 show a D-glucose administration group (Group A, n = 8), an α, α-trehalose administration group (Group B, n = 8), a maltose administration group (Group C, n = 8), Isomerized sugar administration group (group D, n = 8), fructose administration group (group E, n = 8), distilled water administration group (group F: control 1, n = 5), and standard feed breeding group (group G) : Control 2, n = 5) shows body weight, food intake, and drinking water change (average value of mice in each group) during the test period. As shown in FIGS. 9 to 11, during the test period, no significant differences were observed in changes in body weight, food intake, and water consumption among mice in groups A to E. In addition, the amount of food consumed by the F group mice was slightly higher than that of the A to E group mice, and the amount of water consumed was slightly lower. In the group G mice, no significant difference was observed in the amount of food intake compared to the mice in the groups A to F, but the amount of drinking water was large and the body weight gain was small. From the results of FIG. 10, the mice in groups A to F ingested about 2.2 to 3.2 g / day / animal of high fat diet (total amount of fatty acid 31.9%). It can be seen that about 0.7 to 1 g / day / animal was ingested. On the other hand, from the results shown in FIG. 12, the mice in groups A to F were treated with water (D-glucose, α, α-trehalose, maltose, isomerized sugar, or fructose concentration 2.5% (w / v)) at about 1. Since they ingested 5 to 3 g / day / animal, they ingested about 0.04 to 0.08 g / day / animal of D-glucose, α, α-trehalose, maltose, isomerized sugar, or fructose. You can see that That is, D-glucose, α, α-trehalose, maltose, isomerized sugar, or fructose means that about 5 to 11% of the total amount of fatty acid ingested by the mouse was administered.
図12は、飼育試験開始後、14週間目に耐糖能を評価するために行なったD−グルコース負荷試験(糖負荷試験)結果(各群マウスの平均値)を示す。図12に示すとおり、高脂肪飼料で飼育したA乃至F群のマウス[A乃至E群のマウス(各群n=8)及びF群のマウス(n=5)]の血糖値は、標準飼料で飼育したG群(対照2、n=5)のマウスと比べ高かった。また、高脂肪飼料で飼育したA乃至F群のマウスの内、α,α−トレハロースを投与したB群のマウスの血糖値は、糖負荷試験開始後、30〜120分間の全期間に亘って、A群及びC乃至F群のマウスと比べ低い値であった。とりわけ、糖負荷試験開始後、120分間後におけるB群のマウスの血糖値は、A群及びD乃至F群のいずれのマウスと比べても有意に低く(p<0.05)、C群のマウスと比べても低い傾向が認められた(p=0.07)。 FIG. 12 shows the results of D-glucose tolerance test (glucose tolerance test) (average value of each group of mice) conducted to evaluate glucose tolerance 14 weeks after the start of the breeding test. As shown in FIG. 12, the blood glucose levels of the A to F group mice [A to E group mice (each group n = 8) and F group mice (n = 5)] bred with a high-fat diet are the standard diet. It was higher than the mice of Group G (Control 2, n = 5) reared in In addition, among the mice of Groups A to F bred with a high fat diet, the blood glucose level of the mice of Group B administered with α, α-trehalose is 30 to 120 minutes after the start of the glucose tolerance test. The values were lower than those of the mice in Groups A and C to F. In particular, the blood glucose level of the B group mice after 120 minutes after the start of the glucose tolerance test was significantly lower than that of any of the A group and D to F mice (p <0.05). A lower tendency was observed compared to mice (p = 0.07).
実験1の糖負荷試験(飼育期間7週間目)においては、高脂肪飼料とともにα,α−トレハロースを投与したマウスにおいて、α,α−トレハロースによる血糖値の有意な低下促進作用は認められなかったけれども、飼育期間を14週間に延長した場合には、α,α−トレハロースを投与して飼育したB群のマウスにおいては、D−グルコース、異性化糖、又はフラクトースを投与したA、D、及びE群のマウス、及び蒸留水を投与した対照1(F群)のマウスと比べ、α,α−トレハロースによる血糖値の有意な低下促進作用が認められた。また、B群のマウスの血糖値は、マルトースを投与したC群のマウスと比べても低下傾向が認められた。 In the glucose tolerance test of Experiment 1 (7 weeks of breeding period), α, α-trehalose did not significantly promote blood glucose reduction in mice administered with α, α-trehalose together with high-fat diet. However, when the breeding period was extended to 14 weeks, A, D, and D-glucose, isomerized sugar, or fructose were administered in group B mice fed with α, α-trehalose. Compared with the mice of Group E and the mice of Control 1 (Group F) to which distilled water was administered, α, α-trehalose significantly promoted the blood glucose level reduction. Moreover, the blood glucose level of the mouse | mouth of the B group also showed the fall tendency compared with the mouse | mouth of the C group which administered maltose.
高脂肪飼料摂取試験の期間を14週間とした本実験結果から、マウスに比較的長期間に亘って、高脂肪飼料を摂取させる場合、α,α−トレハロースを継続的に投与すると、高脂肪飼料によりもたらされる耐糖能の低下が有意に改善されることが判明した。これは、B群のマウスにおいては、耐糖能を低下させる、高脂肪飼料によりもたらされるインスリン感受性の低下が、α,α−トレハロースにより、予防ないしは改善されたことによると判断された。 From the results of this experiment in which the period of the high-fat feed intake test was 14 weeks, when a high-fat feed was ingested for a relatively long period of time in mice, when α, α-trehalose was continuously administered, It was found that the decrease in glucose tolerance caused by is significantly improved. This was judged to be due to the prevention or improvement of the decrease in insulin sensitivity caused by the high-fat diet, which decreases glucose tolerance, in the mice in group B by α, α-trehalose.
実験3
<腸間膜脂肪細胞の遺伝子解析>
A.試験方法
マウスにおいて、インスリン抵抗性を惹起することが知られているMCP−1(オフィシャル遺伝子シンボルは、『Ccl2』)遺伝子のmRNA発現量を調べる目的で、既述の実験1において、飼育試験開始後、8週間目に採取し、保存しておいたA乃至G群のマウスの腸間膜脂肪組織を用いて、それら組織における腸間膜脂肪細胞のMCP−1遺伝子のmRNA発現量を以下のようにして調べた。すなわち、各群マウスの腸間膜脂肪細胞につき、全RNAを『RNeasy Lipid Tissue Mini Kit』(株式会社キアゲン製)を用いて、常法にしたがって抽出し、その2μgに、『オリゴdT12−18プライマー』(プライマー含量250ng/μl、インビトロジェン社製)を1μl、10mM−dNTPs(GEヘルスケア・ジャパン株式会社製)を1μl添加し、RNase不含有水で全量を14μlとし、65℃で5分間保った後、氷上にて1分間静置し、5×1stストランド緩衝液4μl、0.1M−ジチオスレイトール1μl、『SuperScript III Reverse Transcriptase』(酵素活性200単位/μl、インビトロジェン株式会社製)を1μl添加し、50℃で30分間、55℃で30分間、70℃で15分間順次保ってcDNAを合成した。Experiment 3
<Genetic analysis of mesenteric adipocytes>
A. Test method In order to examine the mRNA expression level of MCP-1 (official gene symbol is “Ccl2”) gene known to induce insulin resistance in mice, the breeding test was started in Experiment 1 described above Thereafter, using the mesenteric adipose tissue of the mice of groups A to G collected and stored at 8 weeks, the mRNA expression level of the MCP-1 gene in the mesenteric adipocytes in these tissues was expressed as follows: I investigated as follows. That is, for each mesenteric adipocyte of each group of mice, total RNA was extracted according to a conventional method using “RNeasy Lipid Tissue Mini Kit” (manufactured by Qiagen), and 2 μg of the total RNA was extracted with “Oligo dT 12-18 ”. Add 1 μl of “Primer” (primer content 250 ng / μl, manufactured by Invitrogen), 1 μl of 10 mM-dNTPs (manufactured by GE Healthcare Japan), make the total amount 14 μl with RNase-free water, and keep at 65 ° C. for 5 minutes. And then left on ice for 1 minute, 4 μl of 5 × 1st strand buffer, 1 μl of 0.1M-dithiothreitol, 1 μl of “SuperScript III Reverse Transcriptase” (enzyme activity 200 units / μl, manufactured by Invitrogen Corporation) And add for 30 minutes at 50 ° C. CDNA was synthesized by sequentially maintaining at 55 ° C. for 30 minutes and at 70 ° C. for 15 minutes.
