JP2022176267A - Glp-1分泌促進剤 - Google Patents
Glp-1分泌促進剤 Download PDFInfo
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- JP2022176267A JP2022176267A JP2022159528A JP2022159528A JP2022176267A JP 2022176267 A JP2022176267 A JP 2022176267A JP 2022159528 A JP2022159528 A JP 2022159528A JP 2022159528 A JP2022159528 A JP 2022159528A JP 2022176267 A JP2022176267 A JP 2022176267A
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Abstract
Description
腸管には、消化管ホルモンを分泌する内分泌細胞が存在し、他の臓器の機能を調節する。腸管内分泌細胞から分泌される消化管ホルモンの一部は、インクレチンとも呼ばれ、食事摂取に伴い血中に分泌され、膵臓のβ細胞(以下、「膵β細胞」)に作用し、インスリン分泌を促進する。このインクレチンは、インスリン分泌を促進するだけでなく、膵β細胞の再生を促し、また迷走神経を介して中枢神経系にも作用し、摂食行動を抑制するため、糖尿病や肥満症の新規治療薬開発のための標的として注目されている。
糖尿病とは、血糖値やヘモグロビンA1c(HbA1c)値が一定の基準を超えている状態を指す疾患で、国が医療対策において特に重点をおいている疾病の一つである。1型糖尿病では膵臓のβ細胞が何らかの理由によって破壊されることで、血糖値を調節するホルモンの一つであるインスリンが枯渇してしまい、高血糖、糖尿病へと至る。2型糖尿病は、肥満などを原因として、膵臓のランゲルハンス島(膵島)にあるβ細胞からのインスリン分泌量が減少し、筋肉、脂肪組織へのグルコースの取り込み能が低下(インスリン抵抗性が増大)し、結果として血中のグルコースが肝臓や脂肪組織でグリコーゲンとして貯蔵されず、血中濃度が正常範囲を逸脱して高い血糖値となり、高血糖症、インスリン抵抗性、相対的インスリン不足が特徴の長期的代謝異常である。
た。これまでに、GLP-1等のインスリン分泌促進剤、スルホニルウレア剤、グルコーストランスポーター(GLUT)阻害剤等の薬剤が開発されていた。しかし、副作用の問題や、常用による効果の低減等の問題があった。また、インスリン過剰分泌による低血糖等が問題となっており、そのような問題を解決する医薬の開発が望まれていた。
[態様1]
プロピオン酸、酪酸、吉草酸、パントテン酸、コール酸、3-アミノイソ酪酸、γ-アミノ酪酸、2-アミノ酪酸、ピペコリン酸、オルニチン、シトルリン、チロシンメチルエステル、ピペリジン、タウリン、ピリドキサール、ピリドキサミン、ピリドキシン、サルコシン、N,N-ジメチルグリシン、シトシン、1,3-ジアミノプロパン、ニコチン酸、インドール-3-アセトアミド、D-アラニン、5-ヒドロキシリシン、1-メチルニコチナミド、チアミン、カルニチン、グルコン酸、プロスタグランジンE2、メチオニンスルホキシド、スペルミジン及びスペルミン、からなる群から選択される、1またはそれ以上の化合物を含む、GLP-1分泌促進剤。
[態様2]
態様1に記載のGLP-1分泌促進剤を含む、インスリン分泌促進用組成物。
[態様3]
態様1に記載のGLP-1分泌促進剤を含む、血糖値低下用組成物。
[態様4]
態様1に記載のGLP-1分泌促進剤を含む、糖尿病の予防用組成物又は治療用組成物。
[態様5]
態様1に記載のGLP-1分泌促進剤を含む、肥満の予防用組成物又は改善用組成物。[態様6]
態様1に記載のGLP-1分泌促進剤を含む、食欲を抑制するための組成物。
