2022 Fiscal Year Final Research Report
Elucidation of pathogenesis and treatment of islet mitochondrial dysfunction and inflammation under glucolipotoxicity
| Project/Area Number |
20H03733
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
|
|---|
| Research Institution | Yokohama City University |
|---|
Principal Investigator |
TERAUCHI Yasuo 横浜市立大学, 医学研究科, 教授 (40359609)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
富樫 優 横浜市立大学, 医学部, 講師 (10710444)
白川 純 横浜市立大学, 医学研究科, 客員教授 (70625532)
|
|---|
| Project Period (FY) |
2020-04-01 – 2023-03-31
|
| Keywords | 膵β細胞 / ミトコンドリア / 膵島 / インスリン / UCP2 / Aldolase B / S100A8 / TLR4 |
|---|
| Outline of Final Research Achievements |
Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM). We here highlighted the molecular link between the increase in UCP2 expression in beta-cells and beta-cell failure by using genetically engineered mice and human islets. Beta-cell-specific UCP2-overexpressing transgenic mice (bUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress mediated pathway were observed in bUCP2Tg islets. Our findings provide a new mechanism of beta-cell dysfunction by UCP2 and AldB.
Obesity and diabetes are independent risk factors for death during sepsis. S100A8, an alarmin, is related to inflammation, obesity, and diabetes. We now revealed the role of S100A8 in sepsis of obesity and diabetes models.
|
| Free Research Field |
内分泌・代謝学
|
| Academic Significance and Societal Importance of the Research Achievements |
UCP2はミトコンドリアタンパクであり、ミトコンドリア機能障害に関与し、S100A8はマクロファージ等との細胞間相互作用を介して膵島炎症を引き起こす。現在市販されている経口血糖治療薬のうち、膵β細胞のミトコンドリアや炎症を直接標的とする薬剤は少ない。本研究で得られた知見は、ミトコンドリアや膵島炎症を標的とした新たな糖尿病治療法の開発へ応用できる。実際、私たちはUCP2やAldBが膵β細胞機能や量に及ぼす影響とその詳細な分子機構に基づき、生体内で健康的に機能的な膵β細胞量を増大させる「膵β細胞のhealthy expansion」を目指した研究を発展的に展開している。
|
