Elucidation of the mechanism of insulin-induced changes in the expression of drug transporters and the establishment of a method to predict the changes in genetic function

• Project/Area Number: 17K08954
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kyushu University
• Principal Investigator: Hirota Takeshi 九州大学, 薬学研究院, 准教授 (80423573)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: P糖タンパク質 / インスリン / microRNA / 薬剤反応性

Outline of Final Research Achievements

We focused on the regulation of gene expression by insulin as a mechanism to cause changes in the expression of the drug efflux transporter P-glycoprotein (P-gp). In human hepatocarcinoma HepG2 cells, insulin significantly reduced the protein expression level of P-gp, but did not alter mRNA. We performed an exhaustive analysis of insulin-induced expression variation of microRNAs (miRNAs) with translational repression functions. Detailed analysis in the regulation of P-gp expression by the identified miRNAs showed that insulin increased the binding of miRNAs to Argonaute 2 (Ago2). These results suggest that up-regulation of miRNA and Ago2 binding is responsible for insulin-induced changes in P-gp expression. We established the method to isolate liver-derived exosomes from peripheral blood, suggesting that miRNA can be used as a biomarker for P-gp functional variation.

Academic Significance and Societal Importance of the Research Achievements

糖尿病は肝臓がんのリスクファクターであることが知られている一方で、肝臓がんに適応のあるドキソルビシンは、P-gpにより排出される。本研究によりインスリンはP-gp発現を低下させ、ドキソルビシンの細胞毒性を増加させることが示唆された。以上より、P-gpの基質薬物を服用する糖尿病患者に対して適切な投与設計を行う必要があると考えられる。また、インスリンによるP-gp発現変化の指標となるバイオマーカーとして肝由来exosomeのmiRNAが有用となる可能性を示唆した。今後バイオマーカーの感度・特異度の検証が重要となるが、糖尿病患者における薬物の個別適正医療実現において重要な研究成果であると言える。