PCR解析に必要なMCP−1遺伝子のプライマーは、常法に準じて、ジェンバンク(GenBank)の『Accession No.NM 011333』に基づいて、『Primer 3 ソフトウェア』(スティーブ・ローゼン及びヘレン・スカレツスキーにより開発されたプライマー設計支援ソフトウェア、公式サイト「http://primer3.sourceforge.net/」から入手可能)を用いて設計し、リアルタイムPCR解析は、『Light Cycler 480 システム』(ロシュ・ダイアグノスティック株式会社製)を用いて行った。リアルタイムPCR解析における内部標準としては、サイクロフィリンA(CypA:オフィシャル遺伝子シンボルは、『Ppia』)(ジェンバンクの『Accession No.NM 008907』)遺伝子を用いた。 Primers for the MCP-1 gene necessary for PCR analysis are in accordance with a conventional method, “Accession No.” of GenBank. Based on “NM 013333”, using “Primer 3 software” (primer design support software developed by Steve Rosen and Helen Skaletsky, available from the official website “http://primer3.sourceforge.net/”) Designed and real-time PCR analysis was performed using “Light Cycler 480 System” (Roche Diagnostics). As an internal standard in the real-time PCR analysis, a cyclophilin A (CypA: the official gene symbol is “Ppia”) (Genbank “Accession No. NM 008907”) gene was used.
B.試験結果
図13は、飼育試験開始後、8週間目におけるD−グルコース投与群(A群、n=8)、α,α−トレハロース投与群(B群、n=8)、マルトース投与群(C群、n=8)、異性化糖投与群(D群、n=8)、フラクトース投与群(E群、n=8)、蒸留水投与群(F群:対照1、n=5)、及び標準飼料飼育群(G群:対照2、n=5)における、腸間膜脂肪細胞のMCP−1遺伝子のmRNA発現量をそれぞれ、蒸留水投与群(F群:対照1、n=5)におけるMCP−1遺伝子のmRNA発現量を1.0としたときの相対値で表したものである。図13に示すとおり、A、C、E、及びF群のマウスにおいては、G群(対照2)のマウスと比べ、有意(p<0.05)に高いMCP−1遺伝子のmRNA発現量を示した。B群及びD群のマウスと、対照2(G群)のマウスとの間で、MCP−1遺伝子のmRNA発現量に統計学上の有意差は認められなかったが、B群及びD群のマウスにおける、MCP−1遺伝子のmRNA発現量はいずれも、F群(対照1)のマウスと比べ、有意(p<0.05)に減少していた。B. Test Results FIG. 13 shows the D-glucose administration group (Group A, n = 8), α, α-trehalose administration group (Group B, n = 8), maltose administration group (C) at 8 weeks after the start of the breeding test. Group, n = 8), isomerized sugar administration group (Group D, n = 8), fructose administration group (Group E, n = 8), distilled water administration group (Group F: control 1, n = 5), and In the standard feed breeding group (G group: control 2, n = 5), the mRNA expression level of the MCP-1 gene of mesenteric adipocytes was respectively measured in the distilled water administration group (F group: control 1, n = 5). This is expressed as a relative value when the mRNA expression level of the MCP-1 gene is 1.0. As shown in FIG. 13, in the mice in groups A, C, E, and F, the MCP-1 gene mRNA expression level was significantly (p <0.05) higher than that in group G (control 2). Indicated. There was no statistically significant difference in the mRNA expression level of the MCP-1 gene between the B group and D group mice and the control 2 (G group) mice. The mRNA expression level of the MCP-1 gene in the mice was significantly decreased (p <0.05) compared to the mice in the F group (control 1).
実験1乃至3において、高脂肪飼料を用いてマウスを飼育するに際し、α,α−トレハロースを投与した場合には、α,α−トレハロースを投与しなかった場合と比べ、インスリン濃度及びHOMA−IR値の上昇が顕著に抑制され、耐糖能が改善され、腸間膜脂肪細胞の肥大化も顕著に抑制されたこと、更には、インスリン抵抗性を誘導することが知られているMCP−1遺伝子のmRNA発現量を抑制する傾向が示された。これらの結果から、α,α−トレハロースには、インスリン抵抗性を効果的に予防ないしは改善する作用があると判断される。 In Experiments 1 to 3, when the mice were bred using a high-fat diet, the insulin concentration and HOMA-IR were higher when α, α-trehalose was administered than when α, α-trehalose was not administered. MCP-1 gene, which is known to significantly increase the level of glucose, improve glucose tolerance, significantly suppress mesenteric adipocyte hypertrophy, and induce insulin resistance There was a tendency to suppress the mRNA expression level. From these results, it is determined that α, α-trehalose has an action of effectively preventing or improving insulin resistance.
実験4
<中性脂肪蓄積抑制試験>
各種糖質による中性脂肪蓄積抑制作用を調べる実験系として、脂肪前駆細胞であるマウス3T3−L1細胞株(ATCC CL−173)を用いて下記の実験を行った。すなわち、10%牛胎仔血清(FCS)含有ダルベッコMEM培地(日水製薬株式会社販売、以下、単に「D−MEM培地」と言う。)に最終濃度が2mg/mLとなるようにD−グルコースを添加した培地を用いて、マウス3T3−L1細胞株を懸濁し、当該細胞を3×104個/穴の割合で、予めアテロコラーゲン(株式会社高研販売)をコーティングした24穴プレートに播種し、37℃、5%CO2下で3日間培養した。次いで、培養上清を、脂肪前駆細胞の分化誘導剤(デキサメタゾン0.1μg/mL及びインスリン10μg/mL)と、糖質として、実験1で用いたと同じD−グルコース、α,α−トレハロース、マルトース、異性化糖、又はフラクトースを4mM含むD−MEM培地と交換し、細胞を常法に従って3日間培養した。なお、糖質として、D−グルコース、α,α−トレハロース、マルトース、異性化糖、及びフラクトースを添加した系をそれぞれ、A系、B系、C系、D系、及びE系とした。また、対照としては、分化誘導剤は添加するも、糖質は無添加の系(対照1)と、分化誘導剤及び糖質のいずれも無添加の系(対照2)とを設けた。培養終了後、A乃至E系及び対照1、2の培養上清を、インスリンを濃度5μg/mL及びD−グルコースを濃度4mg/mLで含むD−MEM培地と交換した後、細胞を3日間培養した。その後、2日毎に、A乃至E系、対照1、2の培養上清をそれぞれ、D−グルコースを濃度4mg/mL含み、分化誘導剤は含まないD−MEM培地にて交換し、最初の分化誘導剤による刺激を開始してから10日目に培養細胞における中性脂肪蓄積量を以下に示す方法により測定した。すなわち、各実験系における培養上清を除去した後、培養細胞をダルベッコ・リン酸緩衝生理食塩水(日水製薬株式会社販売、以下、単に「D−PBS」と言う。)にて3回洗浄し、10%ホルマリン/D−PBSにて、4℃下、1時間処理して固定し、乾燥した後、これに、染色色素である「オイルレッドO」を含む溶液を添加し、室温で15分間保持して細胞を染色した。その後、各実験系における細胞を蒸留水で3回洗浄し、イソプロパノール(特級試薬級の原液)0.3mL/穴を添加して細胞内に取り込まれた染色色素を抽出し、得られた抽出液につき、染色色素の吸収波長である490nmにおける吸光度(A490)を測定した。対照1と対照2の吸光度差を求め、この吸光度差に対するA乃至E系及び対照1の吸光度(A490)の百分率(%)を求めた。結果は図14に示す。Experiment 4
<Triglyceride accumulation suppression test>
As an experimental system for examining the neutral fat accumulation inhibitory action of various carbohydrates, the following experiment was conducted using a mouse 3T3-L1 cell line (ATCC CL-173) which is a preadipocyte. That is, D-glucose was added to Dulbecco's MEM medium containing 10% fetal calf serum (FCS) (sold by Nissui Pharmaceutical Co., Ltd., hereinafter simply referred to as “D-MEM medium”) so that the final concentration was 2 mg / mL. Using the added medium, the mouse 3T3-L1 cell line is suspended, and the cells are seeded at a rate of 3 × 10 4 cells / hole in a 24-well plate previously coated with atelocollagen (sales by Koken Co., Ltd.) The cells were cultured at 37 ° C. and 5% CO 2 for 3 days. Then, the culture supernatant was used as a precursor for differentiation of adipose precursor cells (dexamethasone 0.1 μg / mL and insulin 10 μg / mL), and the same D-glucose, α, α-trehalose, maltose as used in Experiment 1 as a carbohydrate. Then, the isomerized sugar or fructose was replaced with a D-MEM medium containing 4 mM, and the cells were cultured for 3 days according to a conventional method. In addition, the system which added D-glucose, (alpha), (alpha)-trehalose, maltose, isomerized sugar, and fructose as a saccharide | sugar was made into A type | system | group, B type | system | group, C type | system | group, D type | system | group, and E type | system | group, respectively. As a control, a system in which a differentiation inducer was