Involvement of mtROS and Warburg effect in diabetic complications progression mechanism by hypoglycemia

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09393
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: Kukidome Daisuke 熊本大学, 医学部附属病院, 助教 (10555759)
• Co-Investigator(Kenkyū-buntansha): 荒木 栄一 熊本大学, 大学院生命科学研究部(医), 教授 (10253733) ; 松村 剛 熊本大学, 大学院生命科学研究部(医), 准教授 (20398192) ; 西川 武志 熊本大学, 大学院生命科学研究部(医), 特任准教授 (70336212)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: ミトコンドリア由来活性酸素種 / 低血糖 / 糖尿病 / 動脈硬化 / 糖尿病細小血管合併症

Outline of Final Research Achievements

Results: We found that low glucose (LG) increased mtROS generation in endotherial cells (ECs); this effect was suppressed by overexpression of manganese superoxide dismutase (MnSOD). Comprehensive metabolic analysis using capillary electrophoresis-mass spectrometry and oxygen consumption rate assessment revealed that the pathway from fatty acid to acetyl-CoA via fatty acid oxidation (FAO) was upregulated in ECs under LG. In addition, etomoxir, a specific inhibitor of the free fatty acid transporter, decreased LG-induced mtROS production. These results suggested that LG increased mtROS generation through activation of FAO. We further revealed that LG inhibited eNOS phosphorylation and increased the expression of VCAM-1 and ICAM-1. These effects were prevented either by overexpression of MnSOD or by etomoxir.
Conclusions: These findings suggested that activation of FAO followed by mtROS production could be a novel therapeutic target for endothelial dysfunction during hypoglycemia.

Free Research Field

代謝・内分泌