[態様7]
態様1に記載のGLP-1分泌促進剤を含む、飲食品。
本発明は、一態様において、GLP-1分泌促進剤に関する。
本発明は、一態様において、本発明のGLP-1分泌促進剤を含む組成物に関する。本発明の組成物は、非限定的に、「インスリン分泌促進」、「血糖値低下」、「糖尿病の予
防又は治療」、「肥満の予防用又は改善」、「食欲の抑制」の1つまたは複数の用途を有しうる。「GLP-1分泌促進剤」の意義は、「1.GLP-1分泌促進剤」の項目に記載した通りである。本発明の組成物は、医薬組成物であっても、食品組成物であってもよい。食品組成物には、通常の飲食品の他に、調味料、サプリメント等の態様も含む。
L以上、30mg/dL、40mg/dL以上減少することを意味する。
また、前記GLP-1分泌促進剤を含む組成物の製剤化の際、非限定的に、賦形剤、結合剤、崩壊剤、滑沢剤、安定剤、保存剤、矯味矯臭剤、希釈剤等の製剤化に必要な添加剤を加えてもよい。
本発明は、一態様において、本発明のGLP-1分泌促進剤を含む、飲食品、に関する。
マウス由来小腸内分泌L細胞株であるGLUTag細胞は、カナダトロント大学のDaniel J. Drucker教授から譲り受けた。GLUTag細胞は100mmディッシュで培養し、1000mg/Lグルコース、584mg/LL-グルタミン、3.7g/L炭酸水素ナトリウム、110mg/Lピルビン酸ナトリウム入りのダルベッコ改変イーグル培地(シグマ アルドリッチ ジャパン合同会社、東京、日本)に、非働化した10%ウシ胎児血清(シグマ アルドリッチ ジャパン合同会社、東京、日本)、100U/mLペニシリン・0.1mg/mLストレプトマイシン(シグマ アルドリッチ ジャパン合同会社、東京、日本)を添加したものを培養液として用いた。37℃、5% CO2下で培養し、100mmディッシュの80%~90%まで細胞が増殖した際にトリプシン処理をして、継代を行った。
GLUTag細胞で実験を行う際は、試験に供する各種物質を、後述のグルコース入りのイメージング記録用溶液に溶解した。
2:233、2012)。
本実施例では、GLUTag細胞またはSTC-1細胞を、各種物質を含む刺激溶液を添加した培養液中で培養し、カルシウム2+イメージングによりGLP-1分泌を観察した。
ガラスボトムディッシュのカバーガラス上に、細胞を定着させるため、カバーガラスをポリL-リジン(シグマ アルドリッチ ジャパン合同会社、東京、日本)でコートした。15分間UV投射した35mmガラスボトムディッシュのカバーガラス上に、1mg/mL PポリL-リジン(シグマ アルドリッチ ジャパン合同会社、東京、日本)を200μL滴下し、30分間静置し、リン酸緩衝生理食塩水(Phosphate Buffered Saline:PBS)で3回洗浄した。
Fluo4-AMを導入したGLUTag細胞の培養ディッシュを、0.1mMグルコース入りのイメージング記録用溶液で2回洗浄した。その後、0.1mMグルコース入りのイメージング記録用溶液1.9mLに置換して、観察を行った。Fluo4-AMを導入したSTC-1細胞の培養ディッシュは、2.2mMグルコース入りの記録用溶液で2回洗浄し、2.2mM グルコース入りの記録用溶液2mLに置換して、観察を行った。
0, Carl Zeiss)を用い、青励起にBP470/40の励起フィルターとFT495のダイクロイックミラーのセット(B38-HE,Carl Zeiss)を用い、カメラ(ORCA-Flash4.0V2,C11440,浜松ホトニクス株式会社、静岡、日本)を用いて撮影した。対物レンズは開口数1.00の油浸40倍レンズ(UPlanApo,オリンパス)を用いた。IX71倒立顕微鏡では、キセノンランプ(オリンパス)を用いて励起し、蛍光フィルターを通して、Evolve EM-CCDカメラ(Photometrics, Tuscon, Arizona, USA)で撮影し、対物レンズは開口数1.35の油浸40倍(オリンパス)を用いた。
