JP2018115131A - Oral composition for promoting sugar uptake - Google Patents
Oral composition for promoting sugar uptake Download PDFInfo
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- JP2018115131A JP2018115131A JP2017007898A JP2017007898A JP2018115131A JP 2018115131 A JP2018115131 A JP 2018115131A JP 2017007898 A JP2017007898 A JP 2017007898A JP 2017007898 A JP2017007898 A JP 2017007898A JP 2018115131 A JP2018115131 A JP 2018115131A
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Abstract
Description
本発明は、筋肉細胞若しくは筋肉組織に対する糖（グルコース）取り込み促進作用を有するトリペプチド、並びに当該トリペプチドの糖取り込み促進用組成物、抗疲労用組成物、または血糖値上昇抑制用組成物の有効成分としての用途に関する。 INDUSTRIAL APPLICABILITY The present invention is effective for a tripeptide having an action of promoting sugar (glucose) uptake to muscle cells or muscle tissues, and a composition for promoting sugar uptake, anti-fatigue, or a composition for suppressing an increase in blood glucose level of the tripeptide. It relates to the use as an ingredient.
糖（グルコース）は、骨格筋細胞（筋肉細胞）に取り込まれると、エネルギー生産の源になるグリコーゲンとして筋肉組織内に貯蔵されるが、この筋肉組織中のグリコーゲン貯蔵量と筋肉の抗疲労（持久力）との間には、正の相関があることが報告されている（非特許文献１）。このため、筋肉組織中の貯蔵量が多いほど、運動等による筋肉疲労が軽減される。 When sugar (glucose) is taken up by skeletal muscle cells (muscle cells), it is stored in muscle tissue as glycogen, which is a source of energy production. The amount of glycogen stored in muscle tissue and muscle anti-fatigue (endurance) It has been reported that there is a positive correlation with (force) (Non-patent Document 1). For this reason, muscle fatigue due to exercise or the like is reduced as the amount of storage in the muscle tissue is increased.
このため、筋肉の持久力、抗疲労力、または疲労回復力を高めるためには、筋肉組織中のグリコーゲン貯蔵量を高めることが重要である。 For this reason, it is important to increase the amount of glycogen stored in the muscle tissue in order to increase the endurance, anti-fatigue, or fatigue recovery of the muscle.
従来、糖取り込み促進作用を有する物質として、微生物由来の低分子物質や天然植物抽出物（非特許文献２）、乳ホエイタンパク質またはその加水分解物（特許文献１）、アラキドン酸（特許文献２）、ロイシン（非特許文献３）、イソロイシン（非特許文献４）、並びにロイシン及びイソロイシンを有するジペプチド（特許文献３、非特許文献５）等が知られており、抗疲労剤や血糖値上昇抑制剤としての用途も提案されている。 Conventionally, low molecular weight substances derived from microorganisms, natural plant extracts (Non-patent Document 2), milk whey proteins or hydrolysates thereof (Patent Document 1), arachidonic acid (Patent Document 2) , Leucine (Non-Patent Document 3), isoleucine (Non-Patent Document 4), dipeptides having leucine and isoleucine (Patent Document 3, Non-Patent Document 5), and the like are known, anti-fatigue agents and blood glucose level increase inhibitors Applications have also been proposed.
かかる実情に鑑み、本発明は筋肉細胞若しくは筋肉組織に対して糖（グルコース）取り込み促進作用を有する物質、及びそれを含有する組成物（糖取り込み促進用組成物）、特に経口摂取可能な組成物を提供することを課題とする。また本発明は、当該糖取り込み促進作用を有する物質を含む組成物の他の用途、具体的には抗疲労用組成物、または血糖値上昇抑制用組成物としての用途を提供することを課題とする。 In view of such circumstances, the present invention is a substance having an action of promoting sugar (glucose) uptake to muscle cells or muscle tissue, and a composition containing the substance (composition for promoting sugar uptake), particularly a composition that can be taken orally. It is an issue to provide. Another object of the present invention is to provide another use of the composition containing the substance having an action of promoting sugar uptake, specifically, an application as an anti-fatigue composition or a composition for suppressing an increase in blood glucose level. To do.
本発明者らは上記課題に鑑み、鋭意検討を重ねていたところ、ピログルタミン酸残基をＮ末端に有するトリペプチド、具体的にはピログルタミル−ロイシル−プロリン（pGlu-Leu-Pro）に筋肉細胞への糖取り込み促進作用があること、またその糖取り込み促進作用は従来その作用が知られているロイシンやイソロイシン、並びにロイシン及びイソロイシンを有するジペプチドよりも強く、低濃度で同等若しくはそれ以上の作用効果を発揮することを見出した。 In view of the above problems, the present inventors have made extensive studies, and found that a tripeptide having a pyroglutamic acid residue at the N-terminus, specifically, pyroglutamyl-leucyl-proline (pGlu-Leu-Pro) and muscle cells. Has the effect of promoting the uptake of sugar, and the action of promoting the uptake of sugar is stronger than leucine and isoleucine, and dipeptides having leucine and isoleucine, which have been known to have the same action, and equivalent or higher effects at low concentrations I found out that
本発明はかかる知見に基づいて完成したものであり、下記の実施態様を包含するものである。 The present invention has been completed based on this finding, and includes the following embodiments.
項１．pGlu-Leu-Pro及びpELP前駆物質からなる群より選択される少なくとも１種を有効成分とする糖取り込み促進用経口組成物。
項２．上記pELP前駆物質が、pGlu-Leu-Proのアミノ酸配列を有する、可食性植物に由来するタンパク質、ペプチド、またはそれらの加水分解物である項１記載の糖取り込み促進用経口組成物。
Item 1. An oral composition for promoting sugar uptake comprising at least one selected from the group consisting of pGlu-Leu-Pro and a pELP precursor as an active ingredient.
Item 2. Item 2. The oral composition for promoting sugar uptake according to Item 1, wherein the pELP precursor is a protein, peptide derived from an edible plant having the amino acid sequence of pGlu-Leu-Pro, or a hydrolyzate thereof.
項３．筋持久力の向上、筋肉の疲労軽減、筋肉の疲労回復促進、体力の増進、及び運動パフォーマンスの向上からなる群から選択される少なくとも１つのために使用される項１または２に記載する糖取り込み促進用経口組成物。なお、当該経口組成物は、糖取り込み促進という意図の有無にかかわらず、実質的に糖取り込み促進作用を有し、筋持久力の向上、筋肉の疲労軽減、筋肉の疲労回復促進、体力の増進、及び運動パフォーマンスの向上からなる群から選択される少なくとも１つのために使用されるものであればよい。つまり、当該発明は、pGlu-Leu-Pro及びpELP前駆物質からなる群より選択される少なくとも１種を有効成分とする、筋持久力の向上用組成物、筋肉の疲労軽減用組成物、筋肉の疲労回復促進用組成物、体力の増進用組成物、または運動パフォーマンス向上用組成物と言い換えることができる。 Item 3. Item 3. The sugar intake according to item 1 or 2, which is used for at least one selected from the group consisting of improving muscle endurance, reducing muscle fatigue, promoting recovery from muscle fatigue, enhancing physical strength, and improving exercise performance. Oral composition for promotion. It should be noted that the oral composition has an effect of promoting sugar uptake regardless of the intention of promoting sugar uptake, improving muscle endurance, reducing muscle fatigue, promoting muscle fatigue recovery, and improving physical strength. And at least one selected from the group consisting of improving athletic performance. That is, the invention relates to a composition for improving muscle endurance, a composition for reducing muscle fatigue, comprising at least one selected from the group consisting of pGlu-Leu-Pro and pELP precursor as an active ingredient, In other words, it can be restated as a composition for promoting fatigue recovery, a composition for enhancing physical strength, or a composition for improving exercise performance.
項４．血糖値上昇抑制のために使用される項１または項２に記載する糖取り込み促進用経口組成物。当該経口組成物も、糖取り込み促進という意図の有無にかかわらず、実質的に糖取り込み促進作用を有し、血糖値上昇抑制のために使用されるものであればよい。つまり、当該発明は、pGlu-Leu-Pro及びpELP前駆物質からなる群より選択される少なくとも１種を有効成分とする血糖値上昇抑制用組成物と言い換えることができる。
項５．飲食物である項１乃至４のいずれかに記載する糖取り込み促進用経口組成物。
Item 4. Item 3. The oral composition for promoting sugar uptake according to Item 1 or Item 2 used for suppressing an increase in blood glucose level. The oral composition may also be used as long as it has an action of promoting glucose uptake and is used for suppressing an increase in blood sugar level, regardless of the intention of promoting sugar uptake. That is, the present invention can be paraphrased as a composition for suppressing an increase in blood glucose level, which comprises at least one selected from the group consisting of pGlu-Leu-Pro and a pELP precursor as an active ingredient.
