JP2004359607A - Agent for preventing/treating diabetic disease, and functional food for preventing/ameliorating diabetic disease - Google Patents
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、特定の化合物、より詳しくはアセキサム酸亜鉛を有効成分として含有する糖尿病性骨粗鬆症、糖尿病性高血糖症、糖尿病性高脂血症等の糖尿病性疾患の予防・治療剤や、糖尿病性疾患の予防・改善用機能性食品又は食品素材に関する。
【０００２】
【従来の技術】
わが国において多くの患者数を有する糖尿病は、慢性の高血糖とそれにともなう慢性の全身性代謝障害を主な特徴とする疾患であり、生活習慣病として位置づけられ、２１世紀の高齢化社会における大きな問題として取りあげられている。糖尿病は、インスリンが分泌されずブトウ糖の代謝がうまくなされないために血液中のブドウ糖濃度が増加し、高血糖状態となる結果、様々な症状が出現する病気であり、インスリン依存性糖尿病（Ｉ型糖尿病）とインスリン非依存性糖尿病（ＩＩ型糖尿病）に分類され、いずれもその発症には、遺伝因子と環境因子が関連している。インスリン依存性糖尿病（Ｉ型糖尿病）は若年で発病し、インスリンを注射しなければ治療できない。インスリン非依存性糖尿病（ＩＩ型糖尿病）は遺伝的要素が強いとされ、生まれつきインスリンをつくる細胞の力が弱い体質の人が、肥満、運動不足、ホルモンの分泌状態の変化等の誘因によりインスリンの供給が減少し必要量を満たさなくなり発病する。
【０００３】
また、糖尿病には種々の合併症があり、その中で、糖尿病疾患の合併症として、糖尿病性骨粗鬆症が医療の面から重要な課題として注目されている。かかる糖尿病性骨粗鬆症に関与する因子としてインスリン欠乏状態、高血糖状態、それに動脈硬化や神経障害、腎障害といった糖尿病に伴う合併症が挙げられ、絶対的および相対的インスリン欠乏が、骨芽細胞の機能や数を低下させ、さらに高血糖状態の持続で骨芽細胞内にソルビトールが蓄積することで骨芽細胞機能の低下が招来され、糖尿病初期には、尿糖排泄に伴う尿中カルシウム排泄の増加で、二次的に副甲状腺ホルモンの分泌が増加し骨吸収促進が起こるものの、長期的には副甲状腺の副甲状腺ホルモン分泌能が低下し、最終像は低回転型骨粗鬆症を呈するとされている（例えば、非特許文献１参照。）。更に、糖尿病状態では尿中亜鉛排泄が亢進し、生体内亜鉛レベルは負に傾くことが知られている。
【０００４】
糖尿病の治療剤としては、インシュリンの分泌を促すスルフォニウムウレア系製剤、食後の過血糖を抑制するα−グルコシダーゼ阻害剤、あるいは最近ではインシュリン抵抗性を改善するチアゾリジン系製剤等が用いられているが、製剤の投与又は服用により種々の副作用を伴うことがある等、治療剤として充分なものがない。特に、糖尿病状態において生じる骨量減少に起因する糖尿病性骨粗鬆症は難治性疾患であり、有効な治療剤がないのが現状である。
【０００５】
ところで、体内の亜鉛の欠乏は骨成長の遅延の誘因となることから、骨代謝調節における亜鉛の役割が明らかにされ、亜鉛が強い骨形成促進作用を発現することが解明されている。本発明者は既にアセキサム酸亜鉛が骨疾患予防・治療剤として有効であることを報告している（例えば、非特許文献２、特許文献１参照。）。
【０００６】
その他、アセキサム酸やその誘導体等を用いたものとして、例えば、生理学的に許容可能な活性ケア試薬としてアセキサム酸、及びこの活性試薬を含む脂肪相を含む唇のためのケアまたはメークアップ組成物（例えば、特許文献２参照。）や、アセキサム酸を鎮静剤として使用した化粧品または皮膚科用組成物（例えば、特許文献３参照。）等が知られているが、アセキサム酸亜鉛を用いた糖尿病性疾患の予防・治療剤等は知られていない。
【０００７】
【特許文献１】
特開平１０−２１８７６７号公報
【特許文献２】
特開平１１−２５５６１８号公報
【特許文献３】
特開２００２−３９３７１８号公報
【非特許文献１】
ＣＬＩＮＩＣＡＬ ＣＡＬＣＩＵＭ２０００年１０月号（Ｖｏｌ．１０ Ｎｏ．１０）ｐ９（１１８９）〜ｐ１６（１１９６）
【非特許文献２】
Ｙａｍａｇｕｃｈｉ Ｍ． Ｇａｏ ＹＨ． Ｇｅｎｅｒａｌ Ｐｈａｒｍａｃｏｌｏｇｙ ３０（３） ４２３−４２７， １９９８
【０００８】
【発明が解決しようとする課題】
本発明の課題は、糖尿病性高血糖症、糖尿病性高脂血症、糖尿病性骨粗鬆症等の糖尿病性疾患を改善することができる、副作用の少ない糖尿病性疾患の予防・治療剤や、糖尿病性疾患の予防・改善用機能性食品又は食品素材を提供することにある。
【０００９】
【課題を解決するための手段】
本発明者は、亜鉛化合物が糖尿病に対し有効に作用することを想定し鋭意研究を行った結果、アセキサム酸亜鉛に糖尿病性高血糖症、糖尿病性高脂血症、糖尿病性骨粗鬆症等の糖尿病疾患を改善する作用があることをたまたま見い出した。すなわち、ストレプトゾトシン投与によって、膵臓β細胞からのインスリン分泌障害により糖尿病状態が惹起されたＩ型糖尿病のモデル動物である実験的糖尿病ラットに、アセキサム酸亜鉛を経口投与したところ、血清中のカルシウムの上昇と無機リンの低下、高血糖、高脂血症が有意に改善され、また、実験的糖尿病ラットにおいて骨幹部組織や骨幹端部組織のカルシウム量や、ＤＮＡ量の減少が引き起こされ、アルカリ性ホスファターゼ活性の低下が観られたが、このカルシウム量やＤＮＡ量の減少、アルカリ性ホスファターゼ活性の低下がアセキサム酸亜鉛の経口投与によって極めて有意に改善されることの知見を得て、アセキサム酸亜鉛がＩ型及びＩＩ型の糖尿病に対する修復作用を発揮することを見い出し、本発明を完成するに至った。なお、アセキサム酸亜鉛と同様に、従来骨疾患治療剤として知られているカルシトニン、ビタミンＤ３化合物、ビタミンＫ２（メナキノン−４）、ビスホスホネート化合物、副甲状腺ホルモン等について、糖尿病性疾患の予防・治療効果調べてみたが、これらいずれにも糖尿病性疾患の予防・治療効果が認められなかった。
【００１０】
すなわち本発明は、一般式（Ｉ）
【化３】
【００１１】
また、本発明は、一般式（Ｉ）
【化４】
【００１２】
【発明の実施の形態】
本発明の糖尿病性疾患の予防・治療剤や、糖尿病性疾患の予防・改善用機能性食品又は食品素材としては、一般式（Ｉ）［式中、Ｒ１、Ｒ２は独立してＣ１〜Ｃ６のアルキル基を表し、ｍ、ｎは独立して１〜２０の整数を表す。］で示される化合物を有効成分として含有するものであれば特に制限されるものではない。かかる一般式（Ｉ）で示される化合物は分子量が１０００以下であり水に易溶であって、それゆえ腸管吸収が容易で、糖尿病疾患に対する優れた効能を有する。一般式（Ｉ）におけるカルバモイル基の置換基Ｒ１、Ｒ２は、独立してＣ１〜Ｃ６のアルキル基を示し、Ｃ１〜Ｃ６のアルキル基としては、具体的には、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基等を挙げることができる。
【００１３】
