关键词: 糖尿病, 妊娠, 胰岛素抵抗, Nrf2-Keap1-ARE信号通路

Abstract: Objective To conduct an in-depth study of the mechanism of Nrf2-Keap1-ARE signaling pathway in the offspring of patients with gestational diabetes mellitus (GDM), and to pay special attention to its regulatory role in the occurrence of insulin resistance. 
Methods Sixty successfully modeled rats were randomly divided into an empty lentivirus group (20 rats), an Nrf2 siRNA group (20 rats), and an insulin intervention group (20 rats). Rats in the three groups were intervened on the 5th day of pregnancy. After the empty lentivirus group completed modeling, 200uL of blank virus vector was injected into the tail vein. The Nrf2 siRNA group was injected with 200uL of Nrf2 siRNA vector. The insulin intervention group was injected with 4 U/kg of glargine insulin daily in the lower right abdomen of the rats. Three groups were all intervened for 2 weeks, and the glucose tolerance and insulin resistance, insulin tolerance, oxidative stress indicators in pancreatic tissue, Nrf2, Keap1, and ARE protein content and mRNA levels in pancreatic tissue of offspring rats were analyzed at 8, 16, and 24 weeks after birth. 
Results The insulin resistance indexes at 8, 16, and 24 weeks after birth were 0.65±0.13, 1.03±0.31, and 2.81±0.65, respectivelyin the empty lentivirus group, 0.97±0.22, 1.74±0.77, and 2.98±0.95, respectivelyin the Nrf2 siRNA groups, and 1.08±0.39, 2.66±0.92, and 4.42±1.04, respectively in the insulin intervention group. The blood glucose concentrations at 8, 16, and 24 weeks after birth were (2.18±0.09), (3.05±0.35), and (4.34±2.10) mmol/L, respectively in the empty lentivirus group, (2.58±0.37), (3.18±0.77), and (4.92±2.08) mmol/L, respectively in the Nrf2 siRNA group, and (2.89±0.39), (4.69±1.47), and (6.18±2.33) mmol/L, respectively in the insulin intervention group. In the pancreatic tissue of offspring rats, the empty lentivirus group showed higher levels of oxidative stress, while the insulin intervention group showed lower levels of oxidative stress (P＜0.05). The mRNA levels of Nrf2, Keapl, and ARE in the empty lentivirus group were lower than those in the Nrf2 siRNA group and insulin intervention group (P＜0.05). 
Conclusion Nrf2-Keap1-ARE signaling pathway may affect insulin sensitivity by regulating the level of oxidative stress, thus affecting the glucose metabolism of diabetic offspring during pregnancy. Activating this signaling pathway is expected to become a potential therapeutic strategy for the treatment of GDM and its related complications, providing new ideas for personalized clinical treatment. 

Key words: diabetes, gestational, insulin resistance, Nrf2 Keap1 ARE signaling pathway