Involvement of DAG metabolism in beta-cell dysfunction during type 2 diabetes
| Project/Area Number |
17K01857
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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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| Research Field |
Applied health science
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| Research Institution | University of Shizuoka |
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Principal Investigator |
Kaneko Yukiko 静岡県立大学, 薬学部, 講師 (00381038)
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| Co-Investigator(Kenkyū-buntansha) |
石川 智久 静岡県立大学, 薬学部, 教授 (10201914)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 糖尿病 / 膵β細胞 / インスリン分泌 / ジアシルグリセロール / ジアシルグリセロールキナーゼ / インスリン / 糖脂肪毒性 / シグナル伝達 / 脂質 |
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| Outline of Final Research Achievements |
The intracellular DAG level is strictly controlled, primarily by DAG kinase (DGK), an enzyme catalyzing the conversion of DAG to phosphatidic acid. We have previously shown a crucial role of DGK in GSIS. Of the 10 known DGK isoforms, we focused on type-I DGK isoforms (i.e., DGKα, DGKγ), which are activated by Ca2＋. We investigated the effects of DAG accumulated via the reduced activity of type I DGKs on insulin secretion. DAG accumulation through declined type I DGK activity shows a dual effect on insulin secretion depending on the degree of accumulation; a mild DAG accumulation induces a PKC-dependent stimulatory effect on insulin secretion, whereas an excessive DAG accumulation suppresses it in a PKC-independent manner, possibly via attenuation of VDCC activity. Moreover, glucose tolerance was reduced in type I DGK knockout mice. Thus, type I DGKs are likely to play a pivotal role in maintaining appropriate insulin secretion by optimizing DAG levels.
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| Academic Significance and Societal Importance of the Research Achievements |
肥満を伴う２型糖尿病発症過程において引き起こされるGLadaptationとGL-toxicity というインスリン分泌異常の一連の流れにtype I DGK 機能が関与しているという新たな発想に基づき計画された。本研究より、膵β細胞内ではtype I DGKの働きにより細胞内DAG量が適切に調節されていること、これらの調節機能の破綻によりインスリン分泌異常からの糖尿病増悪へと繋がる可能性が明らかとなった。本研究よりβ細胞内DAGの蓄積を調節し、β細胞機能障害からの回復を目的とした、全く新しい作用機序を有する糖尿病治療薬の開発につながることが期待される。
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Report
(4 results)
Research Products
(34 results)