かかる一般式（Ｉ）で示される化合物としては、具体的には、ジ（Ｎ−メチル−５−カルバモイルペンタン酸）亜鉛、ジ（Ｎ−エチル−５−カルバモイルペンタン酸）亜鉛、ジ（Ｎ−メチル−６−カルバモイルヘキサン酸）亜鉛、ジ（Ｎ−エチル−６−カルバモイルヘキサン酸）亜鉛、ジ（Ｎ−メチル−７−カルバモイルヘプタン酸）亜鉛、ジ（Ｎ−メチル−５−カルバモイルヘプタン酸）亜鉛等を具体的に挙げることができる。このうち特に、式（ＩＩ）
【化５】
【００１４】
このような一般式（Ｉ）で示される化合物は血液中の亜鉛濃度の上昇作用、血糖量の降下作用、血液中の脂肪酸エステル濃度の降下作用、血液中のカルシウム濃度の降下作用、血液中の無機リン濃度の上昇作用、骨幹部組織及び骨幹端部組織中のカルシウム濃度の上昇作用、骨幹部組織及び骨幹端部組織中のＤＮＡ含有量の上昇作用、骨幹部組織及び骨幹端部組織中のアルカリ性ホスファターゼ活性上昇作用を有し、糖尿病性骨粗鬆症、糖尿病性高血糖症、糖尿病性高脂血症等に対して優れた効能を有する。
【００１５】
本発明の糖尿病性疾患の予防・治療剤は、薬学的に許容される通常の担体、結合剤、安定化剤、賦形剤、希釈剤、ｐＨ緩衝剤、崩壊剤、可溶化剤、溶解補助剤、等張剤等の各種調剤用配合成分を添加することができる他、他の糖尿病性高血糖症、糖尿病性高脂血症、糖尿病性骨粗鬆症等の糖尿病性疾患の治療薬と併用することもできる。
【００１６】
本発明の糖尿病性疾患の予防・治療剤の調製方法としては、公知の方法に基づき調製した一般式（Ｉ）で示される化合物をミキサー等で粉末とし、得られた粉末を常法により顆粒化、カプセル化、錠剤化する方法等を具体例に例示することができる。また、アセキサム酸亜鉛の調製方法としては公知の方法を具体例に例示することができる。
【００１７】
本発明において糖尿病性疾患とは、Ｉ型及び／又はＩＩ型糖尿病及びこれら糖尿病に起因する種々の合併症等の疾病の症状を呈した状態をいい、糖尿病性疾患としては、糖尿病性骨粗鬆症、糖尿病性高血糖症、糖尿病性高脂血症、糖尿病により体重が減少する症状や、糖尿病により血中ミネラル濃度が変動する症状、神経障害や網膜症や腎臓障害等の合併症などの症状を呈した状態を具体的に例示することができる。そして、本発明の糖尿病性疾患の予防・治療剤は、糖尿病性骨粗鬆症、糖尿病性高血糖症、糖尿病性高脂血症等の糖尿病性疾患の予防・改善作用を有することから、糖尿病患者又は糖尿病予備軍の人に経口投与することによる糖尿病性疾患の予防・治療方法に、あるいは、食品に添加配合することにより該食品を糖尿病性疾患の予防・改善作用を有する機能性食品や、薬理組成物食品素材として、有利に用いることができる。かかる本発明の糖尿病性疾患の予防・治療剤は通常経口投与され、治療剤として用いる場合は、アセキサム酸亜鉛として１日あたり１ｍｇ〜５ｇ／Ｋｇ体重、好ましくは１０〜１０００ｍｇ／Ｋｇ体重の範囲で摂取することにより、糖尿病性疾患を改善することができるが、症状、性別、年齢等に応じて、摂取量は適宜調整することができる。また、本発明の糖尿病性疾患の予防薬として使用する場合は、予め摂取することにより糖尿病性疾患の罹患率を低下させることができる。予防剤としての摂取方法は治療剤として用いる場合と同様の方法によることができ、摂取量は治療剤より少量から同量とすることができる。
【００１８】
アセキサム酸亜鉛を有効成分として含有する本発明の糖尿病性疾患の予防・改善用機能性食品又は食品素材は、前記本発明の糖尿病性疾患の予防・治療剤を飲食品原料の一部として用いたり、あるいは製造工程又は製造後に添加・配合することにより得ることができる。かかる機能性食品としては特に制限されるものではなく、クッキー、パン、ケーキ、煎餅などの焼き菓子、ラムネ菓子等などの錠菓、羊羹などの和菓子、プリン、ゼリー、アイスクリーム類などの冷菓、チューインガム、キャンディ等の菓子類や、クラッカー、チップス等のスナック類や、うどん、そば等の麺類や、かまぼこ、ハム、魚肉ソーセージ等の魚肉練り製品や、チーズ、バターなどの乳製品や、みそ、しょう油、ドレッシング、マヨネーズ、甘味料等の調味類や、豆腐、こんにゃく、その他佃煮、餃子、コロッケ、サラダ、スープ、シチュー等の各種総菜や、ヨーグルト、ドリンクヨーグルト、ジュース、牛乳、豆乳、酒類、コーヒー、紅茶、煎茶、ウーロン茶、スポーツ飲料等の各種飲料などを具体的に例示することができる。例えば、アセキサム酸亜鉛を微粉末化し、該微粉末を常法に従い打錠することにより錠菓を製造することができ、この場合かかる微粉末を造粒した後に打錠することもできる。また、アセキサム酸亜鉛を微粉末化し、これに乳糖、デキストリン、乾燥酵母等を配合したものを打錠することもできる。
【００１９】
【実施例】
以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。
実施例１［材料］
実験動物は、ウイスター系雄ラット（４週齢；体重９０〜１００ｇ）（日本ＳＬＣ（浜松）から入手）を用いた。また、ストレプトゾトシン（ｓｔｒｅｐｔｏｚｏｔｏｃｉｎ；ＳＴＺ）（Ｓｉｇｍａ社（米国）製）を、生理食塩水（１５０ｍＭ ＮａＣｌ）を５０ｍＭ クエン酸ナトリウム水溶液中に溶解し、ＳＴＺ液を調製した。
アセキサム酸亜鉛（Ｚｉｎｃ ａｃｅｘａｍａｔｅ；ニッショー医薬品研究所より恵与）を亜鉛量として２．５ｍｇ／ｍｌになるように精製蒸留水で溶解し、投与試料溶液を調製した。比較例として、硫酸亜鉛（和光純薬工業；大阪）の亜鉛量として同じ濃度（２．５ｍｇ／ｍｌ）の投与試料溶液を調製した。
【００２０】
実施例２［投与方法］
上記ラットに体重１００ｇ当り６．０ｍｇのＳＴＺ液を１回皮下投与し、以後亜鉛化合物を投与しないものをＳＴＺ投与（ＩＩ群）とした。ＳＴＺ投与後３時間目にラット体重１００ｇ当り亜鉛量として２．５ｍｇの硫酸亜鉛溶液（ＩＩＩ群）、又は２．５ｍｇのアセキサム酸亜鉛溶液（ＩＶ群）を、胃ゾンデを用いて１日１回１４日間にわたって経口投与した。この間、固型飼料（オリエンタル酵母、ＭＦ）と精製蒸留水を自由に摂取させ、亜鉛化合物の最終投与の２４時間目に屠殺した。また、ＳＴＺと亜鉛化合物を共に投与しないものを対照（Ｉ群）とした。なお、各群６匹の構成とした。
【００２１】
実施例３［測定項目と測定方法］
上記各群のラットを、それぞれ最終投与の２４時間後にエーテル麻酔下で体重を測定した後、心臓穿刺により採血後屠殺し、大腿骨を摘出した。採血の３０分後に血液を２５００回転で５分間遠心分離して血清を採取し、血清中のグルコース濃度は和光純薬工業株式会社製のグルコース測定用キット「グルコース−テストワコー」を、血清中のトリグリセライド濃度は和光純薬工業株式会社製のトリグリセライド測定用キット「トリグリセライド−テストワコー」を、血清中のカルシウム濃度は和光純薬工業株式会社製のカルシウム測定用キット「カルシウムＣ−テストワコー」を、血清中の無機リン濃度は和光純薬工業株式会社製の無機リン濃度測定用キット「ピーテストワコー」を、それぞれ使用説明書のとおり用いて定量した。また大腿骨は、筋肉組織を除去し、骨幹部（ｄｉａｐｈｙｓｉｓ；皮質骨で硬い骨質をもつ）組織と骨幹端部（ｍｅｔａｐｈｙｓｉｓ；海綿骨で軟い骨質をもつ）組織に分け、冷０．２５Ｍショ糖溶液中で骨髄細胞を洗浄除去した。それぞれの骨組織を用いて、以下に記載の方法でカルシウム量、骨の石灰化の促進に関する最も重要な酵素であるアルカリ性ホスファターゼの発現量、及び骨組織中の細胞数の指標としてＤＮＡ量をそれぞれ測定した。