Item 5. Item 5. The oral composition for promoting sugar uptake according to any one of Items 1 to 4, which is a food or drink.
本発明の経口組成物によれば、pGlu-Leu-Proの作用に基づいて、筋肉組織への糖取り込みを効果的に促進することができ、それにより筋肉組織へのグリコーゲン貯蔵を促進することができ、筋持久力の向上、筋肉の疲労軽減、筋肉の疲労回復促進、体力の増進、または／および運動パフォーマンスの向上を図ることが可能になる。 According to the oral composition of the present invention, it is possible to effectively promote sugar uptake into muscle tissue based on the action of pGlu-Leu-Pro, thereby promoting glycogen storage in muscle tissue. It is possible to improve muscle endurance, reduce muscle fatigue, promote recovery from muscle fatigue, increase physical strength, and / or improve exercise performance.
また、本発明の経口組成物を食前、または食事と一緒に服用することで、血液中の糖の筋肉細胞（筋肉組織）への取り込みを促進することができ、その結果、血糖値の上昇を抑制することが可能になる。 In addition, by taking the oral composition of the present invention before or together with a meal, it is possible to promote the uptake of sugar in blood into muscle cells (muscle tissue), and as a result, increase in blood sugar level. It becomes possible to suppress.
本発明の糖取り込み促進用経口組成物は、pGlu-Leu-ProおよびpELP前駆物質からなる群より選択される少なくとも１種を有効成分とすることを特徴とする。 The oral composition for promoting sugar uptake according to the present invention comprises at least one selected from the group consisting of pGlu-Leu-Pro and a pELP precursor as an active ingredient.
本発明の有効成分のひとつとして使用されるpGlu-Leu-Proは、ピログルタミン酸（pGlu）、ロイシン（Leu）及びプロリン（Pro）の３つのアミノ酸がペプチド結合してなるトリペプチドである。特に断りのない限り、「pGlu」はピログルタミン酸のＬ-またはＤ-異性体の両方を含み、同様に「Leu」および「Pro」もそれぞれロイシンおよびプロリンのＬ-またはＤ-異性体の両方を含む。好ましくはいずれのアミノ酸も天然に存在するＬ-異性体である。 PGlu-Leu-Pro used as one of the active ingredients of the present invention is a tripeptide formed by peptide bonding of three amino acids, pyroglutamic acid (pGlu), leucine (Leu) and proline (Pro). Unless otherwise noted, “pGlu” includes both the L- or D-isomer of pyroglutamic acid, and similarly “Leu” and “Pro” include both the L- or D-isomer of leucine and proline, respectively. Including. Preferably any amino acid is a naturally occurring L-isomer.
pELP前駆物質としては、酵素による加水分解によりpGlu-Leu-Pro（pELP）を生成する、pGlu-Leu-Proのアミノ酸配列を含むタンパク質やペプチドを挙げることができる。ここで酵素による加水分解には生体内での反応も含まれる。例えば、pELP前駆物質には、pGlu-Leu-Pro（pELP）の直接的な前駆体（direct precuser）となるタンパク質やペプチド、及び当該前駆体の前駆体、つまりpGlu-Leu-Pro（pELP）のプロ前駆体（proprecuser）となるタンパク質やペプチド、並びにその更なる前駆体が含まれる。 Examples of the pELP precursor include proteins and peptides containing the amino acid sequence of pGlu-Leu-Pro that generate pGlu-Leu-Pro (pELP) by enzymatic hydrolysis. Here, the hydrolysis by an enzyme includes a reaction in vivo. For example, pELP precursors include proteins and peptides that are direct precusers of pGlu-Leu-Pro (pELP), and precursors of the precursors, that is, pGlu-Leu-Pro (pELP) Included are proteins and peptides that become proprecusers, as well as further precursors thereof.
pGlu-Leu-Pro（pELP）の直接的な前駆体としては、制限されないものの、グルタミン（Gln）、ロイシン（Leu）及びプロリン（Pro）の３つのアミノ酸がペプチド結合してなるトリペプチド（Gln-Leu-Pro）を例示することができる。またpGlu-Leu-Pro（pELP）のプロ前駆体としては、アミノ酸配列中にGln-Leu-Proの配列を含むペプチドを挙げることができる。具体的には、米ペプチド、米糠ペプチド、コーンペプチド、大豆ペプチド、エンドウペプチド及び小麦ペプチド等、可食性植物に由来するペプチドを例示することができる。 Although not limited as a direct precursor of pGlu-Leu-Pro (pELP), a tripeptide (Gln-) in which three amino acids of glutamine (Gln), leucine (Leu) and proline (Pro) are bound by a peptide. Leu-Pro). Examples of the pro-precursor of pGlu-Leu-Pro (pELP) include a peptide containing the Gln-Leu-Pro sequence in the amino acid sequence. Specifically, peptides derived from edible plants such as rice peptide, rice bran peptide, corn peptide, soybean peptide, pea peptide and wheat peptide can be exemplified.
制限されないものの、米ペプチドとしては19 kDa globulin（別名：Alpha-globulin）（由来：Oryza sativa subsp. japonica (Rice)）（http://www.uniprot.org/uniprot/P29835）を挙げることができる。当該米ペプチドは186アミノ酸残基からなるペプチド（うちN末端からの22アミノ酸配列はシグナルペプチド領域）であり、166-168の領域にGln-Leu-Proを含んでいる。 Although not limited, rice peptides include 19 kDa globulin (also known as Alpha-globulin) (origin: Oryza sativa subsp. Japonica (Rice)) (http://www.uniprot.org/uniprot/P29835) . The rice peptide is a peptide consisting of 186 amino acid residues (of which the 22 amino acid sequence from the N-terminal is the signal peptide region) and contains Gln-Leu-Pro in the region of 166-168.
コーンペプチドとしては10 kD zein protein（由来：Zea mays(Maize)）（http://www.uniprot.org/uniref/UniRef100_Q41881）を挙げることができる。当該コーンペプチドは150アミノ酸残基からなるペプチドであり、124-126の領域にGln-Leu-Proを含んでいる。またコーンペプチドとしては19kD alpha zeinB1（由来： Zea mays (Maize)）（http://www.uniprot.org/uniref/UniRef100_Q946V6）を挙げることができる。当該コーンペプチドは234アミノ酸残基からなるペプチドであり、83-85および135-137の領域にGln-Leu-Proを含んでいる（Patrick Argos, et al., THE JOURNAOLF BIOLOGICAL CHEMISTRY,Vol.257, No.17, pp. 9984-9990, 1982, Fig.2参照）。 Examples of the corn peptide include 10 kD zein protein (derived from Zea mays (Maize)) (http://www.uniprot.org/uniref/UniRef100_Q41881). The corn peptide is a peptide consisting of 150 amino acid residues and contains Gln-Leu-Pro in the region of 124-126. Further, examples of the corn peptide include 19 kD alpha zeinB1 (derived from Zea mays (Maize)) (http://www.uniprot.org/uniref/UniRef100_Q946V6). The corn peptide is a peptide consisting of 234 amino acid residues and contains Gln-Leu-Pro in the region of 83-85 and 135-137 (Patrick Argos, et al., THE JOURNAOLF BIOLOGICAL CHEMISTRY, Vol.257, No. 17, pp. 9984-9990, 1982, see Fig. 2).
大豆ペプチドとしては、Basic 7S globulin（由来：Glycine max (Soybean) (Glycine hispida)）（http://www.uniprot.org/uniprot/P13917）を挙げることができる。当該大豆ペプチドは427アミノ酸残基からなるペプチド（うちN末端からの24アミノ酸配列はシグナルペプチド領域）であり、362-364の領域にGln-Leu-Proを含んでいる。 Examples of soy peptides include Basic 7S globulin (derived from Glycine max (Soybean) (Glycine hispida)) (http://www.uniprot.org/uniprot/P13917). The soybean peptide is a peptide consisting of 427 amino acid residues (of which the 24 amino acid sequence from the N-terminal is the signal peptide region) and contains Gln-Leu-Pro in the region of 362-364.
