| Project/Area Number |
18K19556
|
|---|
| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
Kubota Naoto 東京大学, 医学部附属病院, 准教授 (50396719)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
笹子 敬洋 東京大学, 医学部附属病院, 助教 (20550429)
中村 元信 東京大学, 医学部附属病院, 助教 (40459524)
|
|---|
| Project Period (FY) |
2018-06-29 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
|
|---|
| Keywords | 糖尿病 / 腎臓 / 糖新生 / インスリン抵抗性 |
|---|
| Outline of Final Research Achievements |
We found that proximal tubules (PT)-specific IRS 1/2 double-knockout mice exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of FoxO1. In contrast, glucose deacetylated PGC1α, a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究は、長年解明されていない“腎臓における糖新生の調節機構とその破綻の分子メカニズム”を解明しようとするものであり、極めて独創性・新規性が高く、また、肥満・2型糖尿病患者が直面している病態を解明しようとしている点で社会的意義も大きい。本研究は、腎臓の糖代謝調節機構の解明を通してその生理的/病態生理的役割を解明し、腎臓生理の根本原理に迫る斬新なプロジェクトであり、糖尿病や腎不全の予防・進行抑制さらに治療につながる卓越した成果が期待できる。
|
