Therapeutic potential of intestinal epithelial NAMPT-mediated NAD+ biosynthesis in insulin resistance
| Project/Area Number |
18K15399
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52010:General internal medicine-related
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| Research Institution | Keio University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | NAD合成系 / 腸管 / インクレンチン / 食後高血糖 / 肥満 / 腸管NAMPT / 腸管NAD+合成系 / インスリン初期分泌不全 / インクレチン分泌 / NMN / NAMPT-NAD+合成系 / インクレチン / 腸管NAMPT-NAD合成系 / NAD中間代謝産物NMN / インスリン抵抗性 |
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| Outline of Final Research Achievements |
The purpose of the present project was to test the hypothesis that intestinal NAMPT-mediated NAD+ biosynthesis plays a critical role in obesity-associated insulin resistance. To this end, we generated and analyzed intestinal epithelial cells-specific Nampt knockout mouse model, namely INKO mice.
We found that INKO mice did not exhibit insulin resistance. However, INKO had decreased production of glucagon-like peptide-1 (GLP-1), resulting in reduced early-phase insulin secretion and postprandial hyperglycemia. Importantly, nicotinamide mononucleotide (NMN), a product of NAMPT reaction, restored intestinal NAD+ levels and increased GLP-1 production in high fat diet-induced obese mice. Taken together, our results demonstrate that intestinal NAMPT-mediated NAD+ biosynthesis is essential for a normal glucoregulatory response via regulating GLP-1 production.
This work provides therapeutic insights into intestinal NAD+ biology in the obesity-associated dysregulation of glucose metabolism.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の検討により、腸管NAMPT-NAD+合成系の障害が、GLP-1分泌不全、インスリン初期分泌不全及び食後高血糖の原因の一端であることが示された。さらに、NMNによる腸管NAD+量の回復が、内因性GLP-1分泌を促進することより、食後高血糖への新たな治療法開発に繋がる可能性が示唆された。
Funagata試験では、食後高血糖が心血管疾患発症の重大なリスクファクターであることが示されており、腸管NAMPT-NAD+合成系を標的としたNMN経口投与による腸管NAD+量の回復は、新たな心血管疾患発症の予防法開発につながる可能性が高い。今後トランスレーショナルリサーチを積極的に展開していきたい。
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Report
(4 results)
Research Products
(13 results)
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[Journal Article] Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men2020
Author(s)
Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H
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Journal Title
Endocrine Journal
Volume: 67
Issue: 2
Pages: 153-160
DOI
NAID
ISSN
0918-8959, 1348-4540
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors.2019
Author(s)
Hiratsuka K, Monkawa T, Akiyama T, Nakatake Y, Oda M, Goparaju SK, Kimura H, Chikazawa-Nohtomi N, Sato S, Ishiguro K, Yamaguchi S, Suzuki S, Morizane R, Ko SBH, Itoh H, Ko MSH
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Journal Title
Scientific reports
Volume: 9
Issue: 1
Pages: 913-913
DOI
Related Report
Peer Reviewed / Open Access
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