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肥満糖尿病モデルdb/dbマウスにおけるDPP-4阻害薬とチアゾリジン誘導体の併用による相加的膵β細胞保護作用とその分子機構
https://kwmed.repo.nii.ac.jp/records/1650
https://kwmed.repo.nii.ac.jp/records/165088dd50e5-ce22-4cf4-a771-663d39486a40
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
KJ00009282399.pdf (967.2 kB)
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| Item type | [ELS]学術雑誌論文 / Journal Article(1) | |||||||||||
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| 公開日 | 2017-01-23 | |||||||||||
| タイトル | ||||||||||||
| タイトル | 肥満糖尿病モデルdb/dbマウスにおけるDPP-4阻害薬とチアゾリジン誘導体の併用による相加的膵β細胞保護作用とその分子機構 | |||||||||||
| 言語 | ja | |||||||||||
| タイトル | ||||||||||||
| タイトル | The molecular mechanism by which the combination treatment with DPP-4 inhibitor and thiazolidine derivative yields the additive effect on the preservation of pancreatic β-cell mass and function in obese diabetic model db/db mice | |||||||||||
| 言語 | en | |||||||||||
| 言語 | ||||||||||||
| 言語 | jpn | |||||||||||
| 資源タイプ | ||||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||||||||
| 資源タイプ | journal article | |||||||||||
| 著者 |
蛭川, 英典
× 蛭川, 英典
× Hirukawa, Hidenori
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| 著者所属(日) | ||||||||||||
| ja | ||||||||||||
| 川崎医科大学糖尿病・代謝・内分泌内科学 | ||||||||||||
| 著者所属(英) | ||||||||||||
| en | ||||||||||||
| Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School | ||||||||||||
| キーワード | ||||||||||||
| 言語 | ja | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | DPP-4阻害薬 | |||||||||||
| キーワード | ||||||||||||
| 言語 | ja | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | チアゾリジン誘導体 | |||||||||||
| キーワード | ||||||||||||
| 言語 | ja | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | 膵β細胞量 | |||||||||||
| キーワード | ||||||||||||
| 言語 | ja | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | 細胞動態 | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | Thiazolidine derivative | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | DPP-4 inhibitor | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | Pancreatic β-cell mass | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | Cellular kinetics | |||||||||||
| 記事種別(日) | ||||||||||||
| 内容記述タイプ | Other | |||||||||||
| 内容記述 | 原著 | |||||||||||
| 言語 | ja | |||||||||||
| 抄録(日) | ||||||||||||
| ja | ||||||||||||
| 2型糖尿病の病態とりわけ膵β細胞機能低下は経年的に進行するため,いかに細胞機能保護を計るかは長期血糖管理の上で重要な課題である.経口糖尿病治療薬の中でもDPP-4阻害薬とpioglitazone(PIO)は膵β細胞保護効果作用を有する.本研究では両薬の併用による相加的な膵β細胞保護効果作用とその分子機構について検討した.肥満糖尿病モデルdb/dbマウス雄性6週齢をALO,PIO,併用,コントロールの4群に分け4週間の介入を行った.さらに,介入後に膵島の形態学的,機能的解析に加え,laser capture microdissection法およびreal-time RT-PCRを用いた膵島コア領域遺伝子発現解析を行った.その結果,血糖値は全介入群で有意に低下し,併用群でより顕著であった.インスリン抵抗性はPIO群と併用群で改善した.膵β細胞量はコントロール群に比しALO群またはPIO群で増加傾向,併用群で有意な増加を認め,膵島インスリン含量とグルコース刺激性インスリン分泌の改善を伴った.膵β細胞増殖能はALO群,PIO群で増加傾向,併用群で有意な増加を示し,アポトーシスはALO群,PIO群で減少傾向,併用群で有意な減少をみた.遺伝子解析では,Insulin遺伝子発現量はALO群と併用群で増加し,PIO群ではインスリン抵抗性改善を反映し減少傾向を示した.GLUT2遺伝子発現は全実薬群で増加傾向を認め,併用群でその傾向は強かった.PDX-1,MafA,Cyclin DおよびBcl-2遺伝子はALO群,PIO群で増加傾向を示し,併用群で顕著であった.膵β細胞量および機能維持に必須であるIRS-2遺伝子の発現量はALO群で増加傾向を示し,併用群で顕著に増幅された.また,GLP-1R遺伝子発現はALO群,PIO群で増加傾向を示し,併用群で顕著であった.肥満2型糖尿病モデルdb/dbマウスに対するALOとPIOの併用投与は,少なくとも一部はGLP-1シグナルを介したIRS-2発現調節により相加的な膵β細胞保護効果を発揮する可能性が示された. | ||||||||||||
| 抄録(英) | ||||||||||||
| en | ||||||||||||
