Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church St., Minneapolis, MN 55455, USA; Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL 33458, USA.
Metabolism. 2021 Apr;117:154711. doi: 10.1016/j.metabol.2021.154711. Epub 2021 Jan 23.
Type 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whether DNA damage plays a role in the pathogenesis of the disease is unclear. Here, we used mice deficient for the DNA excision-repair gene Ercc1 to study the impact of persistent endogenous DNA damage accumulation on energy metabolism, glucose homeostasis and beta-cell function.
ERCC1-XPF is an endonuclease required for multiple DNA repair pathways and reduced expression of ERCC1-XPF causes accelerated accumulation of unrepaired endogenous DNA damage and accelerated aging in humans and mice. In this study, energy metabolism, glucose metabolism, beta-cell function and insulin sensitivity were studied in Ercc1 mice, which model a human progeroid syndrome.
Ercc1 mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivity was increased, whereas, plasma insulin levels were decreased in Ercc1 mice. Fasting induced hypoglycemia in Ercc1 mice, which was the result of increased glucose disposal. Ercc1 mice exhibit a significantly reduced beta-cell area, even compared to control mice of similar weight. Glucose-stimulated insulin secretion in vivo was decreased in Ercc1 mice. Islets isolated from Ercc1 mice showed increased DNA damage markers, decreased glucose-stimulated insulin secretion and increased susceptibility to apoptosis.
Spontaneous DNA damage accumulation triggers an adaptive response resulting in improved insulin sensitivity. Loss of DNA repair, however, does negatively impacts beta-cell survival and function in Ercc1 mice.
2 型糖尿病（T2DM）是一种与年龄相关的疾病，其特征是由于胰岛素抵抗和β细胞功能下降导致的高血糖。DNA 损伤的积累与 T2DM 有关，但 DNA 损伤是否在疾病的发病机制中起作用尚不清楚。在这里，我们使用 DNA 切除修复基因 Ercc1 缺失的小鼠来研究持续的内源性 DNA 损伤积累对能量代谢、葡萄糖稳态和β细胞功能的影响。
ERCC1-XPF 是多种 DNA 修复途径所必需的内切酶，ERCC1-XPF 的表达减少会导致未修复的内源性 DNA 损伤加速积累，并导致人类和小鼠加速衰老。在这项研究中，我们研究了 Ercc1 小鼠的能量代谢、葡萄糖代谢、β细胞功能和胰岛素敏感性，Ercc1 小鼠模型模拟了人类的早衰综合征。
Ercc1 小鼠表现出生长激素轴的抑制和能量代谢的改变。胰岛素敏感性增加，而血浆胰岛素水平降低。Ercc1 小鼠在禁食时会出现低血糖，这是由于葡萄糖摄取增加所致。与体重相似的对照小鼠相比，Ercc1 小鼠的β细胞面积明显减小。Ercc1 小鼠体内的葡萄糖刺激胰岛素分泌减少。从 Ercc1 小鼠分离的胰岛显示出 DNA 损伤标志物增加、葡萄糖刺激的胰岛素分泌减少和对细胞凋亡的敏感性增加。
自发的 DNA 损伤积累引发适应性反应，导致胰岛素敏感性提高。然而，DNA 修复的丧失会对 Ercc1 小鼠的β细胞存活和功能产生负面影响。