added but no carbohydrate was added (control 1) and a system in which neither a differentiation inducer nor a carbohydrate was added (control 2) were provided. After completion of the culture, the culture supernatants of the A to E systems and the controls 1 and 2 were replaced with a D-MEM medium containing insulin at a concentration of 5 μg / mL and D-glucose at a concentration of 4 mg / mL, and then the cells were cultured for 3 days. did. Thereafter, every two days, the culture supernatants of the A to E systems and the controls 1 and 2 were replaced with a D-MEM medium containing 4 mg / mL D-glucose and no differentiation inducer, respectively. On the 10th day after the start of stimulation with the inducer, the amount of triglyceride accumulated in the cultured cells was measured by the method shown below. That is, after removing the culture supernatant in each experimental system, the cultured cells were washed three times with Dulbecco's phosphate buffered saline (sold by Nissui Pharmaceutical Co., Ltd., hereinafter simply referred to as “D-PBS”). After treatment with 10% formalin / D-PBS at 4 ° C. for 1 hour to fix and dry, a solution containing “Oil Red O” as a staining dye was added to the solution, and the mixture was stirred at room temperature for 15 Cells were stained by holding for minutes. Thereafter, the cells in each experimental system were washed three times with distilled water, 0.3 mL / well of isopropanol (special grade reagent stock solution) was added to extract the staining dye incorporated into the cells, and the resulting extract was obtained. The absorbance (A 490 ) at 490 nm, which is the absorption wavelength of the staining dye, was measured. The difference in absorbance between Control 1 and Control 2 was determined, and the percentage (%) of the absorbance (A 490 ) of the A to E systems and Control 1 with respect to this absorbance difference was determined. The results are shown in FIG.
図14に示すとおり、A乃至E系の内、B系の吸光度(A490)は約70%と、対照1と比べ有意(p<0.05)に低い値を示した。これは、B系にあっては、分化誘導剤による脂肪前駆細胞の脂肪細胞への分化誘導によりもたらされる中性脂肪蓄積が、α,α−トレハロースにより有意に抑制されたことを意味する。一方、D−グルコース、マルトース、異性化糖、及びフラクトースをそれぞれ添加したA系及びC乃至E系における吸光度(A490)は約90%とB系と較べ低値を示し、しかも対照1と比べ有意差は認められなかった。これは、A系及びC乃至E系においては、分化誘導剤による脂肪前駆細胞の脂肪細胞への分化誘導によりもたらされる中性脂肪蓄積が有意に抑制されなかったことを意味する。As shown in FIG. 14, among the A to E systems, the absorbance (A 490 ) of the B system was about 70%, which was significantly lower (p <0.05) than that of the control 1. This means that in the B system, accumulation of neutral fat caused by induction of differentiation of preadipocytes into adipocytes by a differentiation inducer was significantly suppressed by α, α-trehalose. On the other hand, the absorbance (A 490 ) in the A system and the C to E systems to which D-glucose, maltose, isomerized sugar, and fructose were added, respectively, was about 90%, which was lower than that of the B system. There was no significant difference. This means that, in the A system and the C to E systems, the accumulation of neutral fat caused by the differentiation induction of the adipose precursor cells into the adipocytes by the differentiation inducer was not significantly suppressed.
本実験において、α,α−トレハロースは、脂肪前駆細胞の脂肪細胞への分化誘導によりもたらされる中性脂肪蓄積を有意に抑制したことから、α,α−トレハロースは、脂肪蓄積、殊に、内臓脂肪蓄積に起因するインスリン抵抗性を予防ないしは改善する作用を有する糖質であることが強く示唆される。 In this experiment, α, α-trehalose significantly suppressed neutral fat accumulation caused by induction of differentiation of preadipocytes into adipocytes. It is strongly suggested that it is a carbohydrate having an action of preventing or improving insulin resistance caused by fat accumulation.
実験5
<臨床試験>
実験1乃至3において、マウスを用いる動物実験により、α,α−トレハロースがインスリン抵抗性を効果的に予防ないしは改善する作用を有することを認めた。また、実験4においては、培養細胞を用いての試験において、α,α−トレハロースが脂肪前駆細胞の脂肪細胞への分化誘導によりもたらされる脂肪蓄積を有意に抑制することを認めた。これらの実験結果を踏まえ、本実験においては、α,α−トレハロースがインスリン抵抗性に及ぼす影響について、ヒトを被験者とする臨床試験を行った。本臨床試験における被験者としては、閉経を迎える更年期女性を選択した。その理由は、更年期女性においては、通常、インスリン感受性を高めるエストロゲンの分泌が減少する一方、プロゲステロンによってインスリン抵抗性が上昇し、このエストロゲンの減少によって内臓脂肪がつきやすく、さらに運動不足や栄養過多になると肥満となり、インスリン抵抗性が惹起されることに鑑み、更年期女性は、本実験目的の被験者として適切であると判断したからである。より詳細には、医師の診断により、体脂肪率30%以上の肥満と判定され、インスリン抵抗性が既に惹起されているかその予備軍と診断された更年期女性10名(54乃至61歳)を無作為に2群(各群5名からなる「試験群」と「対照群」)に分け、α,α−トレハロースのインスリン抵抗性改善作用について調べた。なお、試験開始前の問診によれば、いずれの被験者も、日常的に、魚肉よりも牛・豚肉などの獣肉中心の食事を比較的多く摂るとともに、脂肪酸を比較的多く含むケーキ類、脂肪・油脂食品などを好んで食するなど、一日当たりの脂肪酸摂取量が比較的多い食習慣を有していた。Experiment 5
<Clinical trial>
In Experiments 1 to 3, animal experiments using mice confirmed that α, α-trehalose has an effect of effectively preventing or improving insulin resistance. Further, in Experiment 4, in the test using cultured cells, it was confirmed that α, α-trehalose significantly suppressed fat accumulation caused by induction of differentiation of preadipocytes into adipocytes. Based on these experimental results, in this experiment, a clinical study was conducted on the effect of α, α-trehalose on insulin resistance in human subjects. Menopausal women who were menopause were selected as subjects in this clinical trial. The reason for this is that in menopausal women, the secretion of estrogen, which increases insulin sensitivity, usually decreases, while progesterone increases insulin resistance, and this decrease in estrogen tends to cause visceral fat, resulting in lack of exercise and overnutrition. This is because, in view of obesity and insulin resistance being induced, it was determined that the menopausal woman was appropriate as a subject for the purpose of this experiment. More specifically, 10 menopausal women (54 to 61 years old) who were determined to be obese with a body fat percentage of 30% or more by diagnosis of a physician and who had already been induced to have insulin resistance or who had a reserve army. The test was divided into two groups (“test group” and “control group” consisting of 5 members in each group), and the insulin resistance improving action of α, α-trehalose was examined. In addition, according to the interview before the start of the study, each subject regularly eats a relatively large meal of beef and pork, such as beef and pork, rather than fish, as well as cakes, fat / Had a dietary habit of relatively high daily intake of fatty acids, such as eating oils and fats.
