Analyses of effects on glucose metabolism and identification of pathogenic mechanism of insulin-resistant diabetes mellitus due to DNA repair deficiency.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07746
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Takasawa Kei 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (50749463)
• Co-Investigator(Kenkyū-buntansha): 鹿島田 健一 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (80451938)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: DNA損傷修復異常 / インスリン抵抗性 / Bloom症候群

Outline of Final Research Achievements

We have established a system to analyze phosphorylation profiles downstream of insulin receptor upon insulin and IGF-1 stimulation for human B cell line derived from Bloom syndrome patients and transformed by Epstein-Barr Virus.In addition, we obtained cell-lines derived from patients with insulin receptor deficiencies, ataxia telangiectasia, and activated PI3K-delta syndrome, Baller-Gerold syndrome, Werner syndrome, and LIG4 syndrome for parallel analysis.
Based on clinical information on patients with Bloom syndrome in Japan, we have identified the presence of insulin resistance that becomes apparent around puberty and IGF-1 non-response that may be a factor in growth failure as a clinical feature of Bloom syndrome. Given the fact, we plan to propose a treatment strategy for diabetes mellitus and insulin resistance in patients with Bloom syndrome.

Free Research Field

小児内分泌学

Academic Significance and Societal Importance of the Research Achievements

発癌性や免疫調節異常を呈するDNA損傷修復異常症の一つである、Bloom症候群において小児期より高度インスリン抵抗性呈し、若年発症糖尿病を来すことを明らかにした。
Bloom症候群において、インスリン抵抗性（→糖尿病発症）、成長因子であるIGF-1への不応性（→成長障害）が共存することから、その分子学的発症機序を明らかにすることで、発癌と糖尿病発症、成長障害の新たな相関性を探求する。
同時に種々の類縁疾患（インスリン受容体異常症、毛細血管拡張性運動失調症、活性化 PI3K-delta症候群、Werner症候群、LIG4症候群）の患者由来細胞を樹立し、並行解析を行うことで、上記の機序を補填していく。