エンドウペプチドとしては、His5 protein（由来：Pisumsativum subsp. elatius）（http://www.uniprot.org/uniref/UniRef100_A0A0C7L825）を挙げることができる。当該エンドウペプチドは256アミノ酸残基からなるペプチドであり、137-139の領域にGln-Leu-Proを含んでいる。 小麦ペプチドとしては、γgliadin（由来：Triticum aestivum(Wheat)）（http://www.uniprot.org/uniref/UniRef100_P04730）を挙げることができる。当該小麦ペプチドは244アミノ酸残基からなるペプチドであり、175-177の領域にGln-Leu-Proを含んでいる。また小麦ペプチドとしては、HMW gluteninsubunit 1By9（由来：Triticum aestivum (Wheat)）（http://www.uniprot.org/uniref/UniRef100_Q03871）を挙げることができる。当該小麦ペプチドは705アミノ酸残基からなるペプチドであり、688-690の領域にGln-Leu-Proを含んでいる。 Examples of the pea peptide include His5 protein (derived from Pisumsativum subsp. Elatius) (http://www.uniprot.org/uniref/UniRef100_A0A0C7L825). The pea peptide is a peptide consisting of 256 amino acid residues and contains Gln-Leu-Pro in the region of 137-139. Examples of wheat peptides include γgliadin (derived from Triticum aestivum (Wheat)) (http://www.uniprot.org/uniref/UniRef100_P04730). The wheat peptide is a peptide consisting of 244 amino acid residues and contains Gln-Leu-Pro in the region of 175-177. Examples of wheat peptides include HMW gluteninsubunit 1By9 (derived from Triticum aestivum (Wheat)) (http://www.uniprot.org/uniref/UniRef100_Q03871). The wheat peptide is a peptide consisting of 705 amino acid residues and contains Gln-Leu-Pro in the region of 688-690.
小麦ペプチドとしては、αgliadin（由来：Triticum aestivum(Wheat)）（http://www.uniprot.org/uniref/UniRef100_A0A023WGB8）を挙げることができる。当該小麦ペプチドは279アミノ酸残基からなるペプチドであり、135-137および254-256の領域にGln-Leu-Proを含んでいる。 Examples of wheat peptides include αgliadin (derived from Triticum aestivum (Wheat)) (http://www.uniprot.org/uniref/UniRef100_A0A023WGB8). The wheat peptide is a peptide consisting of 279 amino acid residues and contains Gln-Leu-Pro in the region of 135-137 and 254-256.
さらに、生体内における酵素反応によってpGlu-Leu-Pro（pELP）となる、上記直接前駆体及びプロ前駆体以外の、さらなる前駆体としては、上記と同様に、アミノ酸配列中にGln-Leu-Proの配列を含むタンパク質またはそのサブユニットを挙げることができる。具体的には、米タンパク質（グロブリン）、米糠タンパク質、コーングルテン、大豆タンパク質、エンドウタンパク質及び小麦グルテン等の可食性植物に由来するタンパク質、並びにαZeinやβZein等のZeinの一部のサブユニットを挙げることができる。 Further, as a further precursor other than the direct precursor and the pro-precursor, which becomes pGlu-Leu-Pro (pELP) by an enzymatic reaction in vivo, as described above, Gln-Leu-Pro is included in the amino acid sequence. Or a subunit thereof. Specifically, protein derived from edible plants such as rice protein (globulin), rice bran protein, corn gluten, soy protein, pea protein and wheat gluten, and some subunits of Zein such as αZein and βZein be able to.
本発明が対象とするpGlu-Leu-ProおよびpELP前駆物質は、その調製方法を特に問うものではないが、一例を挙げると、例えば（i）固相法などのペプチド合成の定法を用いてアミノ酸から合成する方法、（ii）pGlu-Leu-Proまたは／およびpELP前駆物質を含有する可食性植物またはその部分から抽出し、必要であればそれをさらに精製処理する方法、または（iii）可食性植物またはその部分から抽出したpELP前駆物質（ペプチド若しくはタンパク質）を酵素で加水分解し、必要であればそれをさらに精製処理する方法等によって調製することができる。ちなみに、本発明において、上記加水分解に際して酵素に代えて酸を用いることは、ピログルタミン酸がグルタミン酸になることから好ましくない。なお、精製方法としては、吸着処理法、膜分離法、溶媒分画法、ＨＰＬＣ等のカラムクロマトグラフィー等の定法を用いることができる。 The pGlu-Leu-Pro and pELP precursors targeted by the present invention are not particularly limited in their preparation method. For example, (i) For example, (i) an amino acid using a conventional peptide synthesis method such as a solid phase method (Ii) extraction from an edible plant or part thereof containing pGlu-Leu-Pro or / and pELP precursor and further purification if necessary, or (iii) edible A pELP precursor (peptide or protein) extracted from a plant or a part thereof can be prepared by a method of hydrolyzing with an enzyme and further purifying it if necessary. Incidentally, in the present invention, it is not preferable to use an acid instead of an enzyme in the hydrolysis because pyroglutamic acid becomes glutamic acid. As a purification method, a conventional method such as an adsorption treatment method, a membrane separation method, a solvent fractionation method, or column chromatography such as HPLC can be used.
pGlu-Leu-ProおよびpELP前駆物質の調製方法として具体的には、例えば、（i）の固相法によるpGlu-Leu-Proの合成は、例えばWO2010/032322を参考にして、ペプチド合成機を用いて下記の方法で実施することができる。なお、下記方法で使用される保護及び脱保護反応、縮合反応、洗浄方法、並びに固相担体との結合及び解離反応は定法に従うことができる。 Specifically, as a method for preparing pGlu-Leu-Pro and pELP precursors, for example, the synthesis of pGlu-Leu-Pro by the solid phase method of (i) is carried out using a peptide synthesizer with reference to, for example, WO2010 / 032322. The following method can be used. In addition, the protection and deprotection reaction, the condensation reaction, the washing method, and the binding and dissociation reaction with the solid phase carrier that are used in the following methods can follow conventional methods.
［固相法によるpGlu-Leu-Proの合成］
（a）Ｃ末端アミノ酸であるプロリンのカルボキシル基を固相担体（2-chlorotrityl chloride resin：Barlos樹脂）に結合させて、Pro-Barlos樹脂を得る。
（b）ロイシンのアミノ基をFmoc基等の保護基によって保護し、Fmoc-Leuを調製する。
（c）Fmoc-Leuを活性化して、活性化Fmoc-Leuを得る。
（d）Pro-Barlos樹脂に活性化Fmoc-Leuを加えて縮合反応させ、洗浄し、Fmoc-Leu-Pro-Barlos樹脂を得る。
（e）Fmoc-Leu-Pro-Barlos樹脂のFmoc基を除去し、洗浄し、Leu-Pro-Barlos樹脂を得る。
（f）Leu-Pro-Barlos樹脂に、pyroGluを縮合させて洗浄し、pGlu-Leu-Pro-Barlos樹脂を得る。
（g）pGlu-Leu-Pro-Barlos樹脂から固相担体（Barlos樹脂）を解離し、洗浄し、目的のトリペプチド（pGlu-Leu-Pro）を含む調製物を得る。
[Synthesis of pGlu-Leu-Pro by solid phase method]
(A) Pro-Barlos resin is obtained by binding the carboxyl group of proline, which is a C-terminal amino acid, to a solid phase carrier (2-chlorotrityl chloride resin: Barlos resin).
(B) Fmoc-Leu is prepared by protecting the amino group of leucine with a protecting group such as Fmoc group.
(C) Activate Fmoc-Leu to obtain activated Fmoc-Leu.
(D) Activated Fmoc-Leu is added to Pro-Barlos resin to cause a condensation reaction, and washed to obtain Fmoc-Leu-Pro-Barlos resin.
(E) Fmoc group of Fmoc-Leu-Pro-Barlos resin is removed and washed to obtain Leu-Pro-Barlos resin.
(F) Condensation of pyroGlu with Leu-Pro-Barlos resin and washing to obtain pGlu-Leu-Pro-Barlos resin.
(G) The solid phase carrier (Barlos resin) is dissociated from the pGlu-Leu-Pro-Barlos resin and washed to obtain a preparation containing the target tripeptide (pGlu-Leu-Pro).
斯くして得られるpGlu-Leu-Pro含有調製物は、次いでＨＰＬＣで精製することで、純度95％以上のトリペプチド（pGlu-Leu-Pro）として調製することができる。 The pGlu-Leu-Pro-containing preparation thus obtained can be prepared as a tripeptide (pGlu-Leu-Pro) with a purity of 95% or more by subsequent purification by HPLC.
