高水平的 DNA 损伤和衰老标志物与 2 型糖尿病患者白蛋白尿和限制性肺病的进展有关。
Elevated markers of DNA damage and senescence are associated with the progression of albuminuria and restrictive lung disease in patients with type 2 diabetes.
机构信息
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; European Molecular Biology Laboratory, Advanced Light Microscopy Facility, Heidelberg, Germany.
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
出版信息
EBioMedicine. 2023 Apr;90:104516. doi: 10.1016/j.ebiom.2023.104516. Epub 2023 Mar 17.
BACKGROUND
This study was conducted to investigate the cascade involving DNA damage, senescence, and senescence-associated secretory phenotype (SASP) in experimental diabetes and in a four-year follow-up study in patients with pre-diabetes and type 2 diabetes.
METHODS
Kidney, lung, and liver were studied in 4 months diabetic db/db mice and age-matched controls for the presence of DNA damage and fibrosis. DNA damage (comet-tail-length and ɤH2Ax-positivity in white blood cells), urinary p21-excretion, and plasma IL-6 and TGF-β1 were determined from 115 healthy participants, 34 patients with pre-diabetes and 221 with type 2 diabetes. Urinary albumin-creatinine-ratio, lung function, and transient elastography of the liver were performed in a prospective follow-up study over 4 years.
FINDINGS
db/db mice showed an increased nuclear ɤH2AX signal in all tissues as compared to the background control. Markers for DNA damage, senescence, and SASP were increased in patients with diabetes. The presence of nephropathy, restrictive lung disease (RLD), and increased liver stiffness was in a cross-sectional design associated with increased markers for DNA damage, senescence, and SASP. The progression of nephropathy over 4 years was predicted by increased DNA damage, senescence, and SASP, while the progression of RLD was associated with increased DNA damage and IL-6 only. The progression of liver stiffness was not associated with any of these parameters. HbA1c was not predictive for progression.
INTERPRETATION
In db/db mice, the cascade of DNA damage is associated with diabetes-related complications. In patients with diabetes, the progression of complications in the kidney and lung is predicted by markers reflecting DNA damage, and senescence-triggered organ fibrosis.
FUNDING
This work was supported by the German Research Foundation (DFG) in the CRC 1118 and CRC 1158, by the GRK DIAMICOM, by the German Center for Diabetes Research (DZD e.V.), and by the Ministry of Science, Research and the Arts, Baden-Württemberg (Kompetenznetzwerk Präventivmedizin).
背景
本研究旨在探讨实验性糖尿病中涉及 DNA 损伤、衰老和衰老相关分泌表型（SASP）的级联反应，并在四年的随访研究中探讨前驱糖尿病和 2 型糖尿病患者的情况。
方法
在 4 个月龄的糖尿病 db/db 小鼠和年龄匹配的对照组中，研究了肾脏、肺和肝脏中 DNA 损伤和纤维化的存在情况。从 115 名健康参与者、34 名前驱糖尿病患者和 221 名 2 型糖尿病患者中测定了 DNA 损伤（彗星尾长度和白细胞中的 γH2AX 阳性）、尿 p21 排泄、血浆白细胞介素-6（IL-6）和转化生长因子-β1（TGF-β1）。在 4 年的前瞻性随访研究中，对参与者进行了尿白蛋白/肌酐比、肺功能和肝脏瞬时弹性检测。
结果
与背景对照组相比，db/db 小鼠的所有组织中核 γH2AX 信号均增加。糖尿病患者的 DNA 损伤、衰老和 SASP 标志物均增加。在横断面设计中，肾病、限制性肺疾病（RLD）和肝硬度增加与 DNA 损伤、衰老和 SASP 标志物增加相关。4 年内肾病的进展与 DNA 损伤、衰老和 SASP 标志物增加相关，而 RLD 的进展仅与 DNA 损伤和 IL-6 相关。肝硬度的进展与这些参数均无关。HbA1c 对进展无预测作用。
解释
在 db/db 小鼠中，DNA 损伤级联与糖尿病相关并发症有关。在糖尿病患者中，肾脏和肺部并发症的进展可由反映 DNA 损伤和衰老触发的器官纤维化的标志物预测。
资助
本研究由德国研究基金会（DFG）在 CRC 1118 和 CRC 1158、GRK DIAMICOM、德国糖尿病研究中心（DZD e.V.）和巴登-符腾堡州科学、研究和艺术部（Kompetenznetzwerk Präventivmedizin）资助。
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