試験群の各被験者に対し、無水物換算でα,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)を5乃至20g/日の範囲で6カ月間に亘って経口摂取させ、α,α−トレハロースのインスリン抵抗性に及ぼす影響について調べた。各被験者には、α,α−トレハロースを上記摂取量の範囲内で経口摂取することを条件に、α,α−トレハロースの摂取方法、摂取時間の指定はせず、各被験者毎に好みの方法、好みの時間にα,α−トレハロースを経口摂取させ、かつ、特段の食事制限を課すことなく、各自の通常の生活習慣にしたがって生活させた。なお、各被験者には、予め、1日当たり、無水物換算で20gのα,α−トレハロース(無水物換算で5gずつ、ポーションタイプのポリエチレン製容器に収容したもの4個分に相当)を6カ月分配布し、上記摂取量の範囲内で、α,α−トレハロースを毎日経口摂取させた。試験終了後、各被験者から未使用分のα,α−トレハロースを全て回収し、各被験者毎に一日当たりのα,α−トレハロース摂取量を算出した。 Each subject in the test group was orally ingested with α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) over a period of 6 to 20 g / day in terms of anhydride. The effect of α, α-trehalose on insulin resistance was examined. Each subject is allowed to take α, α-trehalose orally within the above range of intake, and the α, α-trehalose intake method and the intake time are not specified, and each subject has a favorite method. Then, α, α-trehalose was orally ingested at a desired time and was allowed to live according to their normal lifestyle without imposing special dietary restrictions. Each subject previously received 20 g of α, α-trehalose in terms of anhydride (corresponding to 4 g each in a portion-type polyethylene container in terms of anhydride) for 6 months. The α, α-trehalose was orally ingested every day within the above intake range. After the test, all unused α, α-trehalose was collected from each subject, and the amount of α, α-trehalose intake per day was calculated for each subject.
一方、対照群の各被験者には、α,α−トレハロースを摂取させなかった以外は、試験群と同様にして、特段の食事制限を課すことなく、各自の通常の生活習慣にしたがって生活させた。試験終了後、各群の被験者全てにつき、市販の身長計(商品名『YG−200』、株式会社ヤガミ製)を用いて身長を測定するとともに、体重、体脂肪率を市販の体重・体脂肪計(商品名『TBF−102』、株式会社タニタ製)を用いて測定した。BMIは身長、体重に基づいて、常法により算出した。また、常法により、インスリン抵抗性を判断するための指標であるHOMA−IR値を求めた。その結果を表5に示す。なお、表5には、試験開始前、予め、上記測定計を用いて測定しておいた、各群の各被験者の身長、体重、体脂肪率、BMI、及びHOMA−IR値を併記した。 On the other hand, each subject in the control group was allowed to live according to their normal lifestyle without imposing special dietary restrictions in the same manner as in the test group, except that they did not take α, α-trehalose. . After completion of the test, all subjects in each group were measured for height using a commercially available height meter (trade name “YG-200”, manufactured by Yagami Co., Ltd.), and the body weight and body fat percentage were measured using commercially available body weight and body fat. Measurement was performed using a total (trade name “TBF-102”, manufactured by Tanita Co., Ltd.). BMI was calculated by a conventional method based on height and weight. Further, the HOMA-IR value, which is an index for judging insulin resistance, was determined by a conventional method. The results are shown in Table 5. In Table 5, the height, weight, body fat percentage, BMI, and HOMA-IR values of each subject in each group, which were measured in advance using the above-described meter before the start of the test, are also shown.
表5に示す試験開始前後における試験群と対照群の被験者の身長、体重、体脂肪率、BMI、及びHOMA−IR値を比較検討した結果、試験群及び対照群のいずれにおいても、身長、体重に有意差は認められなかった。一方、体脂肪率、BMI値は、対照群においては有意差は認められなかったが、体脂肪率は、試験群においては有意(p<0.05)ないしは顕著な低下が認められた。また、HOMA−IR値は、対照群においては、有意差は認められなかったが、試験群においては、有意(p<0.05)な低下が認められた。しかも、試験後、試験群におけるHOMA−IR値は、対照群と比べ有意(p<0.05)に低い値であった。なお、試験群の各被験者は、表5に示すとおり、無水物換算でα,α−トレハロースを、一日当たり、約5乃至16gの量を経口摂取していることからみて、α,α−トレハロースを摂取しなかった対照群の被験者と比べ、α,α−トレハロースを摂取した分、カロリー摂取量は多かったにも拘わらず、両群の被験者間で、体重増加に有意差が認められなかったことは、全く予期しなかった結果であった。 As a result of comparing the height, weight, body fat percentage, BMI, and HOMA-IR values of subjects in the test group and the control group before and after the start of the test shown in Table 5, the height and weight were measured in both the test group and the control group. There was no significant difference. On the other hand, the body fat percentage and the BMI value were not significantly different in the control group, but the body fat percentage was significantly (p <0.05) or significantly decreased in the test group. Moreover, the HOMA-IR value was not significantly different in the control group, but was significantly (p <0.05) lower in the test group. Moreover, after the test, the HOMA-IR value in the test group was significantly lower (p <0.05) than that in the control group. In addition, as shown in Table 5, each subject in the test group is taking α, α-trehalose in an amount of about 5 to 16 g per day in terms of anhydride. Compared with subjects in the control group who did not take sucrose, there was no significant difference in body weight gain between subjects in both groups, even though the caloric intake was higher by the amount of α, α-trehalose. That was an unexpected result.
上記の結果は、体脂肪率30%以上の肥満状態のヒトでみられる特異な現象であるか否かは定かではないとしても、肥満状態のヒトがα,α−トレハロースを上記範囲で日常的に経口摂取した場合には、体重増加を引き起こすことなく、体脂肪率、BMIが、有意ないしは顕著に低下し、HOMA−IR値が有意に低下すると判断される。また、上記したとおり、試験群のHOMA−IR値が、対照群と比べ、有意に低下したという事実は、実験1乃至3で得られた動物実験結果と同様、α,α−トレハロースには、ヒトにおいてもインスリン抵抗性を効果的に予防及び/又は改善する作用を有することを如実に示すものである。また、本実験において、試験群の各被験者が一日当たり摂取したα,α−トレハロース経口摂取量は、約5乃至16gであったことから、α,α−トレハロースをこの量で、又はこの量に準じてヒトに経口摂取させるか投与する場合には、ヒトにおけるインスリン抵抗性を効果的に予防及び/又は改善できると判断される。 Although it is not certain whether the above results are a unique phenomenon seen in obese humans with a body fat ratio of 30% or more, obese humans routinely use α, α-trehalose within the above range. When taken orally, the body fat percentage and BMI are significantly or significantly reduced without causing weight gain, and the HOMA-IR value is significantly reduced. Further, as described above, the fact that the HOMA-IR value of the test group was significantly lower than that of the control group is similar to the results of animal experiments obtained in Experiments 1 to 3, in α, α-trehalose. This clearly shows that humans also have the action of effectively preventing and / or improving insulin resistance. Further, in this experiment, the α, α-trehalose oral intake taken by each subject in the test group per day was about 5 to 16 g. Therefore, α, α-trehalose was added to this amount or to this amount. Accordingly, when it is orally ingested or administered to humans, it is judged that insulin resistance in humans can be effectively prevented and / or improved.