なお、pELP前駆物質の固相法による合成も、そのアミノ酸配列に応じて、上記方法に準じて定法により実施することができる。 The synthesis of the pELP precursor by the solid phase method can also be carried out by a conventional method according to the above method depending on the amino acid sequence.
また（iii）の加水分解法によるpGlu-Leu-ProまたはpELP前駆物質の調製は、例えばKiyono T, et al.: Identification o pyroglutamyl peptides in Japanese rice wine, sake:Presence of hepatoprotectivepyroGlu-Leu. J Agric Food Chem, 61 ; 11660-11667 (2013)の記載を参考にして、下記の方法で実施することができる。なお、下記方法で使用される加水分解方法、カラム吸着及び溶出方法等は定法に従うことができる。 The preparation of pGlu-Leu-Pro or pELP precursor by the hydrolysis method of (iii) is, for example, Kiyono T, et al .: Identification o pyroglutamyl peptides in Japanese rice wine, sake: Presence of hepatoprotectivepyro Glu-Leu. J Agric Food Chem, 61; 11660-11667 (2013), with reference to the description, can be carried out by the following method. In addition, the hydrolysis method used in the following method, column adsorption, elution method, etc. can follow a conventional method.
［加水分解によるpGlu-Leu-ProまたはpELP前駆物質の調製］
（a）アミノ酸配列pGlu-Leu-Proを含む可食性植物由来タンパク質を原料として、これを酵素を用いて加水分解する。
（b）上記で調製されるタンパク質加水分解物からピログルタミル基をＮ末端にもつペプチドを濃縮する。具体的には、下記（ア）〜（オ）の工程を実施する。
（ア）強カチオン交換樹脂（例えば、AG50W-x8、Bio-Rad）を50容量％エタノール水溶液に分散させ、カラムに充填して洗浄する。
（イ）上記で調製したカラムに10mM 塩酸水溶液を流して、カラムを平衡化する。
（ウ）平衡化したカラムに、上記（b）で調製したタンパク質加水分解物（例えば、0.1g/mL）を供し、カラムに吸着しない画分（ピログルタミルペプチド含有画分）を回収し、真空乾燥する。
（エ）上記画分を、0.1%トリフルオロ酢酸を含む30%アセトニトリル水溶液で平衡化したサイズ排除クロマトグラフィー（ SuperdexPeptide 10/300 GL、GEヘルスケア）でさらに分画する。この際、波長216nmの吸光度をモニターし、pGlu-Leu-Proの分子量（339）の近い画分を回収する。
（オ）回収した画分をさらに下記条件の逆相クロマトグラフィーで分画する。
[Preparation of pGlu-Leu-Pro or pELP precursor by hydrolysis]
(A) Using an edible plant-derived protein containing the amino acid sequence pGlu-Leu-Pro as a raw material, it is hydrolyzed using an enzyme.
(B) Concentrate a peptide having a pyroglutamyl group at the N-terminus from the protein hydrolyzate prepared above. Specifically, the following steps (a) to (e) are performed.
(A) A strong cation exchange resin (for example, AG50W-x8, Bio-Rad) is dispersed in a 50% by volume aqueous ethanol solution, packed in a column, and washed.
(A) Flow 10 mM hydrochloric acid solution through the column prepared above to equilibrate the column.
(C) The equilibrated column is subjected to the protein hydrolyzate prepared in (b) above (for example, 0.1 g / mL), and the fraction not adsorbed on the column (the fraction containing pyroglutamyl peptide) is collected and vacuumed. dry.
(D) The above fraction is further fractionated by size exclusion chromatography (SuperdexPeptide 10/300 GL, GE Healthcare) equilibrated with 30% acetonitrile aqueous solution containing 0.1% trifluoroacetic acid. At this time, the absorbance at a wavelength of 216 nm is monitored, and a fraction having a molecular weight (339) close to that of pGlu-Leu-Pro is collected.
(E) The collected fraction is further fractionated by reverse phase chromatography under the following conditions.
カラム： Cosmosil 5C18 MS-II, Nacalai tesuque
移動相Ａ：0.1v/v％ギ酸水溶液
移動相Ｂ：80v/v％アセトニトリルを含む0.1v/v％ギ酸水溶液
グラジェント条件：移動相Ｂの濃度 0％（0 min）→80％（15min）→100％（20 min）
検出波長：214nm。
Column: Cosmosil 5C18 MS-II, Nacalai tesuque
Mobile phase A: 0.1 v / v% formic acid aqueous solution Mobile phase B: 0.1 v / v% formic acid aqueous solution containing 80 v / v% acetonitrile Gradient condition: concentration of mobile phase B 0% (0 min) → 80% (15 min) → 100% (20 min)
Detection wavelength: 214 nm.
なお、ここで可食性植物由来タンパク質としては前述する穀類（小麦、大麦、トウモロコシ、米、米糠）、豆類、及び芋類に由来するタンパク質を挙げることができる。タンパク質加水分解における酵素処理の条件（例えば、基質の濃度、酵素の量、処理温度、ｐＨ、または時間など）は適宜設定することができる。 Here, examples of the edible plant-derived protein include proteins derived from the above-mentioned cereals (wheat, barley, corn, rice, rice bran), beans, and potatoes. Conditions for enzyme treatment in protein hydrolysis (for example, substrate concentration, enzyme amount, treatment temperature, pH, time, etc.) can be appropriately set.
タンパク質の加水分解に使用する酵素としては、プロテアーゼまたはペプチダーゼ挙げることができる。好ましくは食品衛生上無害なものであり、例えばバチラス属またはアスペルギルス属に属する微生物由来のプロテアーゼ；パパイヤ由来のパパインやパイナップル由来のブロメラインなどの植物由来のプロテアーゼ；ペプシンやパンクレアチンなどの動物由来のプロテアーゼを挙げることができる。これらは一種単独で、または２種以上を任意に組み合わせて使用することができる。例えば、可食性植物由来タンパク質として小麦グルテンを使用する場合、酵素としてパンクレアチンおよびアミノペプチダーゼを併用することができる。これらの酵素で例えば37℃、8時間で処理して得られた加水分解物を上記（ア）〜（オ）の工程に供することで所期のpELPを得ることができる。 Examples of the enzyme used for protein hydrolysis include protease and peptidase. Preferably, it is harmless for food hygiene, for example, a protease derived from a microorganism belonging to the genus Bacillus or Aspergillus; a protease derived from a plant such as papaya derived from papaya or a bromelain derived from pineapple; a protease derived from an animal such as pepsin or pancreatin Can be mentioned. These can be used individually by 1 type or in combination of 2 or more types. For example, when wheat gluten is used as the edible plant-derived protein, pancreatin and aminopeptidase can be used in combination. The desired pELP can be obtained by subjecting the hydrolyzate obtained by treatment with these enzymes, for example, at 37 ° C. for 8 hours to the steps (a) to (e) above.
なお、タンパク質加水分解酵素による処理温度（反応温度）は、制限されないものの好ましくは25〜60℃程度、よりこの35〜55℃程度を挙げることができる、また処理時間は制限されないものの、1〜10時間程度を挙げることができる。 In addition, although the processing temperature (reaction temperature) by a protein hydrolase is not restrict | limited, Preferably it is about 25-60 degreeC, More about this 35-55 degreeC can be mentioned, Moreover, although processing time is not restrict | limited, 1-10 Time can be mentioned.
なお、上記方法で調製したペプチドまたはタンパク質が、目的のpGlu-Leu-Proのアミノ酸配列を有するpGlu-Leu-ProまたはpELP前駆物質であることを確認する方法として、ピログルタミルペプチド分析法を挙げることができる（参考：Kiyono T, et al.: J Agric Food Chem, 61 ; 11660-11667 (2013)）。 As a method for confirming that the peptide or protein prepared by the above method is a pGlu-Leu-Pro or pELP precursor having the target pGlu-Leu-Pro amino acid sequence, a pyroglutamyl peptide analysis method may be mentioned. (Reference: Kiyono T, et al .: J Agric Food Chem, 61; 11660-11667 (2013)).
かかる分析法は、例えば以下の方法に従って行うことができる。 Such an analysis method can be performed, for example, according to the following method.
