School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China.
Scientist Emeritus, National Institute of Environmental Health Science, Research Triangle Park, NC, 27709, USA.
Mol Cell Endocrinol. 2022 Jun 1;549:111643. doi: 10.1016/j.mce.2022.111643. Epub 2022 Apr 6.
The loss of functional insulin-producing β-cells is a hallmark of type 1 diabetes mellitus (T1DM). Previously, we reported that the non-steroidal anti-inflammatory drug activated gene-1, or growth differentiation factor-15 (NAG-1/GDF15) inhibits obesity and improves insulin sensitivity in both genetic and dietary-induced obese mice. However, the regulatory role of NAG-1/GDF15 in the structure and function of β-cells and the prevention of T1DM is largely unknown. In the current study, we reported that NAG-1/GDF15 transgenic (Tg) mice are resistant to diabetogenesis induced by multiple low-dose streptozotocin (MLD-STZ) treatment. NAG-1/GDF15 overexpression significantly reduced diabetes incidence, alleviated symptoms of T1DM, and improved MLD-STZ-induced glucose intolerance and insulin resistance. Both the mass and function of pancreatic β cells were preserved in the NAG-1/GDF15 Tg mice as evidenced by significantly increased islet area and insulin production. The mechanistic study revealed that NAG-1/GDF15 significantly inhibited STZ-induced apoptosis and preserved the reduction of proliferation in the islets of the Tg mice as compared to the wild-type (WT) mice upon MLD-STZ treatment. Additionally, NAG-1/GDF15 significantly reduced both the serum and islet levels of the inflammatory cytokines (IL-1β, IL-6, and TNFα), and reduced the expression of NF-κB expression and immune cells infiltration in the islets. Collectively, these results indicate that NAG-1/GDF15 is effective in improving STZ-induced glucose intolerance, probably was mediated via suppressing inflammation, inhibiting apoptosis, and preserving β-cell mass and function.
胰岛素产生β细胞的功能丧失是 1 型糖尿病（T1DM）的标志。以前，我们报道过非甾体抗炎药激活基因-1，或生长分化因子-15（NAG-1/GDF15）可抑制肥胖并改善遗传和饮食诱导肥胖小鼠的胰岛素敏感性。然而，NAG-1/GDF15 在β细胞的结构和功能以及 T1DM 的预防中的调节作用在很大程度上是未知的。在目前的研究中，我们报道 NAG-1/GDF15 转基因（Tg）小鼠对多次低剂量链脲佐菌素（MLD-STZ）治疗引起的糖尿病发生具有抗性。NAG-1/GDF15 的过表达显著降低了糖尿病的发生率，缓解了 T1DM 的症状，并改善了 MLD-STZ 诱导的葡萄糖不耐受和胰岛素抵抗。NAG-1/GDF15 Tg 小鼠的胰岛β细胞的质量和功能均得到保留，这表现为胰岛面积和胰岛素分泌显著增加。机制研究表明，与野生型（WT）小鼠相比，NAG-1/GDF15 显著抑制 STZ 诱导的凋亡，并保留 MLD-STZ 处理后 Tg 小鼠胰岛中增殖的减少。此外，NAG-1/GDF15 还显著降低了血清和胰岛中炎性细胞因子（IL-1β、IL-6 和 TNFα）的水平，并降低了 NF-κB 表达和胰岛中免疫细胞浸润的表达。总之，这些结果表明，NAG-1/GDF15 可有效改善 STZ 诱导的葡萄糖不耐受，可能是通过抑制炎症、抑制细胞凋亡和保留β细胞的质量和功能来实现的。