| This article background is pathophysiology of type 2 diabetes especially pancreatic β-cell dysfunction, and it's progression over time. Thereby the preservation of β-cell function is an important tool to obtain a long-term glycemic control. A dipeptidyl peptidase-4 (DPP-4) inhibitor and pioglitazone (PIO) are known to protect the β-cell damage in diabetic animals. This study will show the effect of combination treatment with DPP-4 inhibitor (alogliptin: ALO) and PIO on the β-cell mass and function was examined in the diabetic state, additionally its molecular mechanism was analyzed. Six week-old male db/db mice were orally received ALO, PIO, ALO+PIO and the vehicle for 4 weeks. After the intervention, effects of 4 regimens on the β-cell mass and function were compared, and the gene expressions for the core area of the islets were also analyzed by using Laser Capture Microdissection and real-time RT-PCR. Blood glucose levels were significantly lower in mice treated with active drugs compared with the vehicle. PIO and combination with PIO and ALO improved insulin sensitivity. The islet insulin content and β-cell mass were significantly increased in mice treated with PIO and ALO, and these effects were further potentiated by concomitant use of two drugs. In addition, these drugs improved the islet morphology. The immunohistochemical analysis showed the drugs accelerated the β-cell proliferation and suppressed the cell apoptosis. The gene expression analysis demonstrated that ALO and the combination treatment increased the insulin mRNA. In contrast, insulin mRNA level was decreased in PIO group. The GLUT2 mRNA was up-regulated by active drug treatment, particularly in the combination with ALO and PIO. Interestingly, the mRNA level of IRS-2 was significantly amplified in the combination of two drugs. Furthermore, GLP-1R mRNA level was up-regulated by PIO and ALO particularly combination treatment, Both ALO and PIO accelerated gene expression related with cell differentiation and proliferation such as PDX-1, MafA, Cyclin D. The Bcl-2 mRNA was also up-regulated. On the other hand, these drugs suppressed the gene expression levels related with the promotion of cellular apoptosis. These effects by PIO and ALO were more significant in the combination treatment. The presented results strongly suggest that the concomitant administration of ALO and PIO shows the additional effect on the β-cell preservation, Two drugs exert a cooperative action on IRS-2 regulation, which is indispensable to conserve the β-cell mass and function, through, at least, enhancement of GLP-1 signaling. | ||||||||||||
| 書誌情報 |
ja : 川崎医学会誌 en : Kawasaki medical journal 巻 40, 号 1, p. 13-26, 発行日 2014 |
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| URL | ||||||||||||
| 識別子 | http://igakkai.kms-igakkai.com/wp/wp-content/uploads/2014/KMJ-J40(1)13.pdf | |||||||||||
| 識別子タイプ | URI | |||||||||||
| DOI | ||||||||||||
| 識別子タイプ | DOI | |||||||||||
| 関連識別子 | https://doi.org/10.11482/KMJ-J40(1)13 | |||||||||||
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| 収録物識別子タイプ | PISSN | |||||||||||
| 収録物識別子 | 0386-5924 | |||||||||||
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| 収録物識別子タイプ | EISSN | |||||||||||
| 収録物識別子 | 2758-089X | |||||||||||
| 雑誌書誌ID | ||||||||||||
| 収録物識別子タイプ | NCID | |||||||||||
| 収録物識別子 | AN00045593 | |||||||||||
| 雑誌書誌ID | ||||||||||||
| 収録物識別子タイプ | NCID | |||||||||||
| 収録物識別子 | AN12940574 | |||||||||||
| 著者版フラグ | ||||||||||||
| 出版タイプ | VoR | |||||||||||