［ピログルタミルペプチド分析法］
（a）対象とするペプチドまたはタンパク質をさらにペプシンとパンクレアチンを用いて加水分解処理する。
（b）上記加水分解処理物を、予め50v/v％エタノール水溶液で洗浄し、10mM 塩酸水溶液で平衡化しておいた強カチオン交換樹脂（例えば、AG50W-x8、Bio-Rad）を供し、カラムに吸着しない画分（ピログルタミルペプチド含有画分）を回収し、真空乾燥する。
（c）これを蒸留水に溶解し、12,000rpmで3分間遠心分離したものを、0.1%トリフルオロ酢酸を含む30%アセトニトリル水溶液で平衡化したサイズ排除クロマトグラフィー（ SuperdexPeptide 10/300 GL、GEヘルスケア）で分画する。この際、波長216nmの吸光度をモニターしながら分画し、得られた画分をそれぞれ回収して乾燥する。
（d）上記で調製した乾燥消化産物を、下記条件のLC-MS/MSを用いて、ピログルタミルペプチドの標準品のピークと比較して、Ｎ末端からpGluを遊離させたペプチドのアミノ酸配列を決定する（プレカーサーイオンスキャン）。
[Pyroglutamyl peptide analysis]
(A) The target peptide or protein is further hydrolyzed using pepsin and pancreatin.
(B) The above hydrolyzed product was washed with a 50 v / v% aqueous ethanol solution and equilibrated with a 10 mM aqueous hydrochloric acid solution, and a strong cation exchange resin (for example, AG50W-x8, Bio-Rad) was applied to the column. The fraction that does not adsorb (the fraction containing pyroglutamyl peptide) is collected and vacuum dried.
(C) Size exclusion chromatography (SuperdexPeptide 10/300 GL, GE Health), which was dissolved in distilled water and centrifuged at 12,000 rpm for 3 minutes, equilibrated with 30% acetonitrile in water containing 0.1% trifluoroacetic acid Fractionation with care. At this time, fractionation is performed while monitoring the absorbance at a wavelength of 216 nm, and the obtained fractions are collected and dried.
(D) The dry digestion product prepared above was compared with the peak of a standard product of pyroglutamyl peptide using LC-MS / MS under the following conditions, and the amino acid sequence of the peptide from which pGlu was released from the N-terminus was obtained. Determine (precursor ion scan).
［LC-MS/MSで分析条件］
使用機器：LCMS-8040（トリプル四重極型高速クロマトグラフ質量分析計、SHIMADZU）
カラム：Cosmosil 5C18 MS-II （2mm×150mm）
移動相Ａ：0.1v/v％ギ酸水溶液
移動相Ｂ：80v/v％アセトニトリルを含む0.1v/v％ギ酸水溶液
グラジェント条件：移動相Ｂの濃度 0％（0min）→80％（15min）→100％（20min）。
[Conditions for LC-MS / MS analysis]
Equipment used: LCMS-8040 (triple quadrupole high-speed chromatograph mass spectrometer, SHIMADZU)
Column: Cosmosil 5C18 MS-II (2mm x 150mm)
Mobile phase A: 0.1 v / v% formic acid aqueous solution Mobile phase B: 0.1 v / v% formic acid aqueous solution containing 80 v / v% acetonitrile Gradient condition: mobile phase B concentration 0% (0 min) → 80% (15 min) → 100% (20min).
測定イオンの設定は、標準品を測定して得られたピークより実施することができる。 The measurement ion can be set from a peak obtained by measuring a standard product.
なお、プレカーサーイオンスキャンとは、Q1（１段目のMS）でスキャンし、Q2（衝突室）で衝突誘導解離した後、Q3（２段目のMS）で特定のm/zに固定して検出する分析モードであり、これにより特定のm/zのフラグメントを生成する化合物だけを特異的に検出することができる。 Precursor ion scan means scanning with Q1 (first stage MS), collision induced dissociation in Q2 (collision chamber), and then fixing to a specific m / z with Q3 (second stage MS). This is an analysis mode for detection, whereby only compounds that produce a specific m / z fragment can be specifically detected.
なお、LC-MS/MS分析に代えて、（c）の工程で得られた反応物を、定法に従ってアミノ酸分析法に供することで、Ｎ末端からpGluを遊離させたペプチドのアミノ酸配列を決定することもできる。 Instead of LC-MS / MS analysis, the amino acid sequence of the peptide from which pGlu was liberated from the N-terminal is determined by subjecting the reaction product obtained in step (c) to amino acid analysis according to a conventional method. You can also.
本発明が対象とする「組成物」には、糖取り込み促進作用を有する有効成分として、pGlu-Leu-ProまたはpELP前駆物質をそれぞれ単独で有する組成物、並びにこれらを２種以上組み合わせて含有する組成物が含まれる。当該組成物に含まれるpGlu-Leu-ProまたはpELP前駆物質の配合割合としては、当該組成物が経口摂取することで体内で筋肉での糖取り込み促進作用を発揮する量であればよく、０．１〜１００重量％の範囲で適宜設定調整することができる。 The “composition” targeted by the present invention contains a composition having pGlu-Leu-Pro or a pELP precursor alone as an active ingredient having an action of promoting sugar uptake, and a combination of two or more thereof. A composition is included. The blending ratio of the pGlu-Leu-Pro or pELP precursor contained in the composition may be an amount that exhibits an action of promoting sugar uptake in muscles in the body when taken orally. It can be appropriately set and adjusted in the range of 1 to 100% by weight.
本発明の組成物は、前述するpGlu-Leu-Proまたは／およびpELP前駆物質（一種またはそれらの組み合わせを含む）を単離若しくは精製された状態で含むものであってもよいし、単離若しくは精製する前の加水分解処理物または溶媒抽出物をそのまま、あるいは濃縮、若しくは凍結乾燥した状態で含むものであってもよい。 The composition of the present invention may contain the aforementioned pGlu-Leu-Pro or / and pELP precursor (including one or a combination thereof) in an isolated or purified state, isolated or The hydrolyzed product or solvent extract before purification may be contained as it is, or it may be concentrated or lyophilized.
また本発明の組成物は、有効成分であるpGlu-Leu-Proまたは／およびpELP前駆物質の他に、他の可食性成分を含んでいてもよい。例えば、加水分解する原料として使用する可食性植物由来タンパク質やペプチド、それを加水分解することによって生じるpGlu-Leu-ProおよびpELP前駆物質以外のペプチド、加水分解に使用した酵素（不活性化物）等の触媒などを挙げることができる。また本発明の組成物の形態（固形製剤、液状製剤）やその用途（飲食物、医薬品）に応じて、それに適した任意の可食性成分を配合することもできる。 The composition of the present invention may contain other edible components in addition to the active ingredient pGlu-Leu-Pro and / or pELP precursor. For example, edible plant-derived proteins and peptides used as raw materials to be hydrolyzed, peptides other than pGlu-Leu-Pro and pELP precursors produced by hydrolyzing them, enzymes used for hydrolysis (inactivated products), etc. And the like. Moreover, according to the form (solid formulation, liquid formulation) of the composition of this invention, and its use (food-drinks, pharmaceuticals), the arbitrary edible component suitable for it can also be mix | blended.
本発明の組成物は経口組成物として、飲食物または経口医薬品として利用することができる。 The composition of the present invention can be used as an oral composition, as a food or drink, or as an oral medicine.