【００２２】
（骨カルシウムの測定）
摘出した大腿骨の組織片を０．２５Ｍショ糖溶液で洗浄、乾燥後、骨重量を測定した。その後、組織片に濃硝酸を加えて１２０℃で１２時間灰化し、原子吸光分光光度計（パーキンエルマー社製「パーキンエルマー３０３」）を用いて骨カルシウム量を定量した。
【００２３】
（アルカリ性ホスファターゼ活性の測定）
摘出した大腿骨の組織片を０．２５Ｍのショ糖液で洗浄し、６．５ｍＭのバルビタール緩衝液（ｐＨ７．４）３ｍＬ中で破砕し、超音波処理した。この液を遠心分離して上清を酵素液としてＷａｌｔｅｒ及びＳｃｈｕｔｔの方法（ｉｎ Ｍｅｔｈｏｄ ｏｆ Ｅｎｚｙｍａｔｉｃ Ａｎａｌｙｓｉｓ， Ｖｏｌ１−２，ｐ８５６， Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ， Ｎｅｗ Ｙｏｒｋ， １９６５）に従って測定した。すなわち、ｐ−ニトロフェニール燐酸を基質として、ジエタノールアミン緩衝液（ｐＨ９．８）２ｍＬに酵素液０．０５ｍＬを添加し、３７℃で３０分間インキュベーションし、０．０５ＮのＮａＯＨを１０ｍＬ添加した後、分光光度計を用いて吸光度（４０５ｎｍ）を測定し、骨に対する予防・治療剤及び骨に対する作用の知られている化合物の骨アルカリ性ホスファターゼ活性を調べた。
【００２４】
（ＤＮＡ量の定量）
骨組織中の細胞数の指標として、ＤＮＡ量を定量した。摘出した大腿骨の組織片を０．２５Ｍのショ糖溶液で洗浄し、湿重量を測定した。その後、０．１ＮのＮａＯＨ４ｍＬ中で粉砕して、４℃で２４時間浸透させた。この液を遠心分離し、上清を試料としてＣｅｒｉｏｔｔｉらの方法（Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．， ２４１： ３４−７７， １９５１）に従って定量した。すなわち、試料２ｍＬに濃塩酸１ｍＬ及び０．０４％のインドール溶液１ｍＬを添加し沸騰水中で１００℃に加熱後、急冷して、クロロホルム４ｍＬで抽出し、クロロホルム層を採取して、分光光度計（４９０ｎｍ）を用いて骨中のＤＮＡ量を測定した。
【００２５】
（データの処理）
得られたデータについて、対照群と亜鉛化合物投与群との２群間の有意差検定はＳｔｕｄｅｎｔ’ｓ ｔ‐ｔｅｓｔ（ｔ検定）を用いて行なった。また、多群間の有意差検定はＡＮＯＶＡ及びＴｕｒｋｅｙ−Ｋｒａｍｅｒの方法を用いて行った。危険率（ｐ）５％未満をもって有意差ありとした。
【００２６】
実施例４［結果］
（体重）
図１に示すように、ラットの体重増加は、ＳＴＺ投与群（ＩＩ群）で有意に抑制された。この抑制は、硫酸亜鉛投与群（ＩＩＩ群）では改善されなかったが、アセキサム酸亜鉛投与群（ＩＶ群）では有意に改善された。なお、対照群（Ｉ群）のデータと比較して危険率（ｐ）１％未満であった場合に“※”印を、ＳＹＺ投与群（ＩＩ群）のデータと比較して危険率（ｐ）１％未満であった場合に“＃”印を、それぞれ図中に付した（以下同様）。更に、アセキサム酸亜鉛の投与量とラットの体重増加の関係を図８に示す。アセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満に改善された。
【００２７】
（血清中の亜鉛濃度）
図２に示すように、血清中亜鉛濃度は、ＳＴＺ投与群（ＩＩ群）で有意に減少し、この減少は硫酸亜鉛投与群（ＩＩＩ群）では改善されなかったが、アセキサム酸亜鉛投与群（ＩＶ群）でほぼ完全に改善された。硫酸亜鉛と比較してアセキサム酸亜鉛は腸管吸収されやすいことが示唆された。更に、アセキサム酸亜鉛の投与量と血清中亜鉛濃度の関係を図９に示す。アセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満に改善された。
【００２８】
（血清中のグルコース濃度、トリグリセライド濃度）
図３（ａ）に示すように、血清中グルコース濃度は、ＳＴＺ投与群（ＩＩ群）で著しく上昇したが、この上昇は硫酸亜鉛投与群（ＩＩＩ群）で危険率（ｐ）５％未満に抑制され、アセキサム酸亜鉛投与群（ＩＶ群）は、硫酸亜鉛投与群と比較してさらに危険率（ｐ）１％未満に改善されることが示された。このように、糖尿病状態における血糖降下作用が硫酸亜鉛投与群（ＩＩＩ群）と比較してアセキサム酸亜鉛投与群（ＩＶ群）で強く発現されることが明らかになった。更に、アセキサム酸亜鉛の投与量と血清中グルコース濃度の関係を図１０（ａ）に示す。アセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満に改善された。
同様のことが、図３（ｂ）に示すように、血清中トリグリセライド濃度においても認められ、また、図１０（ｂ）に示すように、アセキサム酸亜鉛の投与量と血清中トリグリセライド濃度の関係においても、アセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満に改善された。
以上の結果から、アセキサム酸亜鉛には血清脂質濃度降下作用があり、糖尿病状態の高血糖、高脂血症及び体重減少がアセキサム酸亜鉛によって有意に改善されることが明かにされた。
【００２９】
（血清中のカルシウム濃度及び無機リン濃度）
図４（ａ）に示すように、血清中カルシウム濃度が、ＳＴＺ投与群で上昇し、一方、図４（ｂ）に示すように、血清中無機リン濃度は、ＳＴＺ投与群で低下した。これらの変動は、硫酸亜鉛投与群（ＩＩＩ群）では改善されなかったが、アセキサム酸亜鉛投与群（ＩＶ群）で有意に改善された。更に、アセキサム酸亜鉛の投与量と血清中カルシウム濃度の関係を図１１（ａ）に、アセキサム酸亜鉛の投与量と血清中無機リン濃度の関係を図１１（ｂ）に示す。いずれもアセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満に改善された。
糖尿病状態において、血清中の亜鉛濃度、カルシウム濃度、無機リン濃度が変動するが、この変動はアセキサム酸亜鉛の投与によって有意に修復されることが明らかとなり、アセキサム酸亜鉛は優れた抗糖尿病効果を発揮することが明かとなった。
【００３０】
（骨組織中のカルシウム濃度）
図５に示すように、大腿骨組織の骨幹部組織（ａ）及び骨幹端部組織（ｂ）におけるカルシウム濃度がＳＴＺ投与群（ＩＩ群）において低下することが明かにされた。この低下は、アセキサム酸亜鉛投与群（ＩＶ群）において、危険率（ｐ）１％未満に改善された。更に、アセキサム酸亜鉛の投与量と大腿骨組織の骨幹部組織（ａ）及び骨幹端部組織（ｂ）中のカルシウム濃度の関係を図１２（ａ）、（ｂ）に示す。アセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満に改善された。
【００３１】
（骨組織中のアルカリ性ホスフォターゼ濃度）
