Analysis of lipotoxicity and stratagem for diabetes mellitus
Project/Area Number |
18K08518
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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Research Institution | Kagawa University |
Principal Investigator |
Murao Koji 香川大学, 医学部, 教授 (20291982)
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Co-Investigator(Kenkyū-buntansha) |
井町 仁美 香川大学, 医学部, 准教授 (80380187)
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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 |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 糖尿病 / HDL代謝 / 膵β細胞 / 脂肪毒性 / ABCA1 / 細胞内情報伝達系 / インスリン分泌 / 糖毒性 / HDL / SR-BI/CLA-1 / Smad1 / insulin / PREB / 膵ベータ細胞 / 分子メカニズム |
Outline of Final Research Achievements |
Type 2 diabetes is characterized by progressive beta-cell dysfunction and loss of beta-cell mass. The reasons for beta-cell dysfunction in type 2 diabetes are incompletely understood. Recently, not only glucose toxicity in pancreatic β cells but also lipotoxicity has been attracting attention as a cause of insulin secretion deficiency, and a decrease in glucose sensitivity has been pointed out. We have comprehensively elucidated the intracellular signal transduction mechanism of lipotoxicity in pancreatic β cells and elucidated the pathophysiology of insulin secretory deficiency. AngiotensinII and TNF suppressed ABCA1 gene expression and caused insulin secretory deficiency. Conversely, GLP-1 promoted ABCA1 gene expression via the intracellular signal transduction system CaMKK / CaMKIV-PREB and released lipotoxicity.
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Academic Significance and Societal Importance of the Research Achievements |
膵β細胞においては、コレステロール含量が増加することでグルコース依存性インスリン分泌が障害されることが判明した。本実験の特徴は、膵β細胞のコレステロール含量を調節するABCA1の発現調節メカニズムを解明し、加えてコレステロール蓄積によるインスリン分泌不全のメカニズムを網羅的に解析し、最終的にはHDL代謝, ABCA1代謝を賦活することによる膵β細胞の脂肪毒性解除の新たな治療ストラテージを確立することにある。本研究内容は国内外でも特異であり、今後の発展性および患者数増加からの観点からも本研究の社会的ニーズは高いと考えられる。
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Report
(4 results)
Research Products
(15 results)
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[Journal Article] Role of ATP-binding cassette transporter A1 in suppressing lipid accumulation by glucagon-like peptide-1 agonist in hepatocytes2020
Author(s)
Lyu J, Imachi H, Fukunaga K, Sato S, Kobayashi T, Dong T, Saheki T, Matsumoto M, Iwama H, Zhang H, Murao K
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Journal Title
Mol Metab
Volume: 34
Pages: 16-26
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Selective peroxisome proliferator-activated receptor-α modulator K-877 regulates the expression of ATP-binding cassette transporter A1 in pancreatic beta cells.2018
Author(s)
Dong T, Lyu J, Imachi H, Kobayashi T, Fukunaga K, Sato S, Ibata T, Yoshimoto T, Yonezaki K, Iwama H, Zhang G, Murao K.
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Journal Title
Eur J Pharmacol
Volume: 838
Pages: 78-84
DOI
Related Report
Peer Reviewed
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[Journal Article] Effect of TNF-α on the expression of ABCA1 in pancreatic β-cells2018
Author(s)
Sato S, Imachi H, Lyu J, Miyai Y, Fukunaga K, Dong T, Ibata T, Kobayashi T, Yoshimoto T, Kikuchi F, Yonezaki K, Yamaji N, Iwama H, Murao K
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Journal Title
J Mol Endocrinol
Volume: 61
Issue: 4
Pages: 185-193
DOI
Related Report
Peer Reviewed
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[Journal Article] Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells.2018
Author(s)
Lyu J, Imachi H, Fukunaga K, Sato S, Ibata T, Kobayashi T, Dong T, Yoshimoto T, Yonezaki K, Nagata H, Iwama H, Murao K
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Journal Title
J Lipid Res
Volume: 59
Issue: 10
Pages: 1906-1915
DOI
Related Report
Peer Reviewed
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