ここで本発明が対象とする飲食物は、筋肉細胞への糖（グルコース）取り込み促進作用、ひいては筋肉組織へのグリコーゲン貯蔵促進作用を有する飲食物であり、斯くして筋持久力の向上、筋肉の疲労軽減、筋肉の疲労回復促進、体力の増進、または／および運動パフォーマンスの向上を図ることができる。このため本発明の飲食物は、筋持久力の向上、筋肉の疲労軽減、筋肉の疲労回復促進、体力の増進、および運動パフォーマンスの向上からなる群より選択される少なくとも１つを目的（用途）として使用することができるものである。 The foods and drinks targeted by the present invention are foods and drinks that have an action of promoting sugar (glucose) uptake into muscle cells and, in turn, an action of promoting glycogen storage in muscle tissue, thus improving muscle endurance, It is possible to reduce fatigue, promote recovery of muscle fatigue, increase physical strength, and / or improve exercise performance. For this reason, the food and drink of the present invention has at least one purpose (use) selected from the group consisting of improving muscle endurance, reducing muscle fatigue, promoting recovery from muscle fatigue, increasing physical strength, and improving exercise performance. It can be used as
このため本発明の飲食物は、好ましくは筋持久力の向上、筋肉の疲労軽減、筋肉の疲労回復、体力の増進（向上）、または／および運動パフォーマンス向上を希望する被験者（消費者）、ないし筋持久力の低下、筋肉の疲労、体力の低下、または／および運動パフォーマンスの低下が気になる被験者（消費者）に対して、筋持久力の向上効果、筋肉の疲労軽減効果、筋肉の疲労回復効果、体力の増進（向上）効果、運動パフォーマンス向上効果またはこれらを示唆するヘルスクレームを有する保健機能食品（特定保健用食品、機能性表示食品、栄養機能食品）、並びに一般食品として提供することができる。これらの飲食物には、病者用食品、介護食、経管栄養食（胃ろう食、腸ろう食、経鼻経管栄養食）、栄養補助食品、製剤形態（錠剤、軟カプセル剤、硬カプセル剤、散剤、顆粒剤、ドリンク剤、シロップ剤、ゼリー剤等）を有するサプリメントが含まれる。なお、これらの飲食物には、ヒト以外の哺乳類に対して用いられる飼料も含まれる。 For this reason, the food and drink of the present invention is preferably a subject (consumer) who wants to improve muscle endurance, reduce muscle fatigue, recover muscle fatigue, improve (improve) physical strength, and / or improve exercise performance, or For subjects (consumers) who are concerned about decreased muscle endurance, muscle fatigue, physical strength, and / or decreased exercise performance, muscle endurance improvement effect, muscle fatigue reduction effect, muscle fatigue Provide health function foods (specific health foods, functional labeling foods, functional nutrition foods), and general foods that have recovery effects, physical fitness enhancement (improvement) effects, exercise performance improvement effects or health claims that suggest these Can do. These foods and drinks include food for the sick, nursing food, tube feeding (gastric fistula, intestinal fistula, nasal tube feeding), dietary supplements, pharmaceutical forms (tablets, soft capsules, hard Supplements with capsules, powders, granules, drinks, syrups, jellies, etc.). These foods and drinks include feeds used for mammals other than humans.
これらの飲食物の形態は特に制限されるものではない。一例を挙げれば、例えば、飲料、粉末また顆粒状の飲料、ゼリー状食品（ゼリー、寒天、ゼリー状飲料等）、ガム、グミ、キャンディー、クッキー、クラッカー、ビスケット、氷菓（アイスクリーム、アイスキャンディ、シャーベット、かき氷等）、レトルト食品等を制限なく挙げることができる。またサプリメントについては上記するように各種の製剤形態（錠剤、軟カプセル剤、硬カプセル剤、散剤、顆粒剤、ドリンク剤、シロップ剤、ゼリー剤等）を有することができる。 The form of these foods and drinks is not particularly limited. For example, for example, beverages, powdered or granular beverages, jelly-like foods (jelly, agar, jelly-like beverages, etc.), gums, gummi, candy, cookies, crackers, biscuits, ice confectionery (ice cream, ice candy, Sherbet, shaved ice, etc.), retort food, etc. can be mentioned without limitation. Moreover, about a supplement, it can have various formulation forms (a tablet, a soft capsule, a hard capsule, a powder, a granule, a drink, a syrup, a jelly, etc.) as mentioned above.
後述する実験例で示すように、pGlu-Leu-Proは少なくとも５μＭ（0.005mM）で筋肉細胞への糖取り込み促進作用を発揮する。特許第5728512号公報によれば、Ile-Leuは1mMで糖取り込み促進効果があり、ラット（体重約360g）に100mg/kg体重の割合で投与することで血糖値が有意に下がるとされている。かかる知見に基づけば、pGlu-Leu-Proは、体重１kgあたり少なくとも0.5mg（100mg/kg×0.005=0.5mg/kg）の投与で筋肉細胞への糖取り込み促進作用を得ることができ、これに基づいて上記各種の効果を享受することが可能になると考えられる。好ましくは体重１kgあたり0.5〜20mg、より好ましくは0.5〜10mgのpGlu-Leu-Proを服用することが望ましい。このことから、例えば体重50kgのヒトの場合、上記効果を得るためには、１日あたり25mg以上、好ましくは25〜1000mg、より好ましくは25〜500mgのpGlu-Leu-Proを服用することが好ましい。かかる量は１日に単回服用してもよいし、複数回に分けて服用してもよい。例えば、pGlu-Leu-Proを５重量％の割合で含む飲食物の場合、当該飲食物を１日500mg以上摂取することで、１日あたり25mg以上のpGlu-Leu-Proの摂取が可能となる。 As shown in the experimental examples to be described later, pGlu-Leu-Pro exerts an action of promoting sugar uptake into muscle cells at least 5 μM (0.005 mM). According to Japanese Patent No. 5728512, Ile-Leu has an effect of promoting glucose uptake at 1 mM, and it is said that blood glucose level is significantly lowered by administration at a rate of 100 mg / kg body weight to rats (body weight about 360 g) . Based on this finding, pGlu-Leu-Pro can obtain a glucose uptake promoting action into muscle cells by administration of at least 0.5 mg / kg body weight (100 mg / kg × 0.005 = 0.5 mg / kg). Based on this, it is considered possible to enjoy the various effects described above. It is desirable to take 0.5 to 20 mg, more preferably 0.5 to 10 mg of pGlu-Leu-Pro per kg body weight. Therefore, for example, in the case of a human weighing 50 kg, it is preferable to take 25 mg or more, preferably 25 to 1000 mg, more preferably 25 to 500 mg of pGlu-Leu-Pro per day in order to obtain the above effect. . Such an amount may be taken once a day, or may be taken divided into a plurality of times. For example, in the case of foods and drinks containing 5% by weight of pGlu-Leu-Pro, intake of foods and drinks of 500 mg or more per day makes it possible to consume 25 mg or more of pGlu-Leu-Pro per day. .
なお、pELP前駆物質を含む飲食物の場合、当該飲食物は、経口摂取後、体内で酵素や酸で加水分解されて１kg体重あたり少なくとも0.5mg、好ましくは0.5〜20mg、より好ましくは0.5〜10mgのpGlu-Leu-Proを生成する割合で摂取されることが好ましい。 In the case of foods and drinks containing a pELP precursor, the foods are hydrolyzed with enzymes and acids in the body after ingestion and at least 0.5 mg, preferably 0.5 to 20 mg, more preferably 0.5 to 10 mg per kg body weight. Of pGlu-Leu-Pro is preferably ingested at a rate to produce pGlu-Leu-Pro.
当該筋持久力の向上や筋肉の抗疲労を目的とする飲食物は、制限されないものの、例えば、運動前、運動中、運動後、就寝前、飲食前、飲食と同時、筋力を必要とする例えば重労働の前後などに服用することが好ましい。 Foods and drinks for the purpose of improving the muscle endurance and anti-fatigue of the muscles are not limited, but, for example, before exercise, during exercise, after exercise, before going to bed, before eating and drinking, at the same time as eating and drinking, It is preferable to take it before and after heavy labor.
本発明の飲食物は、前述するように、これを服用することで体内において筋肉細胞（筋肉組織）への糖取り込み促進作用を発揮するため、これに伴って血液中に含まれる糖が骨格筋の細胞内に取り込まれて、その量が低減し、結果として血糖値の上昇を抑制することが可能になる。 As described above, the food and drink of the present invention exerts an action of promoting sugar uptake into muscle cells (muscle tissue) in the body by taking this, so that the sugar contained in the blood is accompanied by skeletal muscle. The amount is reduced and the increase in blood glucose level can be suppressed as a result.
ちなみに血液中の糖（グルコース）を骨格筋の細胞内に取り込むには、グルコーストランスポーター４（GLUT4）が重要である。GLUT4は、通常は細胞内に存在するが、pGlu-Leu-Pro等の糖取り込みを促進する刺激が加わると細胞膜に移動して、細胞内への糖の取り込みの輸送通路として機能することが知られている（亀井康富ら、月刊糖尿病,7(1);2-7(2015)、川中健太郎,学術の動向,10；42-46(2006)、特許第5728512号公報等参照）。 Incidentally, glucose transporter 4 (GLUT4) is important for taking sugar (glucose) in blood into cells of skeletal muscle. GLUT4 is normally present in cells, but it is known that when a stimulus that promotes sugar uptake such as pGlu-Leu-Pro is applied, it moves to the cell membrane and functions as a transport pathway for sugar uptake into the cell. (See Kamei Yasutomi et al., Monthly Diabetes Mellitus, 7 (1); 2-7 (2015), Kentaro Kawanaka, Academic Trends, 10; 42-46 (2006), Japanese Patent No. 5728512, etc.).