図６に示すように、大腿骨組織の骨幹部組織（ａ）及び骨幹端部組織（ｂ）におけるアルカリ性ホスフォターゼ濃度がＳＴＺ投与群（ＩＩ群）において低下することが明かにされた。この低下は、アセキサム酸亜鉛投与群（ＩＶ群）において、危険率（ｐ）１％未満に改善された。しかしながら、硫酸亜鉛投与群（ＩＩＩ群）では、骨幹部組織におけるアルカリ性ホスファターゼ活性が硫酸亜鉛投与群（ＩＩＩ群）で有意差（ｐ）１％未満に上昇した（この上昇効果はアセキサム酸亜鉛の効果と比較して有意差（ｐ）１％未満に減弱されていた）のみで、他のものについては有意な効果を発揮しなかった。更に、アセキサム酸亜鉛の投与量と大腿骨組織の骨幹部組織（ａ）及び骨幹端部組織（ｂ）中のアルカリ性ホスファターゼ活性の関係を図１３（ａ）、（ｂ）に示す。アセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満であった。
【００３２】
（骨組織中のＤＮＡ濃度）
図７に示すように、大腿骨組織の骨幹部組織（ａ）及び骨幹端部組織（ｂ）におけるＤＮＡ濃度の有意な低下がＳＴＺ投与群（ＩＩ群）において明かにされた。この低下は、アセキサム酸亜鉛投与群（ＩＶ群）において、危険率（ｐ）１％未満に改善され、硫酸亜鉛投与群（ＩＩＩ群）と比較して、ＤＮＡ濃度が改善されることが明かになった。更に、アセキサム酸亜鉛の投与量と大腿骨組織の骨幹部組織（ａ）及び骨幹端部組織（ｂ）中のＤＮＡ濃度の関係を図１４（ａ）、（ｂ）に示す。アセキサム酸亜鉛１０ｍｇ／１００ｇの投与量でＳＴＺ投与群（ＩＩ群）と比較して危険率（ｐ）１％未満に改善された。
【００３３】
（まとめ）
以上の結果から明らかなように、糖尿病状態の血液中の亜鉛濃度の下降や、カルシウム濃度の上昇、無機リン濃度の下降、骨組織中のカルシウム濃度、ＤＮＡ濃度、アルカリ性ホスファオターゼ活性の下降等、骨減少に対してアセキサム酸亜が骨形成促進作用を有し、有意な改善効果を発現することが初めて明かにされ、硫酸亜鉛では改善効果がほとんどみられないことから、アセキサム酸亜鉛においてかかる糖尿病状態の骨減少に対する改善効果は特異な現象である。さらに、糖尿病状態における体重増加の抑制、高血糖及び高脂血症がアセキサム酸亜鉛投与で改善されたのに対し、硫酸亜鉛投与ではみられなかったことから、アセキサム酸亜鉛の抗糖尿病作用は特異なものである。ＳＴＺ投与による糖尿病はＩ型（インスリン分泌障害による糖尿病）であるが、アセキサム酸亜鉛投与による高血糖及びトリグリセライド血症を有意に改善できたことから、アセキサム酸亜鉛はＩＩ型糖尿病状態に対しても改善効果を発揮し得るものと推察される。このように、アセキサム酸亜鉛は、糖尿病性骨量減少に係わる糖尿病性骨粗鬆症をも改善でき、抗糖尿病疾患予防・治療剤としての優れた有効性を有することが明らかにされた。
【００３４】
【発明の効果】
本発明によると、一般式（Ｉ）で示される化合物を有効成分として含有することで、糖尿病性疾患において血液中の亜鉛濃度や無機リン濃度を上昇させ、カルシウム濃度の下降を図り、骨組織内のカルシウム濃度やＤＮＡ濃度の上昇を図り、アルカリ性ホスフォターゼ活性の上昇を図り、副作用が少なく、糖尿病性骨粗鬆症、高血糖症、高脂血症等の糖尿病性疾患を治療することができ、予防・改善することができる。
【図面の簡単な説明】
【図１】本発明の糖尿病性疾患の予防・治療剤投与のラットの体重を示す図である。
【図２】本発明の糖尿病性疾患の予防・治療剤投与のラットの血清液中の亜鉛濃度を示す図である。
【図３】（ａ）本発明の糖尿病性疾患の予防・治療剤投与のラットの血清中のグルコース濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与のラットの血清中のトリグリセライド濃度を示す図である。
【図４】（ａ）本発明の糖尿病性疾患の予防・治療剤投与のラットの血清中のカルシウム濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与のラットの血清中の無機リン濃度を示す図である。
【図５】（ａ）本発明の糖尿病性疾患の予防・治療剤投与のラットの骨幹部組織中のカルシウム濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与のラットの骨幹端部組織中のカルシウム濃度を示す図である。
【図６】（ａ）本発明の糖尿病性疾患の予防・治療剤投与のラットの骨幹部組織中のホスフォターゼ濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与のラットの骨幹端部組織中のホスフォターゼ濃度を示す図である。
【図７】（ａ）本発明の糖尿病性疾患の予防・治療剤投与のラットの骨幹部組織中のＤＮＡ濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与のラットの骨幹端部組織中のＤＮＡ濃度を示す図である。
【図８】本発明の糖尿病性疾患の予防・治療剤の投与量とラットの体重の関係を示す図である。
【図９】本発明の糖尿病性疾患の予防・治療剤の投与量とラットの血清中の亜鉛濃度の関係を示す図である。
【図１０】（ａ）本発明の糖尿病性疾患の予防・治療剤の投与量とラットの血清中のグルコース濃度の関係を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤の投与量とラットの血清中のトリグリセライド濃度の関係を示す図である。
【図１１】（ａ）本発明の糖尿病性疾患の予防・治療剤の投与量とラットの血清中のカルシウム濃度の関係を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤の投与量とラットの血清中の無機リン濃度の関係を示す図である。
【図１２】（ａ）本発明の糖尿病性疾患の予防・治療剤投与量とラットの骨幹部組織中のカルシウム濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与量とラットの骨幹端部組織中のカルシウム濃度を示す図である。
【図１３】（ａ）本発明の糖尿病性疾患の予防・治療剤投与量とラットの骨幹部組織中のアルカリ性ホスフォターゼ濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与量とラットの骨幹端部組織中のアルカリ性ホスフォターゼ濃度を示す図である。
【図１４】（ａ）本発明の糖尿病性疾患の予防・治療剤投与量とラットの骨幹部組織中のＤＮＡ濃度を示す図である。
（ｂ）本発明の糖尿病性疾患の予防・治療剤投与量とラットの骨幹端部組織中のＤＮＡ濃度を示す図である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a prophylactic / therapeutic agent for diabetic diseases such as diabetic osteoporosis, diabetic hyperglycemia, diabetic hyperlipidemia and the like, which contain a specific compound, more specifically zinc acexamic acid, as an active ingredient. The present invention relates to a functional food or a food material for preventing or improving a disease.