実験1乃至5の結果は、ヒトを含む哺乳類が、日常的に比較的多量の高脂肪食品/飼料などを摂取するか投与される場合であっても、本発明のα,α−トレハロースを有効成分とするインスリン抵抗性の予防及び/又は改善剤を日常的に摂取させるか投与することにより、高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善できることを示すものである。 The results of Experiments 1 to 5 show that the α, α-trehalose of the present invention is effective even when mammals including humans ingest or administer a relatively large amount of high fat food / feed, etc. on a daily basis. It shows that insulin resistance caused by high-fat food / feed can be effectively prevented and / or improved by daily intake or administration of an ingredient for preventing and / or improving insulin resistance as a component. is there.
実験6
<急性毒性試験>
7週齢のdd系マウスを用いて、実験1で用いたと同じα,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)を経口投与して急性毒性試験を行なった。その結果、α,α−トレハロースは低毒性の物質で、投与可能な最大投与量においても死亡例は認められなかった。この結果から、α,α−トレハロースのLD50値は、50g/kgマウス体重以上と判断された。Experiment 6
<Acute toxicity test>
A 7-week-old dd mouse was orally administered with the same α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories) as used in Experiment 1, and an acute toxicity test was conducted. As a result, α, α-trehalose was a low-toxic substance, and no death was observed even at the maximum dose that could be administered. From this result, the LD 50 value of α, α-trehalose was determined to be 50 g / kg mouse body weight or more.
本実験結果から、本発明のα,α−トレハロースを有効成分とするインスリン抵抗性の予防及び/又は改善剤は、ヒトを含む哺乳類に安全かつ安心して日常的に摂取させるか投与することのできる薬剤である。 From these experimental results, the preventive and / or ameliorating agent for insulin resistance comprising α, α-trehalose of the present invention as an active ingredient can be safely ingested or administered daily to mammals including humans. It is a drug.
以下、実施例に基づいて本発明をより詳細に説明する。しかしながら、本発明は、これら実施例によりなんら限定されるものではない。 Hereinafter, the present invention will be described in more detail based on examples. However, the present invention is not limited to these examples.
<インスリン抵抗性の予防及び/又は改善剤>
無水物換算で、α,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)5gを超純水95mlに溶解し、常法にしたがって精密濾過して、100ml容ボトルに無菌的に充填して、液剤形態のインスリン抵抗性の予防及び/又は改善剤を得た。<Insulin resistance preventive and / or ameliorating agent>
In terms of anhydride, 5 g of α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) is dissolved in 95 ml of ultrapure water, subjected to microfiltration according to a conventional method, and aseptically obtained in a 100 ml bottle. To prevent and / or improve insulin resistance in a liquid form.
本品は、取扱性、保存安定がともに性良好で、ヒト成人(体重60kg)一日当たりの摂取量又は投与量として、通常、本品を1/5乃至4本程度、日常的に摂取することにより、高脂肪食品によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。また、本品は、哺乳類に対し、日常的に摂取させるか投与することにより、高脂肪飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。 This product has good handling and storage stability and should be taken on a daily basis, usually about 1/5 to 4 of this product as a daily intake or dose for a human adult (60 kg body weight). Thus, it is possible to effectively prevent and / or improve insulin resistance caused by the high fat food. In addition, this product can effectively prevent and / or improve insulin resistance caused by high-fat diet by daily ingestion or administration to mammals.
<インスリン抵抗性の予防及び/又は改善剤>
無水物換算で、α,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)150質量部をミキサーで攪拌しつつ、これにプルラン(商品名『PI−20』、株式会社林原商事販売)を2%含有する水溶液10質量部を均一に噴霧し、粉剤形態のインスリン抵抗性の予防及び/又は改善剤を得た。<Insulin resistance preventive and / or ameliorating agent>
In an anhydrous form, 150 parts by mass of α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) was stirred with a mixer, and then pullulan (trade name “PI-20”, Hayashibara Co., Ltd.). 10 parts by mass of an aqueous solution containing 2% of commercial sales) was uniformly sprayed to obtain an agent for preventing and / or improving insulin resistance in powder form.
本品は、取扱性、水への分散性・溶解性、保存安定性のいずれもが良好で、ヒトを含む哺乳類に対し、日常的に摂取させるか投与することにより、高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。 This product has good handling properties, dispersibility / solubility in water, and storage stability, and can be taken or administered to mammals including humans on a daily basis. The resulting insulin resistance can be effectively prevented and / or ameliorated.
<インスリン抵抗性の予防及び/又は改善剤>
無水物換算で、α,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)95質量部及びα−グルコシルヘスペリジン(商品名『林原ヘスペリジンS』、株式会社林原商事販売)5質量部とを均一に攪拌し、攪拌混合し、常法にしたがって、顆粒形成機にかけて顆粒化し、硬質カプセルに充填して、カプセル剤形態のインスリン抵抗性の予防及び/又は改善剤を得た。<Insulin resistance preventive and / or ameliorating agent>
In terms of anhydride, 95 parts by mass of α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 5 mass of α-glucosyl hesperidin (trade name “Hayashibara Hesperidin S”, sold by Hayashibara Corporation) The mixture was stirred and mixed uniformly, and granulated by a granulating machine according to a conventional method, and filled into a hard capsule to obtain an insulin resistance preventing and / or improving agent in the form of a capsule.
本品は、取扱性、保存安定性が良好で、α,α−トレハロースによるインスリン抵抗性改善作用と、α−グルコシルヘスペリジンの中性脂肪低減作用とが相まって、これをヒトを含む哺乳類に対し、日常的に摂取させるか投与することにより、高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。 This product has good handleability and storage stability, combined with insulin resistance improving action by α, α-trehalose and neutral fat reducing action of α-glucosyl hesperidin. Ingestion or administration on a daily basis can effectively prevent and / or ameliorate insulin resistance caused by high fat food / feed.
<インスリン抵抗性の予防及び/又は改善剤>
無水物換算で、α,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)10質量部及びα−グルコシルルチン(商品名『αGルチン』、株式会社林原商事販売)1質量部とを均一に攪拌し、混合し、常法にしたがって、打錠して、錠剤形態のインスリン抵抗性の予防及び/又は改善剤を得た。<Insulin resistance preventive and / or ameliorating agent>
In terms of anhydride, 10 parts by mass of α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 1 part by mass of α-glucosylrutin (trade name “αG rutin”, Hayashibara Corporation sales) Were uniformly mixed, and tableted according to a conventional method to obtain a preventive and / or ameliorating agent for insulin resistance in tablet form.
本品は、取扱性、保存安定性が良好で、これをヒトを含む哺乳類に対し、日常的に摂取させるか投与することにより、高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。 This product has good handleability and storage stability, and can be effectively ingested or administered to mammals including humans to effectively prevent insulin resistance caused by high-fat foods / feeds. And / or can be improved.
