2. Academic Validation
  3. Deficiency of Trex1 leads to spontaneous development of type 1 diabetes

Deficiency of Trex1 leads to spontaneous development of type 1 diabetes

  • Nutr Metab (Lond). 2024 Jan 2;21(1):2. doi: 10.1186/s12986-023-00777-6.
Jiang-Man Zhao 1,  Zhi-Hui Su 1,  Qiu-Ying Han 1,  Miao Wang 1,  Xin Liu 1,  Jing Li 2,  Shao-Yi Huang 1,  Jing Chen 1,  Xiao-Wei Li 1,  Xia-Ying Chen 1 3,  Zeng-Lin Guo 1,  Shuai Jiang 1,  Jie Pan 1,  Tao Li 1 3,  Wen Xue 4,  Tao Zhou 5 6
Affiliations

Affiliations

  • 1 Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China.
  • 2 Beijing Tongren Eye Center, Beijing Tongren Hospital of Capital Medical University, Beijing, 100730, China.
  • 3 Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, Zhejiang Province, China.
  • 4 Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China. wxue@xmail.ncba.ac.cn.
  • 5 Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China. tzhou@ncba.ac.cn.
  • 6 Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, Zhejiang Province, China. tzhou@ncba.ac.cn.
PMID: 38166933 DOI: 10.1186/s12986-023-00777-6
Abstract

Background: Type 1 diabetes is believed to be an autoimmune condition, characterized by destruction of insulin-producing cells, due to the detrimental inflammation in pancreas. Growing evidences have indicated the important role of type I interferon in the development of type 1 diabetes.

Methods: Trex1-deficient rats were generated by using CRISPR-Cas9. The fasting blood glucose level of rat was measured by a Roche Accuchek blood glucose monitor. The levels of Insulin, islet autoantibodies, and interferon-β were measured using enzyme-linked immunosorbent assay. The inflammatory genes were detected by quantitative PCR and RNA-seq. Hematein-eosin staining was used to detect the pathological changes in pancreas, eye and kidney. The pathological features of kidney were also detected by Masson trichrome and periodic acid-Schiff staining. The distribution of islet cells, immune cells or ssDNA in pancreas was analyzed by immunofluorescent staining.

Results: In this study, we established a Trex1-deletion Sprague Dawley rat model, and unexpectedly, we found that the Trex1-/- rats spontaneously develop type 1 diabetes. Similar to human diabetes, the hyperglycemia in rats is accompanied by diabetic complications such as diabetic nephropathy and cataract. Mechanistical investigation revealed the accumulation of ssDNA and the excessive production of proinflammatory cytokines, including IFN-β, in Trex1 null pancreas. These are likely contributing to the inflammation in pancreas and eventually leading to the decline of pancreatic β cells.

Conclusions: Our study links the DNA-induced chronic inflammation to the pathogenesis of type 1 diabetes, and also provides an animal model for type 1 diabetes studies.

Keywords

TREX1; Type 1 diabetes; Type I interferon.

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