[0002]
[Prior art]
Diabetes, which has a large number of patients in Japan, is a disease characterized mainly by chronic hyperglycemia and accompanying chronic systemic metabolic disorders. It is regarded as a lifestyle-related disease, and a major problem in the aging society in the 21st century. It is taken up as. Diabetes mellitus is a disease in which insulin is not secreted and glucose in the blood is not metabolized properly, resulting in an increase in glucose concentration in the blood and a hyperglycemic state. As a result, various symptoms appear, and insulin-dependent diabetes (I Type diabetes) and non-insulin-dependent diabetes (type II diabetes), both of which are associated with genetic factors and environmental factors. Insulin-dependent diabetes mellitus (type I diabetes) develops at a young age and cannot be treated without insulin injection. Non-insulin-dependent diabetes mellitus (type II diabetes) is considered to have a strong genetic component. People born with weakness in the ability of cells to produce insulin are obliged to induce insulin obesity, lack of exercise, and changes in the secretion of hormones. The supply is reduced and the required amount is not satisfied, and the disease occurs.
[0003]
Diabetes has various complications. Among them, diabetic osteoporosis has attracted attention as an important problem from a medical point of view as a complication of diabetes. Factors involved in such diabetic osteoporosis include insulin deficiency, hyperglycemia, and complications associated with diabetes such as arteriosclerosis, neuropathy, and renal impairment. Sorbitol accumulation in osteoblasts caused by a sustained hyperglycemic condition leads to a decrease in osteoblast function, and in the early stage of diabetes, increased urinary calcium excretion associated with urinary glucose excretion Although secondary secretion of parathyroid hormone increases and bone resorption is promoted, the parathyroid secretion capacity of parathyroid hormone decreases in the long term, and the final image is said to be low-rotation osteoporosis (For example, see Non-Patent
[0004]
As therapeutic agents for diabetes, sulfonium urea-based preparations that promote insulin secretion, α-glucosidase inhibitors that suppress postprandial hyperglycemia, and recently thiazolidine-based preparations that improve insulin resistance have been used. However, there are not enough therapeutic agents, such as various side effects depending on the administration or administration of the preparation. In particular, diabetic osteoporosis caused by bone loss in a diabetic state is an intractable disease, and there is no effective therapeutic agent at present.
[0005]
By the way, since zinc deficiency in the body causes delay in bone growth, the role of zinc in regulating bone metabolism has been clarified, and it has been elucidated that zinc exerts a strong bone formation promoting action. The present inventors have already reported that zinc acexamate is effective as an agent for preventing and treating bone diseases (for example, see Non-Patent Document 2 and Patent Document 1).
[0006]
In addition, care or make-up compositions for lips including acexamic acid as a physiologically acceptable active care reagent, and a fatty phase containing the active reagent, such as those using acexamic acid and derivatives thereof ( For example, Patent Literature 2) and cosmetic or dermatological compositions using acexamic acid as a sedative (for example, see Patent Literature 3) are known, but diabetic using zinc acexamic acid is known. No preventive or therapeutic agent for the disease is known.
[0007]
[Patent Document 1]
JP-A-10-218767
[Patent Document 2]
JP-A-11-255618
[Patent Document 3]
JP-A-2002-393718
[Non-patent document 1]
CLINICAL CALCIUM October 2000 (Vol. 10 No. 10) p9 (1189) to p16 (1196)
[Non-patent document 2]
Yamaguchi M. et al. Gao YH. General Pharmacology 30 (3) 423-427, 1998.
[0008]
[Problems to be solved by the invention]
An object of the present invention is to provide a diabetic hyperglycemia, diabetic hyperlipidemia, diabetic osteoporosis and other diabetic diseases, and a diabetic disease preventive / therapeutic agent with few side effects, and a diabetic disease. To provide a functional food or food material for preventing or improving the above.
[0009]
[Means for Solving the Problems]
The present inventors have conducted intensive studies assuming that zinc compounds effectively act on diabetes.As a result, diabetic hyperglycemia, diabetic hyperlipidemia, and diabetic diseases such as diabetic osteoporosis have been found in zinc asexamate. Happened to have an effect of improving That is, when administration of streptozotocin orally administered zinc acexamate to an experimental diabetic rat, which is a model animal of type I diabetes in which a diabetic state was induced by impaired insulin secretion from pancreatic β cells, increased serum calcium was observed. And the reduction of inorganic phosphorus, hyperglycemia and hyperlipidemia were significantly improved, and in experimental diabetic rats, calcium and DNA in diaphyseal and metaphyseal tissues were reduced, and alkaline phosphatase activity was reduced. However, it was found that oral administration of zinc asexamate significantly reduced the decrease in calcium and DNA levels and the decrease in alkaline phosphatase activity. It has been found that the present invention exerts a repair effect on type II diabetes, and the present invention has been completed. It was. It should be noted that, like zinc acexamate, calcitonin and vitamin D, which are conventionally known as therapeutic agents for bone diseases, 3 Compound, vitamin K 2 The effect of (menaquinone-4), bisphosphonate compound, parathyroid hormone, etc. on diabetic disease prevention and treatment was examined, but none of them showed any effect on prevention or treatment of diabetic disease.