<インスリン抵抗性の予防及び/又は改善剤>
無水物換算で、α,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)5質量部、2−O−α−D−グルコシル−L−アスコルビン酸(商品名『AA2G』、株式会社林原生物化学研究所販売)0.3質量部、及びα−グルコシルルチン(商品名『αGルチン』、株式会社林原商事販売)1質量部を超純水74質量部に溶解し、常法にしたがって精密濾過して、100ml容ボトルに無菌的に充填して、液剤形態のインスリン抵抗性の予防及び/又は改善剤を得た。<Insulin resistance preventive and / or ameliorating agent>
In terms of anhydride, 5 parts by mass of α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), 2-O-α-D-glucosyl-L-ascorbic acid (trade name “AA2G”, Hayashibara Biochemical Laboratories Co., Ltd.) 0.3 parts by mass and α-glucosylrutin (trade name “αG rutin”, Hayashibara Shoji Co., Ltd.) 1 part by mass are dissolved in 74 parts by mass of ultrapure water. And 100 ml bottle was aseptically filled to obtain a preventive and / or ameliorating agent for insulin resistance in liquid form.
本品は、取扱性、保存安定性良好で、ヒト成人(体重60kg)一日当たりの摂取量又は投与量として、通常、本品を1/5乃至4本程度、日常的に摂取することにより、高脂肪食品によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。 This product has good handling and storage stability, and as a human adult (body weight 60 kg), the daily intake or dose of this product is usually about 1/5 to 4 times daily, Insulin resistance caused by high-fat foods can be effectively prevented and / or improved.
<インスリン抵抗性の予防及び/又は改善剤>
無水物換算で、α,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)2質量部、2−O−α−D−グルコシル−L−アスコルビン酸(商品名『AA2G』、株式会社林原生物化学研究所販売)1質量部、及びα−グルコシルヘスペリジン(商品名『αGヘスペリジン』、株式会社林原商事販売)1質量部を超純水79.5質量部に溶解し、常法にしたがって精密濾過して、50ml容ボトルに無菌的に充填して、液剤形態のインスリン抵抗性の予防及び/又は改善剤を得た。<Insulin resistance preventive and / or ameliorating agent>
In terms of anhydride, 2 parts by mass of α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), 2-O-α-D-glucosyl-L-ascorbic acid (trade name “AA2G”, 1 part by mass of Hayashibara Biochemical Laboratories Co., Ltd.) and 1 part by mass of α-glucosyl hesperidin (trade name “αG Hesperidin”, Hayashibara Shoji Co., Ltd.) are dissolved in 79.5 parts by mass of ultrapure water. And then aseptically filled into a 50 ml bottle to obtain a preventive and / or ameliorating agent for insulin resistance in liquid form.
本品は、取扱性、保存安定性良好で、ヒト成人(体重60kg)一日当たりの摂取量又は投与量として、通常、本品を1乃至5本程度、日常的に摂取することにより、高脂肪食品によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善することができる。また、本品は、哺乳類に対し、日常的に摂取させるか投与することにより、高脂肪飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善する善することができる。 This product has good handling and storage stability, and is usually high in fat by daily intake of 1 to 5 of this product as a daily intake or dosage for human adults (body weight 60 kg). Insulin resistance caused by food can be effectively prevented and / or improved. In addition, this product can effectively prevent and / or improve insulin resistance caused by high-fat diet by ingesting or administering to mammals on a daily basis.
以下、本発明のインスリン抵抗性の予防及び/又は改善剤の適用例について参考例として述べる。 Hereinafter, application examples of the agent for preventing and / or improving insulin resistance of the present invention will be described as reference examples.
参考例1
<油脂含有組成物>
実施例2乃至4で得た本発明のインスリン抵抗性の予防及び/又は改善剤10質量部を、パルミチン酸10%、ステアリン酸10%、オレイン酸10%、及びリノール酸10%(総脂肪酸質量40%)含む油脂含有組成物100質量部に配合し、容器に充填して、本発明のインスリン抵抗性の予防及び/又は改善剤を含む油脂含有組成物を得た。Reference example 1
<Oil containing composition>
10 parts by mass of the insulin resistance preventive and / or ameliorating agent of the present invention obtained in Examples 2 to 4 was added 10% palmitic acid, 10% stearic acid, 10% oleic acid, and 10% linoleic acid (total fatty acid mass). 40%) The oil-containing composition containing 100 parts by mass of the oil-containing composition containing the composition and filled in a container to obtain the insulin resistance preventing and / or improving agent of the present invention was obtained.
本品は、取扱性、保存安定性が良好で、自体、インスリン抵抗性を惹起し難い油脂含有組成物である。 This product is a fat-and-oil-containing composition that has good handleability and storage stability and hardly induces insulin resistance.
参考例2
<食用クリーム>
実施例2乃至4で得た本発明のインスリン抵抗性の予防及び/又は改善剤5質量部を、カカオペースト40質量部、及びカカオバター10質量部と混合し、レファイナーに通して粒度を下げた後、コンチェに入れ、50℃で2昼夜練り上げる。この間に、レシチン0.5質量部を加え充分に混和し、分散させた。次いで、温度調節機で31℃に調節し、バターが固まる直前に型に流し込み、振動機でアワ抜きを行ない、10℃の冷却トンネルを20分間くぐらせて固化させた。これを型抜きして包装し製品を得た。Reference example 2
<Edible cream>
5 parts by mass of the insulin resistance preventing and / or improving agent of the present invention obtained in Examples 2 to 4 was mixed with 40 parts by mass of cocoa paste and 10 parts by mass of cocoa butter, and passed through a refiner to reduce the particle size. Then put it in Conche and knead it at 50 ° C for 2 days. During this time, 0.5 part by mass of lecithin was added and thoroughly mixed and dispersed. Next, the temperature was adjusted to 31 ° C. with a temperature controller, poured into a mold just before the butter solidified, drained with a vibrator, and passed through a 10 ° C. cooling tunnel for 20 minutes to solidify. This was punched and packaged to obtain a product.
本品は、取扱性、保存安定性が良好で、口中でなめらかに溶け、上品な甘味とまろやかな風味を有し、自体、インスリン抵抗性を惹起し難い食用クリームである。 This product is an edible cream that has good handleability and storage stability, dissolves smoothly in the mouth, has an elegant sweetness and mellow flavor, and does not itself cause insulin resistance.
参考例3
<生クリーム>
実施例1乃至6で得た本発明のインスリン抵抗性の予防及び/又は改善剤1質量部を、生クリーム5質量部に溶解し、プレートヒーターで加熱殺菌し、無菌的に缶詰して製品を得た。Reference example 3
<Fresh cream>
1 part by mass of the insulin resistance preventive and / or ameliorating agent of the present invention obtained in Examples 1 to 6 is dissolved in 5 parts by mass of fresh cream, sterilized by heating with a plate heater, and aseptically canned to obtain a product. Obtained.
本品は、取扱性、保存安定性が良好で、温和な甘味で、風味もよく、フルーツ、コーヒー、ココア、紅茶などの調味用に用いることのできる、自体、インスリン抵抗性を惹起し難い生クリームである。 This product has good handling and storage stability, mild sweetness, good flavor, and can be used for seasoning fruits, coffee, cocoa, tea, etc. Cream.
参考例4
<ハム>
豚もも肉1,000質量部に、食塩15質量部、及び硝酸カリウム3質量部を均一にすり込んで、冷室に1昼夜堆積する。これを実施例1乃至6で得た本発明のインスリン抵抗性の予防及び/又は改善剤100質量部、水500質量部、食塩100質量部、硝酸カリウム3質量部、及び香辛料からなる塩漬液に冷室で7日間漬け込み、次いで、常法に従い、冷水で洗浄し、ひもで巻き締め、燻煙し、クッキングし、冷却包装して製品を得た。Reference example 4
<Ham>
A pork thigh of 1,000 parts by mass is uniformly rubbed with 15 parts by mass of sodium chloride and 3 parts by mass of potassium nitrate, and deposited overnight in a cold room. This was cooled in a salted solution comprising 100 parts by mass of the insulin resistance preventing and / or improving agent of the present invention obtained in Examples 1 to 6, 500 parts by mass of water, 100 parts by mass of sodium chloride, 3 parts by mass of potassium nitrate, and spices. The product was soaked in a room for 7 days, then washed with cold water, wound with string, smoked, cooked and cooled and packaged according to a conventional method.
