Investigation of the function of STIM in pancreatic b-cells
| Project/Area Number |
19K23966
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0902:General internal medicine and related fields
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| Research Institution | Kyoto University |
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Principal Investigator |
USUI RYOTA 京都大学, 医学研究科, 特定助教 (40850996)
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| Project Period (FY) |
2019-08-30 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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 / カルシウム / β細胞 |
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| Outline of Research at the Start |
細胞内Ca2+流入を担うSOCEを誘導することで小胞体Ca2+濃度を制御する小胞体膜蛋白STIM（stromal interaction molecule）が同定されたが、その生理学的意義や制御機構は不明であるため、このSTIMに注目し、STIMを欠損する膵β細胞株、STIMを膵β細胞特異的に欠損するマウスを作出し、耐糖能やインスリン分泌能、小胞体ストレスマーカーを評価すると同時に、糖尿病モデル、肥満モデルにおけるSTIMの活性と表現系に対する影響を検討することでインスリン分泌、小胞体ストレスへの作用を含めた、STIMの膵β細胞における役割を明確化する。
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| Outline of Final Research Achievements |
Store-operated Ca2+ entry (SOCE) is activated by endoplasmic reticulum (ER) Ca2+ sensor STIM1 which senses depletion of Ca2+ from the ER, and induces extracellular Ca2+ influx through Orai1 to the cytosol to maintain intracellular Ca2+ homeostasis in various cell types, however the role of SOCE in pancreatic b-cells remains largely unknown.
STIM1 or Orai1 KD MIN6 cells and islets from b-cell-specific STIM1 KO mice similarly abolished GPR40 agonist, fas-mediated potentiation of GIIS and fas-induced elevation of intracellular Ca2+ levels, while there was little effect on GIIS itself. In OGTT, blood glucose levels were similar in control mice and STIM1 KO mice without fas administration, however fas-mediated glucose lowering and insulin increasing effect were significantly lower compared with control. GPR40 signal activates STIM1 and SOCE activated by STIM1 is essential for GPR40-mediated potentiation of GIIS.
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| Academic Significance and Societal Importance of the Research Achievements |
膵β細胞にはグルコース応答性インスリン分泌以外にも様々なインスリン分泌調整機構が存在しているが、栄養素の一つである脂肪酸刺激によるインスリン分泌増強作用において、今回新たにSTIM1という因子が重要な役割を担っていることを明らかにした。
糖尿病患者においては膵β細胞のSTIM1発現量が低下しているという報告もあり、本研究における成果とあわせて栄養素、あるいは糖尿病治療薬の効果予測因子としてSTIM1が有用である可能性を示唆した。
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Report
(3 results)
Research Products
(4 results)
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[Journal Article] GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells2019
Author(s)
Usui R, Yabe D, Fauzi M, Goto H, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Kobayashi S, Manebe T, Baba Y, Kurosaki T, Herrera PL, Ogura M, Nagashima K, Inagaki N
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Journal Title
Sci Rep.
Volume: 9
Issue: 1
Pages: 15562-15562
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Store-operated Ca2+ entry activated by STIM1 plays an essential role in GPR40-mediated GIIS potentiation.2019
Author(s)
1.Usui R, Yabe D, Fauzi M, Goto H, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Kobayashi S, Manabe T, Baba Y, Kurosaki T, Ogura M, Nagashima K, Inagaki N
Organizer
American Diabetes Association the 79th Scientific Sessions
Related Report
Int'l Joint Research
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