[0010]
That is, the present invention provides a compound represented by the general formula (I):
Embedded image
[0011]
Further, the present invention provides a compound represented by the general formula (I):
Embedded image
[0012]
BEST MODE FOR CARRYING OUT THE INVENTION
The preventive / therapeutic agent for diabetic diseases and the functional food or food material for preventing / ameliorating diabetic diseases of the present invention include compounds represented by the general formula (I): 1 , R 2 Independently represents a C1 to C6 alkyl group, and m and n each independently represent an integer of 1 to 20. Is not particularly limited as long as it contains the compound represented by the formula (1) as an active ingredient. Such a compound represented by the general formula (I) has a molecular weight of 1,000 or less, is easily soluble in water, and therefore is easily absorbed in the intestinal tract, and has an excellent effect on diabetes. Substituent R of carbamoyl group in general formula (I) 1 , R 2 Independently represents a C1 to C6 alkyl group, and specific examples of the C1 to C6 alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. Can be.
[0013]
As the compound represented by the general formula (I), specifically, zinc di (N-methyl-5-carbamoylpentanoate), zinc di (N-ethyl-5-carbamoylpentanoate), di (N- Zinc methyl-6-carbamoylhexanoate, zinc di (N-ethyl-6-carbamoylhexanoate), zinc di (N-methyl-7-carbamoylheptanoate), di (N-methyl-5-carbamoylheptanoate) Specific examples include zinc and the like. Among them, in particular, the formula (II)
Embedded image
[0014]
Such a compound represented by the general formula (I) has an effect of increasing blood zinc concentration, an effect of lowering blood sugar level, an effect of lowering fatty acid ester concentration in blood, an effect of lowering calcium concentration in blood, The effect of increasing the inorganic phosphorus concentration, the effect of increasing the calcium concentration in the diaphyseal tissue and the metaphyseal tissue, the effect of increasing the DNA content in the diaphyseal tissue and the metaphyseal tissue, It has an alkaline phosphatase activity increasing effect and has excellent effects on diabetic osteoporosis, diabetic hyperglycemia, diabetic hyperlipidemia and the like.
[0015]
The preventive / therapeutic agent for diabetic disease of the present invention comprises a pharmaceutically acceptable usual carrier, binder, stabilizer, excipient, diluent, pH buffer, disintegrant, solubilizer, dissolution aid Agents, isotonic agents, etc. can be added and used in combination with other drugs for treating diabetic diseases such as diabetic hyperglycemia, diabetic hyperlipidemia, and diabetic osteoporosis You can also.
[0016]
As a method for preparing the prophylactic / therapeutic agent for diabetic disease of the present invention, the compound represented by the general formula (I) prepared based on a known method is powdered with a mixer or the like, and the obtained powder is granulated by an ordinary method. Examples of the method include encapsulation, tableting, and the like. In addition, as a method for preparing zinc acexamate, a known method can be exemplified as a specific example.
[0017]
In the present invention, the diabetic disease refers to a state showing symptoms of diseases such as type I and / or type II diabetes and various complications caused by these diabetes, and the diabetic disease includes diabetic osteoporosis, diabetes Symptomatic hyperglycemia, diabetic hyperlipidemia, symptoms of weight loss due to diabetes, symptoms of fluctuations in blood mineral concentration due to diabetes, and complications such as neuropathy, retinopathy and kidney damage The state can be specifically exemplified. And since the preventive / therapeutic agent for diabetic disease of the present invention has a preventive / ameliorating effect on diabetic diseases such as diabetic osteoporosis, diabetic hyperglycemia, and diabetic hyperlipidemia, it is useful for diabetic patients or diabetic patients. A method for preventing or treating diabetic disease by orally administering to a person in the reserve army, or a functional food having a diabetic disease preventing or ameliorating effect by adding and blending to a food, or a pharmacological composition It can be advantageously used as a food material. Such a prophylactic / therapeutic agent for diabetic disease of the present invention is usually orally administered, and when used as a therapeutic agent, zinc acexamate in a range of 1 mg to 5 g / Kg body weight, preferably 10 to 1000 mg / Kg body weight per day. By ingestion, diabetic disease can be improved, but the amount of intake can be appropriately adjusted according to symptoms, gender, age and the like. When used as a prophylactic agent for diabetic disease of the present invention, the prevalence of diabetic disease can be reduced by taking it in advance. The method of ingestion as a prophylactic agent can be the same as that used as a therapeutic agent, and the amount of ingestion can be from a smaller amount to the same amount as the therapeutic agent.
[0018]
The functional food or food material for preventing or ameliorating a diabetic disease of the present invention containing zinc asexamate as an active ingredient may use the agent for preventing or treating a diabetic disease of the present invention as a part of a raw material for food or drink. Alternatively, it can be obtained by adding or blending in the production process or after the production. Such functional foods are not particularly limited, and include cookies, breads, cakes, baked goods such as rice crackers, tablet confections such as ramune confectionery, Japanese sweets such as yokan, puddings, jellies, and ice confections such as ice creams. Sweets such as chewing gum and candy, snacks such as crackers and chips, noodles such as udon and buckwheat, fish paste products such as kamaboko, ham, fish sausage, dairy products such as cheese and butter, miso, soy sauce , Dressings, mayonnaise, sweeteners and other seasonings, tofu, konjac, other tsukudani, dumplings, croquettes, salads, soups, stews, and various other delicatessens, yogurt, drink yogurt, juice, milk, soy milk, alcoholic beverages, coffee, Various drinks such as black tea, green tea, oolong tea, sports drinks and the like can be specifically exemplified. For example, tablet confectionery can be manufactured by pulverizing zinc acexamate and pulverizing the fine powder according to a conventional method. In this case, the fine powder can be granulated and then tableted. In addition, it is also possible to form a tablet obtained by pulverizing zinc acexamate and mixing lactose, dextrin, dried yeast and the like with the powder.
[0019]
【Example】
Hereinafter, the present invention will be described more specifically with reference to examples, but the technical scope of the present invention is not limited to these examples.
Example 1 [Material]
As a test animal, a Wistar male rat (4 weeks old;
Zinc acexamate (provided by Nissha Pharmaceutical Research Institute) was dissolved in purified distilled water so as to have a zinc amount of 2.5 mg / ml to prepare a sample solution for administration. As a comparative example, an administration sample solution having the same concentration (2.5 mg / ml) as zinc content of zinc sulfate (Wako Pure Chemical Industries, Osaka) was prepared.
[0020]
Example 2 [Administration method]
The above rat was subcutaneously administered once with a 6.0 mg STZ solution per 100 g body weight, and the one without the zinc compound thereafter was treated as STZ administration (Group II). Three hours after administration of STZ, 2.5 mg of zinc sulfate solution (group III) or 2.5 mg of zinc acexamic acid solution (group IV) as a zinc amount per 100 g of body weight of the rat was applied once a day using a gastric tube. Oral administration for 14 days. During this time, solid feed (Oriental Yeast, MF) and purified distilled water were freely ingested, and sacrificed 24 hours after the final administration of the zinc compound. The control (group I) was not administered with both STZ and the zinc compound. In addition, each group consisted of 6 animals.
