Mechanism of the regulation of insulin granule exocytosis by glutamate signaling in beta-cells
| Project/Area Number |
19K09026
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
高橋 晴美 神戸大学, 医学研究科, 特命准教授 (50546489)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | インスリン分泌 / インクレチン / グルタミン酸 |
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| Outline of Research at the Start |
インクレチン（GLP-1, GIP）による膵β細胞からのインスリン分泌調節機構の解明は、糖尿病の克服のため極めて重要な課題である。
研究代表者らは、グルコース代謝により産生されたグルタミン酸が、インクレチン/cAMPシグナルによりインスリン顆粒内に取り込まれ、インスリン分泌が促進されることを示した。しかし、インスリン顆粒内に取り込まれたグルタミン酸がインスリン顆粒の開口分泌を増強する分子メカニズムは不明である。
本研究では、インスリン顆粒の網羅的解析により同定された開口分泌関連タンパク質について詳細な機能解析を行うことにより、グルタミン酸によるインスリン開口分泌制御機構を解明することを目的とする。
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| Outline of Final Research Achievements |
Incretins are secreted from enteroendocrine cells upon meal ingestion and potentiate glucose-induced insulin secretion (GIIS) from pancreatic β-cell through cAMP signaling. We previously found that cytosolic glutamate mediates action of incretin/cAMP in insulin secretion. In this study, we aimed to elucidate the mechanisms by which glutamate mediates incretin/cAMP action in β-cell. From comparative proteomic analysis of insulin granule, candidate proteins that are possibly associated with exocytosis induced by glutamate were identified. The investigation of mechanism by which glutamine amplifies insulin secretion revealed that intracellular glutamate converted from glutamine by glutaminase amplified GIIS through elevation of intracellular Ca2+ level without further conversion to α-ketoglutarate, which is the mechanism different from previously known. These results suggest that intracellular glutamate promotes insulin secretion through multiple mechanisms in pancreatic β-cell.
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| Academic Significance and Societal Importance of the Research Achievements |
現在、糖尿病治療において、インクレチン作用を利用したインクレチン関連薬が標準的な治療薬となっており重要な位置を占めている。本研究の成果はインクレチン関連薬の作用機序の解明に繋がることから、本治療薬の新たな可能性や治療抵抗性の症例に対しても有効な治療法の発見が期待できることから、意義は大きい。
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Report
(4 results)
Research Products
(29 results)
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[Journal Article] Tumor-like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin-induced insulin secretion in obese diabetes: a study of ZFDM rat.2020
Author(s)
Hayami T, Yokoi N, Yamaguchi T, Honda K, Murao N, Takahashi H, Wang S, Seino Y, Kamiya H, Yabe D, Sweet IR, Mizoguchi A, Nakamura J, Seino S
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Journal Title
J Diabetes Investig
Volume: -
Issue: 6
Pages: 1434-1447
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes2020
Author(s)
Oduori Okechi S.、Murao Naoya、Shimomura Kenju、Takahashi Harumi、Zhang Quan、Dou Haiqiang、Sakai Shihomi、Minami Kohtaro、Chanclon Belen、Guida Claudia、Kothegala Lakshmi、Tol? Johan、Maejima Yuko、Yokoi Norihide、Minami Yasuhiro、Miki Takashi、Rorsman Patrik、Seino Susumu
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Journal Title
Journal of Clinical Investigation
Volume: 130
Issue: 12
Pages: 6639-6655
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release.2019
Author(s)
Denwood G, Tarasov A, Salehi A, Vergari E, Ramracheya R, Takahashi H, Nikolaev VO, Seino S, Gribble F, Reimann F, Rorsman P, Zhang Q
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Journal Title
J Gen Physiol
Volume: 151(9)
Issue: 9
Pages: 1094-1115
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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