倒立顕微鏡によるイメージングの結果、刺激溶液投与後の各細胞の細胞内カルシウム 2+ 濃度変化率の最大値と記録溶液投与後の各細胞の細胞内カルシウム 2+ 濃度変化率の最大値を統計解析により比較し、有意な差がみられた物質については、GLP-1の分泌を誘導した(+)、有意な差がみられなかった物質については、GLP-1の分泌を誘導しない(-)、と判断した。結果を表1に示す。
ロパン、ニコチン酸、インドール-3-アセトアミド、D-アラニン、5-ヒドロキシリシン、1-メチルニコチナミド、チアミン、カルニチン、グルコン酸、プロスタグランジンE2、メチオニンスルホキシド、スペルミジン及びスペルミンの各種物質が、μM~mM程度の濃度で、GLP-1の分泌誘導効果を示す細胞内Ca2+濃度上昇が見出された。
本実施例では、GLUTag細胞またはSTC-1細胞を、各種物質を含む刺激溶液を添加した培養液中で培養し、酵素免疫定量法(ELISA)によりGLP-1濃度を測定し、GLP-1分泌の促進を定量した。
GLUTag細胞を用いる際は24ウェルプレートに1ウェル1.0×105個となるように細胞を撒き、培養液中で37℃、5% CO2下で2日間インキュベートした。2日後、各ウェルを0.1mMグルコース入りのイメージング記録用溶液で2回洗浄し、実施例1で用いた物質のうち、GLP-1の分泌誘導効果を示す細胞内Ca2+濃度上昇が見られた物質、すなわち表1で(+)の物質の含まれた刺激溶液を500μL加え、培養液中で37℃、5% CO2下で30分間インキュベートした。
(Merck Millipore, Darmstadt, Germany)およびVarioskan LUX(ThermoFisher SCIENTIFIC, Massachusetts, America)を用いて測定した。
STC-1細胞を用いる際は6ウェルプレートに1ウェル1.0×106個となるように細胞を撒き、培養液中で37℃、5% CO2下で2日間インキュベートした。前日に
1000 mg/Lグルコース入りの培養液に交換した。各ウェルを2.2mM グルコース入りのイメージング記録用溶液で2回洗浄し、各条件に対応する刺激溶液を1mL加え、培養液中で37℃、5% CO2下で120分間インキュベートした。その後、細胞培養液を全量1.5mLチューブに回収し、1000×g、4℃で10分間遠心後、そのGLP-1濃度をGLP-1 ELISAキットワコー、高感度品(富士フィルム和光純薬株式会社、大阪、日本)およびVarioskan LUXを用いて測定した。
GLUTag細胞またはSTC-1細胞を、各種物質を含む刺激溶液を添加した培養液中で培養し、酵素免疫定量法(ELISA)によりGLP-1濃度を測定した結果、非限定的に、少なくとも、プロピオン酸、酪酸、吉草酸、パントテン酸、コール酸、タウリン、ピリドキサミン、スペルミジン、スペルミンの各種物質が、μM~mM程度の濃度で、GLP-1分泌を誘導または促進した。
Claims (7)
- スペルミジン、スペルミン、タウリン、カルニチン5-ヒドロキシリシンおよび1-メチルニコチナミドからなる群から選択される、1またはそれ以上の化合物を含む、GLP-1分泌促進剤。
- 請求項1に記載のGLP-1分泌促進剤を含む、インスリン分泌促進用組成物。
- 請求項1に記載のGLP-1分泌促進剤を含む、血糖値低下用組成物。
- 請求項1に記載のGLP-1分泌促進剤を含む、糖尿病の予防用組成物又は治療用組成物。
- 請求項1に記載のGLP-1分泌促進剤を含む、肥満の予防用組成物又は改善用組成物。
- 請求項1に記載のGLP-1分泌促進剤を含む、食欲を抑制するための組成物。
- 請求項1に記載のGLP-1分泌促進剤を含む、飲食品。
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