[0021]
Example 3 [Measurement Items and Measurement Methods]
The rats in each of the above groups were weighed 24 hours after the final administration under ether anesthesia, then blood was collected by cardiac puncture and sacrificed, and the femur was removed. 30 minutes after blood collection, blood was centrifuged at 2500 rpm for 5 minutes to collect serum, and the glucose concentration in the serum was measured using a glucose measurement kit “Glucose-Test Wako” manufactured by Wako Pure Chemical Industries, Ltd. Triglyceride concentration is Wako Pure Chemical Industries Co., Ltd. triglyceride measurement kit `` Triglyceride-Test Wako '', serum calcium concentration Wako Pure Chemical Industries Co., Ltd. calcium measurement kit `` Calcium C-Test Wako '', The inorganic phosphorus concentration in the serum was quantified using an inorganic phosphorus concentration measurement kit "P Test Wako" manufactured by Wako Pure Chemical Industries, Ltd. according to the instruction manual. In addition, the femur is deprived of muscle tissue, divided into diaphyseal (cortical bone and hard bone) and metaphyseal (metaphysis; cancellous bone and soft bone) tissues. The bone marrow cells were washed away in a sugar solution. Using each bone tissue, the amount of calcium, the amount of expression of alkaline phosphatase, which is the most important enzyme related to the promotion of bone calcification, and the amount of DNA as an index of the number of cells in the bone tissue were determined by the methods described below. It was measured.
[0022]
(Measurement of bone calcium)
The excised femoral tissue piece was washed with a 0.25 M sucrose solution, dried, and then the bone weight was measured. Thereafter, concentrated nitric acid was added to the tissue pieces and ashed at 120 ° C. for 12 hours, and the amount of bone calcium was quantified using an atomic absorption spectrophotometer (“Perkin Elmer 303” manufactured by Perkin Elmer).
[0023]
(Measurement of alkaline phosphatase activity)
The extracted femoral tissue pieces were washed with 0.25 M sucrose solution, crushed in 3 mL of 6.5 mM barbital buffer (pH 7.4), and sonicated. This solution was centrifuged, and the supernatant was used as an enzyme solution, and the enzyme solution was measured according to the method of Walter and Schutt (in Method of Enzymatic Analysis, Vol 1-2, p856, Academic Press, New York, 1965). That is, using p-nitrophenyl phosphate as a substrate, 0.05 mL of the enzyme solution was added to 2 mL of diethanolamine buffer (pH 9.8), incubated at 37 ° C. for 30 minutes, and 10 mL of 0.05N NaOH was added. The absorbance (405 nm) was measured using a photometer, and the bone alkaline phosphatase activity of the preventive / therapeutic agent for bone and the compound known to have an effect on bone was examined.
[0024]
(Quantification of DNA amount)
The amount of DNA was quantified as an index of the number of cells in the bone tissue. The excised femoral tissue piece was washed with a 0.25 M sucrose solution, and the wet weight was measured. Then, it was pulverized in 4 mL of 0.1 N NaOH and infiltrated at 4 ° C. for 24 hours. This solution was centrifuged, and the supernatant was used as a sample and quantified according to the method of Ceriotti et al. (J. Biol. Chem., 241: 34-77, 1951). That is, 1 mL of concentrated hydrochloric acid and 1 mL of a 0.04% indole solution were added to 2 mL of a sample, heated to 100 ° C. in boiling water, quenched, extracted with 4 mL of chloroform, the chloroform layer was collected, and a spectrophotometer ( 490 nm) was used to determine the amount of DNA in the bone.
[0025]
(Data processing)
Regarding the obtained data, a significant difference test between the control group and the zinc compound-administered group was performed using Student's t-test (t-test). In addition, a significant difference test between multiple groups was performed using ANOVA and the method of Turkey-Kramer. A significant difference (p) of less than 5% was considered significant.
[0026]
Example 4 [Result]
(body weight)
As shown in FIG. 1, the weight gain of the rats was significantly suppressed in the STZ administration group (Group II). This suppression was not improved in the zinc sulfate administration group (group III), but was significantly improved in the zinc acexamic acid administration group (group IV). When the risk rate (p) was less than 1% as compared with the data of the control group (group I), the mark “*” was compared with the data of the SYZ administration group (group II). ) When it was less than 1%, a “#” mark was added in the figure (the same applies hereinafter). FIG. 8 shows the relationship between the dose of zinc acexamate and the weight gain of rats. At a dose of 10 mg / 100 g of zinc acexamate, the risk factor (p) was improved to less than 1% as compared with the STZ administration group (Group II).
[0027]
(Serum zinc concentration)
As shown in FIG. 2, the serum zinc concentration was significantly reduced in the STZ-administered group (Group II), and this decrease was not improved in the zinc sulfate-administered group (Group III). (Group IV) improved almost completely. It was suggested that zinc acexamate was more likely to be absorbed in the intestinal tract than zinc sulfate. FIG. 9 shows the relationship between the dose of zinc acexamate and the serum zinc concentration. At a dose of 10 mg / 100 g of zinc acexamate, the risk factor (p) was improved to less than 1% as compared with the STZ administration group (Group II).
[0028]
(Serum glucose concentration, triglyceride concentration)
As shown in FIG. 3 (a), the serum glucose concentration significantly increased in the STZ-administered group (group II), but this increase was less than the risk factor (p) of less than 5% in the zinc sulfate-administered group (group III). It was shown to be suppressed, and the risk ratio (p) was further improved to less than 1% in the zinc acexamic acid-administered group (group IV) as compared with the zinc sulfate-administered group. Thus, it was revealed that the hypoglycemic effect in the diabetic state was more strongly expressed in the zinc acexamic acid administration group (Group IV) than in the zinc sulfate administration group (Group III). FIG. 10 (a) shows the relationship between the dose of zinc acexamate and the serum glucose concentration. At a dose of 10 mg / 100 g of zinc acexamate, the risk factor (p) was improved to less than 1% as compared with the STZ administration group (Group II).
The same is observed in serum triglyceride concentration as shown in FIG. 3 (b), and as shown in FIG. 10 (b), the relationship between the dose of zinc acexamate and serum triglyceride concentration. Also, at the dose of 10 mg / 100 g of zinc acexamate, the risk factor (p) was improved to less than 1% as compared with the STZ administration group (group II).
From the above results, it was clarified that zinc acexamate has a serum lipid concentration lowering effect, and that diabetic hyperglycemia, hyperlipidemia and weight loss are significantly improved by zinc acexamic acid.
[0029]
(Calcium concentration and inorganic phosphorus concentration in serum)
As shown in FIG. 4 (a), the serum calcium concentration increased in the STZ administration group, while as shown in FIG. 4 (b), the serum inorganic phosphorus concentration decreased in the STZ administration group. These fluctuations were not improved in the zinc sulfate administration group (Group III), but were significantly improved in the zinc acexamic acid administration group (Group IV). FIG. 11 (a) shows the relationship between the dose of zinc acexamate and the serum calcium concentration, and FIG. 11 (b) shows the relationship between the dose of zinc acexamate and the serum inorganic phosphorus concentration. In each case, the dose rate of zinc acexamate at 10 mg / 100 g improved the risk factor (p) to less than 1% as compared with the STZ administration group (Group II).
In the diabetic state, serum zinc concentration, calcium concentration, and inorganic phosphorus concentration fluctuate, and it is clear that these fluctuations are significantly restored by the administration of zinc acexamate, and zinc acexamate has an excellent antidiabetic effect. It was clear that it would work.
[0030]
(Calcium concentration in bone tissue)
As shown in FIG. 5, it was revealed that the calcium concentration in the diaphyseal tissue (a) and the metaphyseal tissue (b) of the femoral tissue decreased in the STZ-administered group (Group II). This reduction was improved to a risk factor (p) of less than 1% in the group treated with zinc asexamate (Group IV). 12 (a) and 12 (b) show the relationship between the dose of zinc acexamate and the calcium concentration in the diaphyseal tissue (a) and metaphyseal tissue (b) of the femoral tissue. At a dose of 10 mg / 100 g of zinc acexamate, the risk factor (p) was improved to less than 1% as compared with the STZ administration group (Group II).