これらのことからわかるように、本発明の飲食物は、血糖値上昇抑制を目的（用途）として使用することもできる。このため本発明の飲食物は、糖尿病や血糖値上昇が気になる被験者（消費者）に対して、糖尿病予防効果、糖尿病悪化予防効果、糖尿病改善効果、血糖値上昇抑制効果またはこれらを示唆するヘルスクレームを有する保健機能食品（特定保健用食品、機能性表示食品、栄養機能食品）、並びに一般食品として提供することができる。 As can be seen from these, the food and drink of the present invention can also be used for the purpose (use) of suppressing an increase in blood glucose level. Therefore, the food and drink of the present invention suggests a diabetes prevention effect, a diabetes deterioration prevention effect, a diabetes improvement effect, a blood glucose level increase suppression effect or these for a subject (consumer) who is concerned about diabetes or an increase in blood glucose level. It can be provided as a health functional food having a health claim (food for specified health use, functional labeling food, functional nutrition food), and general food.
この場合の服用量も、pGlu-Leu-Proの服用量に換算して体重１kgあたり少なくとも0.5mg、好ましくは0.5〜20mg、より好ましくは0.5〜10mgを挙げることができる。pELP前駆物質を含む飲食物の場合は、上記の通り、経口摂取後、体内で加水分解されて１kg体重あたり少なくとも0.5mg、好ましくは0.5〜20mg、より好ましくは0.5〜10mgのpGlu-Leu-Proを生成する服用量を挙げることができる。 The dose in this case can also be at least 0.5 mg, preferably 0.5 to 20 mg, more preferably 0.5 to 10 mg per kg body weight in terms of pGlu-Leu-Pro dose. In the case of a food or drink containing a pELP precursor, as described above, after oral ingestion, it is hydrolyzed in the body and is at least 0.5 mg / kg body weight, preferably 0.5-20 mg, more preferably 0.5-10 mg of pGlu-Leu-Pro. The dose that produces can be mentioned.
当該血糖上昇抑制を目的とする飲食物は、制限されないものの、食前、または食事と一緒に服用することが好ましい。 Although the food and drink for the purpose of suppressing the increase in blood glucose is not limited, it is preferably taken before meals or with meals.
本発明が対象とする医薬品は、上記飲食物と同様に、筋肉細胞への糖（グルコース）取り込み促進作用、または／及び血糖値上昇抑制作用を作用効果とする経口用の医薬品である。かかる医薬品は、筋肉組織へのグリコーゲン貯蔵促進剤、血糖値上昇抑制剤、糖尿病治療剤、または糖尿病予防剤として使用することができる。 The drug targeted by the present invention is an oral drug having an effect of promoting an action of promoting sugar (glucose) uptake into muscle cells or / and an effect of suppressing an increase in blood glucose level, as in the case of the above-mentioned food and drink. Such a pharmaceutical can be used as a glycogen storage promoter for muscle tissue, a blood sugar level increase inhibitor, a diabetes therapeutic agent, or a diabetes preventive agent.
前述する飲食物と同様に、本発明の医薬品の投与量は、pGlu-Leu-Proの投与量に換算して体重１kgあたり少なくとも0.5mg、好ましくは0.5〜20mg、より好ましくは0.5〜10mgを挙げることができる。pELP前駆物質を含む医薬品の場合は、上記の通り、経口摂取後、体内で加水分解されて１kg体重あたり少なくとも0.5mg、好ましくは0.5〜20mg、より好ましくは0.5〜10mgのpGlu-Leu-Proを生成する投与量を挙げることができる。 Similarly to the food and drink described above, the dosage of the pharmaceutical of the present invention is at least 0.5 mg per kg body weight, preferably 0.5 to 20 mg, more preferably 0.5 to 10 mg in terms of the dosage of pGlu-Leu-Pro. be able to. In the case of a pharmaceutical containing a pELP precursor, as described above, after oral ingestion, it is hydrolyzed in the body, and at least 0.5 mg, preferably 0.5 to 20 mg, more preferably 0.5 to 10 mg of pGlu-Leu-Pro per kg body weight is obtained. The dose to be produced can be mentioned.
またこれを投与するタイミングとしては、用途によって異なり、前記飲食物と同様に、筋肉組織へのグリコーゲン貯蔵促進剤として使用する場合は、運動前、運動中、運動後、就寝前、飲食前、飲食と同時、筋力を必要とする例えば重労働の前後などに服用することが好ましく、血糖値上昇抑制剤、糖尿病予防剤または糖尿病改善剤として使用する場合は食前、または食事と一緒に服用することが好ましい。 In addition, the timing of administering this varies depending on the use. Similarly to the above-mentioned food and drink, when used as a glycogen storage promoter for muscle tissue, before exercise, during exercise, after exercise, before going to bed, before eating, At the same time, it is preferably taken before or after heavy work that requires muscular strength, and when used as a blood glucose level rise inhibitor, diabetes preventive agent or diabetes ameliorating agent, it is preferably taken before meals or with meals. .
なお、本発明の経口組成物（飲食物、医薬品）には、pGlu-Leu-Pro及びpELP前駆物質以外の可食性成分として、例えば、炭水化物、タンパク質、アミノ酸、ミネラル類および／またはビタミン類等を配合することができる。ここで、炭水化物としては、澱粉、コーンスターチ等の多糖類、デキストリン、スクロース、グルコース、フルクトース等のその他の糖類等が挙げられる。また、タンパク質としては、動物性タンパク質であっても、植物性タンパク質であっても、またはそれらの混合物であってもよく、例えば、乳タンパク質、大豆タンパク質、卵タンパク質等が挙げられる。また、アミノ酸としては、必須アミノ酸であるロイシン、イソロイシン、バリン、トリプトファン、フェニルアラニン、リジン、スレオニン、メチオニン、ヒスチジンや、非必須アミノ酸であるグルタミン、グリシン、アラニン、セリン、アスパラギン酸、グルタミン酸、アスパラギン、アルギニン、シスチン、チロシン、プロリン、ヒドロキシプロリン、オルニチン、タウリン等が挙げられる。また、ミネラル類としては、特に限定するものではないが、カルシウム、マグネシウム、鉄等が挙げられる。また、ナトリウムまたはカリウム、あるいはその他の栄養的必須元素である亜鉛、銅、クロム、セレン、マンガン、モリブデン等が挙げられる。また、ビタミン類としては、特に限定するものではないが、栄養的に必須であるビタミンＡ、ビタミンＢ１、ビタミンＢ２、ビタミンＢ６、ビタミンＢ１２、ビタミンＣ、ビタミンＤ，ビタミンＥ，ナイアシン、パントテン酸、葉酸、コエンザイムＱ１０等が挙げられる。 In addition, the oral composition (food / drink, pharmaceutical) of the present invention includes, for example, carbohydrates, proteins, amino acids, minerals and / or vitamins as edible components other than pGlu-Leu-Pro and pELP precursors. Can be blended. Here, examples of the carbohydrate include polysaccharides such as starch and corn starch, and other saccharides such as dextrin, sucrose, glucose and fructose. The protein may be an animal protein, a vegetable protein, or a mixture thereof, and examples thereof include milk protein, soybean protein, egg protein, and the like. As amino acids, leucine, isoleucine, valine, tryptophan, phenylalanine, lysine, threonine, methionine, histidine, and non-essential amino acids glutamine, glycine, alanine, serine, aspartic acid, glutamic acid, asparagine, arginine Cystine, tyrosine, proline, hydroxyproline, ornithine, taurine and the like. Moreover, as minerals, although it does not specifically limit, calcium, magnesium, iron, etc. are mentioned. Moreover, sodium, potassium, or other essential nutrient elements such as zinc, copper, chromium, selenium, manganese, and molybdenum can be used. In addition, vitamins are not particularly limited, but nutritionally essential vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, niacin, pantothenic acid, Examples include folic acid and coenzyme Q10.
以下、実験例及び実施例を用いて本発明を説明する。但し、当該実験例及び実施例は、本発明を説明するための例示であり、本発明はこれらの実験例及び実施例によって何ら制限されるものではない。 Hereinafter, the present invention will be described using experimental examples and examples. However, the experimental examples and examples are examples for explaining the present invention, and the present invention is not limited to these experimental examples and examples.
実験例１
下記の各アミノ酸、およびペプチドの各々について、筋肉細胞への糖（グルコース）取り込み促進作用を評価した。
Experimental example 1
For each of the following amino acids and peptides, the action of promoting sugar (glucose) uptake into muscle cells was evaluated.