本品は、色合いもよく、風味良好で、自体、インスリン抵抗性を惹起し難いハムである。 This product is a ham that has good color, good flavor, and hardly induces insulin resistance.
参考例5
<粉末卵黄>
生卵から調製した卵黄をプレート式加熱殺菌機で60乃至64℃で殺菌し、得られる液状卵黄1質量部に対し、実施例2乃至4で得た本発明のインスリン抵抗性の予防及び/又は改善剤0.1質量部及びマルトース5質量部の割合で混合した後、バットに移し、一夜放置して、固化し、切削機にかけて粉末化し、粉末卵黄を得た。Reference Example 5
<Powdered egg yolk>
Egg yolk prepared from raw eggs is sterilized at 60 to 64 ° C. with a plate-type heat sterilizer, and 1 part by mass of the liquid egg yolk thus obtained is used to prevent and / or prevent insulin resistance of the present invention obtained in Examples 2 to 4. After mixing at a ratio of 0.1 part by weight of the improving agent and 5 parts by weight of maltose, it was transferred to a vat, left to stand overnight, solidified, and powdered by a cutting machine to obtain a powdered egg yolk.
本品は、取扱性、保存安定性が良好で、自体、インスリン抵抗性を惹起し難い粉末卵黄である。 This product is a powdered egg yolk that has good handleability and storage stability and hardly induces insulin resistance.
参考例6
<バターロールパン>
実施例2乃至4で得た本発明のインスリン抵抗性の予防及び/又は改善剤1質量部、強力粉118質量部、砂糖8質量部、食塩1.7質量部、脱脂粉乳2質量部、海洋酵母(三共フーヅ(株)製)2質量部、全卵12質量部、無塩バター10質量部、牛乳20質量部、水75質量部をミキサーにかけ、24℃で、低速6分、中速5分で混捏し、一時停止した後、更に中速で4.5分間混捏し、生地を調製した。次いで、これを醗酵(フロアータイムは50分間)させた。生地は40gに分割して丸めを行い、20分間のベンチタイムで処理した後、40℃、湿度80%のホイロにて50分間発酵させた。発酵終了後、上火230℃、下火200℃のオーブンにて7分間焼成し、バターロールを調製した。Reference Example 6
<Butter roll>
Insulin resistance preventive and / or ameliorating agent of 1 part by weight of the present invention obtained in Examples 2 to 4, 118 parts by weight of strong powder, 8 parts by weight of sugar, 1.7 parts by weight of salt, 2 parts by weight of skim milk powder, marine yeast (Sankyo Food Co., Ltd.) 2 parts by mass, 12 parts by mass of whole egg, 10 parts by mass of unsalted butter, 20 parts by mass of milk, and 75 parts by mass of water are put in a mixer, and at 24 ° C, low speed 6 minutes, medium speed 5 minutes The mixture was kneaded and temporarily stopped, and further kneaded for 4.5 minutes at medium speed to prepare a dough. This was then fermented (floor time was 50 minutes). The dough was divided into 40 g, rounded, treated with a bench time of 20 minutes, and then fermented with a proofer at 40 ° C. and 80% humidity for 50 minutes. After the completion of fermentation, the mixture was baked for 7 minutes in an oven at 230 ° C. and 200 ° C. to prepare a butter roll.
本品は、取扱性、保存安定性が良好で、自体、インスリン抵抗性を惹起し難いバターロールである。 This product is a butter roll that has good handleability and storage stability and hardly induces insulin resistance.
参考例7
<チョコレートバー>
下記原材料を用い、常法にしたがって、大豆パフ入りチョコレートバーを製造した。
<原材料>
大豆パフ 13.5質量部
チョコレート用油脂 60.50質量部
分離大豆蛋白質 5.00質量部
粉末ローヤルゼリー 5.00質量部
α,α−トレハロース(純度99%以上、 14.68質量部
株式会社林原生物化学研究所製)から
なる本発明のインスリン抵抗性の
予防及び/又は改善剤
ヘスペリジン 0.85質量部
スクラロース(高甘味度甘味料) 0.12質量部
香料 適量Reference Example 7
<Chocolate bar>
Using the following raw materials, a chocolate bar containing soybean puffs was produced according to a conventional method.
<Raw materials>
Soy puff 13.5 parts by weight Fats and oils for chocolate 60.50 parts by weight Isolated soy protein 5.00 parts by weight Powdered royal jelly 5.00 parts by weight α, α-trehalose (purity 99% or more, 14.68 parts by weight Hayashibara Biological Co., Ltd. Insulin resistance preventive and / or ameliorating agent of the present invention consisting of Hesperidin 0.85 parts by mass Sucralose (high sweetness sweetener) 0.12 parts by mass Fragrance
本品は、取扱性、保存安定性が良好で、自体、インスリン抵抗性を惹起し難いチョコレートバーである。 This product is a chocolate bar that has good handleability and storage stability, and hardly induces insulin resistance.
参考例8
<バター>
市販のバター10質量部に、実施例2乃至4で得た本発明のインスリン抵抗性の予防及び/又は改善剤5質量部を添加し、均一に混合し、本発明のインスリン抵抗性の予防及び/又は改善剤が配合されたバターを得た。Reference Example 8
<Butter>
To 5 parts by weight of commercially available butter, 5 parts by weight of the insulin resistance preventing and / or improving agent of the present invention obtained in Examples 2 to 4 was added and mixed uniformly to prevent the insulin resistance of the present invention and Butter with / or improved agent was obtained.
本品は、取扱性、保存安定性が良好で、自体、インスリン抵抗性を惹起し難いバターである。 This product has good handleability and storage stability, and is a butter that itself hardly induces insulin resistance.
参考例9
<牛脂>
牛脂10質量部に、実施例2乃至4で得た本発明のインスリン抵抗性の予防及び/又は改善剤5質量部を添加し、均一に混合し、本発明のインスリン抵抗性の予防及び/又は改善剤が配合された牛脂を得た。Reference Example 9
<Beef tallow>
To 5 parts by weight of beef tallow, 5 parts by weight of the insulin resistance preventing and / or improving agent of the present invention obtained in Examples 2 to 4 is added and mixed uniformly to prevent and / or prevent insulin resistance of the present invention. Obtained beef tallow mixed with an improving agent.
本品は、取扱性、保存安定性が良好で、自体、インスリン抵抗性を惹起し難い牛脂である。 This product is beef tallow with good handleability and storage stability and hardly induces insulin resistance.
参考例10
<脂肪乳剤>
本発明のα,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)1質量部、精製ダイズ油10質量部、濃グリセリン1.2質量部、精製卵黄レシチン1.2質量部、及び超純水250質量部とを均一に混合し、常法にしたがって加熱滅菌して、無菌的に300ml容ポリエチレン製バッグに充填して、本発明のインスリン抵抗性の予防及び/又は改善剤が配合された脂肪乳剤を得た。Reference Example 10
<Fat emulsion>
1 part by mass of α, α-trehalose of the present invention (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), 10 parts by mass of purified soybean oil, 1.2 parts by mass of concentrated glycerin, 1.2 parts by mass of purified egg yolk lecithin And 250 parts by mass of ultrapure water are uniformly mixed, heat-sterilized according to a conventional method, and aseptically filled into a 300 ml polyethylene bag, the preventive and / or ameliorating agent for insulin resistance of the present invention Was obtained.