[0031]
(Alkaline phosphatase concentration in bone tissue)
As shown in FIG. 6, it was revealed that the alkaline phosphatase concentration in the diaphyseal tissue (a) and the metaphyseal tissue (b) of the femur tissue decreased in the STZ-administered group (Group II). This reduction was improved to a risk factor (p) of less than 1% in the group treated with zinc asexamate (Group IV). However, in the zinc sulfate administration group (group III), the alkaline phosphatase activity in the diaphyseal tissue increased to a significant difference (p) of less than 1% in the zinc sulfate administration group (group III). (Attenuated to a significant difference (p) of less than 1% as compared to) and did not exert a significant effect on the others. 13 (a) and 13 (b) show the relationship between the dose of zinc acexamate and the alkaline phosphatase activity in the diaphyseal tissue (a) and metaphyseal tissue (b) of the femoral tissue. At a dose of 10 mg / 100 g of zinc acexamate, the risk factor (p) was less than 1% as compared with the STZ administration group (Group II).
[0032]
(DNA concentration in bone tissue)
As shown in FIG. 7, a significant decrease in DNA concentration in the diaphyseal tissue (a) and metaphyseal tissue (b) of the femoral tissue was revealed in the STZ-administered group (Group II). This decrease was improved to a risk factor (p) of less than 1% in the zinc acexamate-administered group (Group IV), and the DNA concentration was clearly improved as compared to the zinc sulfate-administered group (Group III). became. 14 (a) and 14 (b) show the relationship between the dose of zinc acexamate and the DNA concentration in the diaphyseal tissue (a) and metaphyseal tissue (b) of the femoral tissue. At a dose of 10 mg / 100 g of zinc acexamate, the risk factor (p) was improved to less than 1% as compared with the STZ administration group (Group II).
[0033]
(Summary)
As is evident from the above results, bone concentrations such as a decrease in zinc concentration in blood in a diabetic state, an increase in calcium concentration, a decrease in inorganic phosphorus concentration, a decrease in calcium concentration, DNA concentration, and alkaline phosphatase activity in bone tissue, etc. For the first time, it was revealed that acexamic acid has an osteogenesis-promoting effect and a significant improvement effect is exhibited, and zinc sulphate shows almost no improvement effect. The effect of improving bone loss is a unique phenomenon. In addition, the suppression of weight gain, hyperglycemia, and hyperlipidemia in diabetic conditions were improved by zinc asexamate administration, but not by zinc sulfate administration. It is something. Diabetes due to STZ administration is type I (diabetes due to impaired insulin secretion), but hyperglycemia and triglyceridemia can be significantly improved by administration of zinc asexamate. It is presumed that the improvement effect can be exhibited. Thus, it was revealed that zinc acexamate can also improve diabetic osteoporosis associated with diabetic bone loss and has excellent efficacy as an antidiabetic disease preventive / therapeutic agent.
[0034]
【The invention's effect】
According to the present invention, by containing a compound represented by the general formula (I) as an active ingredient, zinc concentration and inorganic phosphorus concentration in blood are increased in diabetic disease, calcium concentration is reduced, and bone tissue is reduced. To increase the calcium concentration and DNA concentration, increase alkaline phosphatase activity, reduce side effects, and treat diabetic diseases such as diabetic osteoporosis, hyperglycemia, hyperlipidemia, and prevent / improve can do.
[Brief description of the drawings]
FIG. 1 is a diagram showing the weight of rats administered with a prophylactic / therapeutic agent for diabetic diseases of the present invention.
FIG. 2 is a graph showing the zinc concentration in the serum of rats administered with the prophylactic / therapeutic agent for diabetic disease of the present invention.
FIG. 3 (a) is a graph showing the glucose concentration in the serum of rats administered with the prophylactic / therapeutic agent for diabetic diseases of the present invention.
(B) is a diagram showing the concentration of triglyceride in the serum of rats administered with the prophylactic / therapeutic agent for diabetic diseases of the present invention.
FIG. 4 (a) is a graph showing the calcium concentration in the serum of rats administered with the prophylactic / therapeutic agent for diabetic diseases of the present invention.
(B) is a graph showing the concentration of inorganic phosphorus in the serum of rats administered with the prophylactic / therapeutic agent for diabetic diseases of the present invention.
FIG. 5 (a) is a graph showing the calcium concentration in the diaphyseal tissue of rats administered with the preventive / therapeutic agent for diabetic disease of the present invention.
(B) is a graph showing the calcium concentration in the metaphyseal tissue of rats administered with the prophylactic / therapeutic agent for diabetic disease of the present invention.
FIG. 6 (a) is a graph showing phosphatase concentrations in diaphyseal tissues of rats administered with the prophylactic / therapeutic agent for diabetic diseases of the present invention.
(B) is a graph showing the phosphatase concentration in the metaphyseal tissue of rats administered with the prophylactic / therapeutic agent for diabetic disease of the present invention.
FIG. 7 (a) is a graph showing the DNA concentration in the diaphyseal tissue of rats administered with the prophylactic / therapeutic agent for diabetic disease of the present invention.
(B) is a graph showing the DNA concentration in the metaphyseal tissue of rats administered with the prophylactic / therapeutic agent for diabetic disease of the present invention.
FIG. 8 is a graph showing the relationship between the dose of the prophylactic / therapeutic agent for diabetic diseases of the present invention and the weight of rats.
FIG. 9 is a graph showing the relationship between the dose of the prophylactic / therapeutic agent for diabetic disease of the present invention and the zinc concentration in serum of rats.
FIG. 10 (a) is a graph showing the relationship between the dose of a prophylactic / therapeutic agent for a diabetic disease of the present invention and the glucose concentration in rat serum.
(B) is a graph showing the relationship between the dose of the prophylactic / therapeutic agent for diabetic disease of the present invention and the concentration of triglyceride in the serum of rats.
FIG. 11 (a) is a graph showing the relationship between the dose of the prophylactic / therapeutic agent for diabetic disease of the present invention and the calcium concentration in serum of rats.
(B) is a graph showing the relationship between the dose of the prophylactic / therapeutic agent for diabetic disease of the present invention and the concentration of inorganic phosphorus in rat serum.
FIG. 12 (a) is a graph showing the dose of a prophylactic / therapeutic agent for a diabetic disease of the present invention and the calcium concentration in diaphyseal tissues of rats.
(B) is a graph showing the dose of a prophylactic / therapeutic agent for a diabetic disease of the present invention and the calcium concentration in metaphyseal tissues of rats.
FIG. 13 (a) is a graph showing the dose of a prophylactic / therapeutic agent for diabetic diseases of the present invention and the concentration of alkaline phosphatase in diaphyseal tissues of rats.
(B) is a graph showing the dose of a prophylactic / therapeutic agent for diabetic disease of the present invention and the concentration of alkaline phosphatase in metaphyseal tissues of rats.
FIG. 14 (a) is a graph showing the dose of a prophylactic / therapeutic agent for a diabetic disease of the present invention and the DNA concentration in the diaphyseal tissue of a rat.
(B) is a graph showing the dose of a prophylactic / therapeutic agent for a diabetic disease of the present invention and the DNA concentration in metaphyseal tissues of rats.
Claims (27)
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