ロイシン（Leu）：協和発酵キリン株式会社から入手
イソロイシン（Ile）：協和発酵キリン株式会社から入手
Ile-Leu：GL Biochem (Shanghai) Ltdから入手
Leu-Pro：化学合成にて製造
pGlu-Leu：RS synthesis（国産化学(株)経由）から入手
pGlu-Pro：GenScript（フナコシ（株）経由）から入手
pGlu-Leu-Pro（pELP）：株式会社医学生物学研究所から入手。
Leucine (Leu): Obtained from Kyowa Hakko Kirin Co., Ltd. Isoleucine (Ile): Obtained from Kyowa Hakko Kirin Co., Ltd.
Ile-Leu: Obtained from GL Biochem (Shanghai) Ltd
Leu-Pro: Manufactured by chemical synthesis
pGlu-Leu: Obtained from RS synthesis (via Kokusan Chemical Co., Ltd.)
pGlu-Pro: Obtained from GenScript (via Funakoshi Co., Ltd.)
pGlu-Leu-Pro (pELP): Obtained from Institute of Medical Biology.
（１）実験方法
下記工程に従って実験を行った。
（a）24wellのプレートに、細胞数が9.5×103 個／wellになるように正常ヒト骨格筋筋芽細胞を播種し、Growth 培地 （Skeletal Muscle Cell Growth Medium：DSファーマバイオメディカル）(1 mL/well)で２日間、37℃、5％CO2の条件下で培養した。
（b）全細胞数の60％がコンフルエント状態に達していることを確認した後、培地をSkeletal Muscle Cell Differentiation Medium（DSファーマバイオメディカル）(1 ml/well)に交換してさらに上記と同条件で７日間培養した。
（c）さらに、ペプチド等を含むDifferentiation mediumに交換し、30分後に培地（上清）を採取し、グルコース量を測定した（培地中のグルコース濃度：5.6mM（＝１g/L）
）。グルコース量測定にはGlucose Colormetric/FluorometricAssay Kit（BioVision）を用いた。このキットは、種々の生体由来試料中のグルコース量を直接測定するもので、キット中のGlucose Enzyme Mixがグルコースを特異的に酸化し、生じた生成物が、グルコースプローブと反応して呈色（λ=570nm)するので、これから正常ヒト骨格筋筋芽細胞中のグルコース濃度を評価することができる。
(1) Experimental method An experiment was performed according to the following steps.
(A) Normal human skeletal muscle myoblasts are seeded on a 24-well plate so that the number of cells is 9.5 × 10 3 cells / well. Growth medium (Skeletal Muscle Cell Growth Medium: DS Pharma Biomedical) (1 mL / well) for 2 days under conditions of 37 ° C. and 5% CO 2 .
(B) After confirming that 60% of the total number of cells has reached the confluent state, the medium was replaced with Skeletal Muscle Cell Differentiation Medium (DS Pharma Biomedical) (1 ml / well), and the same conditions as above. For 7 days.
(C) Further, the medium was replaced with a differentiation medium containing peptides and the like, and after 30 minutes, the medium (supernatant) was collected and the amount of glucose was measured (glucose concentration in the medium: 5.6 mM (= 1 g / L)
). Glucose Colormetric / Fluorometric Assay Kit (BioVision) was used for measuring the amount of glucose. This kit directly measures the amount of glucose in various biological samples. The Glucose Enzyme Mix in the kit specifically oxidizes glucose, and the resulting product reacts with the glucose probe to give a color ( λ = 570 nm), so that the glucose concentration in normal human skeletal muscle myoblasts can be evaluated.
（２）実験結果
骨格筋筋芽細胞中のグルコース濃度を表１に示す。
(2) Experimental results Table 1 shows the glucose concentration in skeletal muscle myoblasts.
この結果からわかるように、本発明が対象とするトリペプチド（pGlu-Leu-Pro）は、従来、糖取り込み促進作用が知られているロイシンやイソロイシン、並びにロイシン及びイソロイシンを有するジペプチド（Ile-Leu）と比較して低濃度で、高い糖取り込み促進作用を発揮することが確認された。このことから、本発明が対象とするトリペプチド（pGlu-Leu-Pro）によれば、筋肉組織への糖取り込みを効果的に促進することができ、それにより筋肉組織へのグリコーゲン貯蔵を促進することができ、筋持久力の向上、筋肉の疲労軽減、筋肉の疲労回復促進、体力の増進、または／および運動パフォーマンスの向上を図ることが可能になる。 As can be seen from these results, the tripeptide (pGlu-Leu-Pro) targeted by the present invention is leucine and isoleucine, which are conventionally known to promote sugar uptake, and dipeptides (Ile-Leu) containing leucine and isoleucine. It was confirmed that it exerts a high sugar uptake-promoting action at a low concentration compared to). Therefore, according to the tripeptide (pGlu-Leu-Pro) targeted by the present invention, it is possible to effectively promote sugar uptake into muscle tissue, thereby promoting glycogen storage in muscle tissue. It is possible to improve muscle endurance, reduce muscle fatigue, promote recovery from muscle fatigue, increase physical strength, and / or improve exercise performance.
また、本発明が対象とするトリペプチド（pGlu-Leu-Pro）を食前、または食事と一緒に服用することで、血液中の糖の筋肉細胞（筋肉組織）への取り込みを促進することができ、その結果、血糖値の上昇を抑制することが可能になる。 In addition, by taking the tripeptide (pGlu-Leu-Pro) targeted by the present invention before or together with meals, it is possible to promote the uptake of sugar in blood into muscle cells (muscle tissue). As a result, an increase in blood sugar level can be suppressed.
実験例２
男性2名、女性2名（体重は不明）に、絶食してから約12時間後に、コーンタンパク質加水分解物（コーンペプチド）を9 g含むタンパク質強化食品を摂取してもらった。摂取前、並びに0.5時間後、1時間後、2時間後、及び4時間後に血液を採取し、採取した血液を除蛋白した後、LC-MS/MSに供して、血液中に含まれるトリペプチド（pGlu-Leu-Pro）の量を測定した。
Experimental example 2
Two men and two women (whose weight was unknown) were asked to eat protein-enriched food containing 9 g of corn protein hydrolyzate (corn peptide) about 12 hours after fasting. Tripeptides contained in blood before ingestion, and after 0.5 hours, 1 hour, 2 hours, and 4 hours, blood was collected, the collected blood was deproteinized, and subjected to LC-MS / MS The amount of (pGlu-Leu-Pro) was measured.
なお、ここで使用したコーンタンパク質加水分解物（コーンペプチド）はとうもろこし蛋白質を酸、アルカリ、または酵素（プロテアーゼ等）を用いて加水分解して得られるアミノ酸が2から10個結合したオリゴペプチドである。これを人工消化液（酵素）で消化し、LC-MSで測定したところ、酵素処理前のものと比較してトリペプチド（pGlu-Leu-Pro）のピークが大きくなったことが確認された。このことから、当該コーンタンパク質加水分解物のアミノ酸配列にはGln-Leu-Proの配列が含まれていると考えられる。 The corn protein hydrolyzate (corn peptide) used here is an oligopeptide in which 2 to 10 amino acids are obtained by hydrolysis of corn protein with acid, alkali, or enzyme (protease etc.). . When this was digested with an artificial digest (enzyme) and measured by LC-MS, it was confirmed that the peak of the tripeptide (pGlu-Leu-Pro) was larger than that before the enzyme treatment. From this, it is considered that the amino acid sequence of the corn protein hydrolyzate contains the sequence of Gln-Leu-Pro.
結果を図１に示す。図１に示すように、コーンタンパク質加水分解物を摂取した後のヒト血液中にpGlu-Leu-Proが存在することが認められた。このことからアミノ酸配列中にGln-Leu-Proの配列を含むコーンタンパク質加水分解物を摂取することで体内でpGlu-Leu-Proが生成されることが確認された。 The results are shown in FIG. As shown in FIG. 1, it was confirmed that pGlu-Leu-Pro was present in human blood after ingesting corn protein hydrolyzate. From this, it was confirmed that pGlu-Leu-Pro was produced in the body by ingesting a corn protein hydrolyzate containing the Gln-Leu-Pro sequence in the amino acid sequence.
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| WO2012102308A1 (en) * | 2011-01-27 | 2012-08-02 | 新田ゼラチン株式会社 | Therapeutic agent and preventive agent for diabetes |
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