本品は、取扱性、保存安定性が良好で、自体、インスリン抵抗性を惹起し難い脂肪乳剤である。 This product is a fat emulsion that has good handleability and storage stability and hardly induces insulin resistance.
参考例11
<パッケージ組体>
実施例2乃至4で得た本発明のインスリン抵抗性の予防及び/又は改善剤10質量部を、遮光性プラスチック製の第1の容器に収容し密閉するとともに、市販の食用菜種油100質量部(脂肪酸組成:パルミチン酸約3%、ステアリン酸約1%、オレイン酸約16%、リノール酸約16%)を遮光性プラスチック製の第2の容器に収容し密閉したものを、第3の遮光性プラスチック製の容器に収容して、本発明のパッケージ組体を得た。第1の容器内に収容されたα,α−トレハロースの量は、第2の容器に収容された食用菜種油によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善し得るα,α−トレハロースの量である。Reference Example 11
<Package assembly>
10 parts by mass of the insulin resistance preventive and / or ameliorating agent of the present invention obtained in Examples 2 to 4 is housed and sealed in a first container made of light-shielding plastic, and 100 parts by mass of commercially available edible rapeseed oil ( Fatty acid composition: about 3% palmitic acid, about 1% stearic acid, about 16% oleic acid, about 16% linoleic acid) in a second light-shielding plastic container, The package assembly of the present invention was obtained by being housed in a plastic container. The amount of α, α-trehalose contained in the first container is the amount of α, α-trehalose that can effectively prevent and / or improve insulin resistance caused by the edible rapeseed oil contained in the second container. Is the amount.
当該パッケージ組体の使用例として、第3の容器から、第1及び第2の容器を取り出し、それら容器内にそれぞれ収容されたα,α−トレハロースと食用菜種油の全量を取り出し、第1の容器に収容されたα,α−トレハロースを直接、又は、適量のミネラルウォーターなどに溶解し、第2の容器に収容された食用菜種油を用いて調理した料理に添加するか、或いはその前後に、複数回に分けて摂取することにより、食用菜種油によりもたらされるインスリン抵抗性を効果的に改善することができる。また、当該パッケージ組体の使用例として、第3の容器から、第1及び第2の容器を取り出し、それら容器内にそれぞれ収容されたα,α−トレハロースと食用菜種油の全量を取り出し混合し、例えば、ドレッシング用食用油として好適に用いることもできる。 As an example of use of the package assembly, the first and second containers are taken out from the third container, and the total amount of α, α-trehalose and edible rapeseed oil respectively contained in the containers is taken out, and the first container The α, α-trehalose contained in the container is dissolved directly or in an appropriate amount of mineral water, etc., and added to a dish prepared using edible rapeseed oil contained in the second container, or before and after By taking in divided portions, the insulin resistance caused by the edible rapeseed oil can be effectively improved. Moreover, as a usage example of the package assembly, the first and second containers are taken out from the third container, and the total amount of α, α-trehalose and edible rapeseed oil respectively contained in the containers is taken out and mixed, For example, it can also be suitably used as an edible oil for dressing.
参考例12乃至55
下記表6に示す参考例12乃至55に列挙した高脂肪食品を、それら各食品中に含まれる脂肪酸総質量に対し、α,α−トレハロース(純度99%以上、株式会社林原生物化学研究所製)からなる本発明のインスリン抵抗性の予防及び/又は改善剤を、無水物換算で、表6に示す配合量となるように添加して製造した。Reference Examples 12 to 55
The high-fat foods listed in Reference Examples 12 to 55 shown in Table 6 below are α, α-trehalose (purity 99% or more, manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) with respect to the total mass of fatty acids contained in each food. Insulin resistance preventive and / or ameliorating agent of the present invention comprising the following components was added so as to have a blending amount shown in Table 6 in terms of anhydride.
参考例12乃至55に示す高脂肪食品のいずれも、自体、ヒトが日常的に比較的多く摂取してもインスリン抵抗性が惹起され難い食品である。 Any of the high-fat foods shown in Reference Examples 12 to 55 is a food that itself is unlikely to cause insulin resistance even when a human ingests a relatively large amount on a daily basis.
本発明のインスリン抵抗性の予防及び/又は改善剤は、所謂、現代病/生活習慣病とも言われている種々の疾患を惹起するインスリン機能不全の予防と改善の鍵を握る、インスリン抵抗性を予防及び/又は改善するための薬剤、詳細には、ヒトを含む哺乳類において、高脂肪食品/飼料によりもたらされるインスリン抵抗性を効果的に予防及び/又は改善するための薬剤であり、しかも、腸間膜脂肪細胞の肥大化を抑制し、耐糖能を改善することのできる薬剤である。当該インスリン抵抗性の予防及び/又は改善剤によれば、インスリン抵抗性を効果的に予防及び/又は改善できることから、例えば、メタボリックシンドローム、癌、アルツハイマー病、睡眠時無呼吸症候群、多のう性卵巣症候群(PCOS)などの疾患を改善できるのではないかと考えられる。また、当該インスリン抵抗性の予防及び/又は改善剤が有効成分とするα,α−トレハロースは、昨今、工業的に廉価かつ大量に市場に供給されている、有用で安全性の高い糖質であることから、これを有効成分とする当該インスリン抵抗性の予防及び/又は改善剤は、経済性、安全性の面からみて、ヒトを含む哺乳類に日常的に安心して摂取させるか投与することができ、しかも、工業的に廉価かつ大量に製造できる優れた実益を有する。 The agent for preventing and / or improving insulin resistance according to the present invention has an insulin resistance which is the key to prevention and improvement of insulin dysfunction causing various diseases, which are also called so-called modern diseases / lifestyle diseases. An agent for preventing and / or improving, in particular, an agent for effectively preventing and / or improving insulin resistance caused by high fat food / feed in mammals including humans, and It is a drug that can suppress hypertrophy of mesenteric fat cells and improve glucose tolerance. According to the agent for preventing and / or improving insulin resistance, since insulin resistance can be effectively prevented and / or improved, for example, metabolic syndrome, cancer, Alzheimer's disease, sleep apnea syndrome, polymorphism It may be possible to improve diseases such as ovarian syndrome (PCOS). In addition, α, α-trehalose, which is an active ingredient of the agent for preventing and / or improving insulin resistance, is a useful and highly safe carbohydrate that has been supplied industrially at a low price and in large quantities. Therefore, the agent for preventing and / or improving insulin resistance containing this as an active ingredient can be taken or administered daily to mammals including humans with peace of mind from the viewpoint of economy and safety. Moreover, it has an excellent practical advantage that it can be industrially inexpensively manufactured in large quantities.
本発明は斯くも顕著なる産業上の有用性を具備する発明であり、斯界に貢献すること誠に多大な発明である。 The present invention is an invention having such remarkable industrial utility, and it is a great invention to contribute to this field.
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CN104208695A (en) * | 2013-05-30 | 2014-12-17 | 苏州科景生物医药科技有限公司 | Multifunctional composition, and preparation method and application thereof |
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JP2007063221A (en) * | 2005-09-01 | 2007-03-15 | Pokka Corp | Insulin resistance improving agent, hypoglycemic agent and diabetes prevention agent |
JP2009179622A (en) * | 2008-02-01 | 2009-08-13 | Unitika Ltd | Composition for oral administration |
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GB2353934A (en) * | 1999-09-09 | 2001-03-14 | British Sugar Plc | Nutritional compositions comprising trehalose for persons suffering from diabetes |
JP2007063221A (en) * | 2005-09-01 | 2007-03-15 | Pokka Corp | Insulin resistance improving agent, hypoglycemic agent and diabetes prevention agent |
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