Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, Mendelssohnstraße 1, D-38106 Braunschweig, Germany.
Int J Mol Sci. 2022 Jun 15;23(12):6693. doi: 10.3390/ijms23126693.
Female New Zealand obese (NZO) mice are an established model of preconceptional (pc.) prediabetes that progresses as gestational diabetes mellitus (GDM) during gestation. It is known that NZO mice show improvement in insulin sensitivity and glucose-stimulated insulin secretion (GSIS) during gestation in vivo. The latter is no longer detectable in ex vivo perifusion experiments in isolated islets of Langerhans, suggesting a modulation by extrapancreatic factors. Here, we demonstrated that plasma 17β-estradiol (E2) levels increased markedly in NZO mice during gestation. The aim of this work was to determine whether these increased E2 levels are responsible for the improvement in metabolism during gestation. To achieve this goal, we examined its effects in isolated islets and primary hepatocytes of both NZO and metabolically healthy NMRI mice. E2 increased GSIS in the islets of both strains significantly. Hepatic glucose production (HGP) failed to be decreased by insulin in NZO hepatocytes but was reduced by E2 in both strains. Hepatocytes of pregnant NZO mice showed significantly lower glucose uptake (HGU) compared with NMRI controls, whereby E2 stimulation diminished this difference. Hepatocytes of pregnant NZO showed reduced glycogen content, increased cyclic adenosine monophosphate (cAMP) levels, and reduced AKT activation. These differences were abolished after E2 stimulation. In conclusion, our data indicate that E2 stabilizes and prevents deterioration of the metabolic state of the prediabetic NZO mice. E2 particularly increases GSIS and improves hepatic glucose utilization to a lower extent.
新西兰肥胖（NZO）雌性小鼠是一种成熟的孕前（pc.）糖尿病前期模型，在妊娠期会进展为妊娠糖尿病（GDM）。已知 NZO 小鼠在体内妊娠期胰岛素敏感性和葡萄糖刺激的胰岛素分泌（GSIS）会改善。在分离的胰岛 Langherhans 体外灌注实验中，后者不再可检测到，这表明胰腺外因素的调节。在这里，我们证明 NZO 小鼠在妊娠期血浆 17β-雌二醇（E2）水平显着增加。这项工作的目的是确定这些增加的 E2 水平是否是妊娠期代谢改善的原因。为了实现这一目标，我们检查了 E2 在 NZO 和代谢健康的 NMRI 小鼠的分离胰岛和原代肝细胞中的作用。E2 显着增加了两种品系胰岛的 GSIS。胰岛素未能降低 NZO 肝细胞中的肝葡萄糖生成（HGP），但 E2 降低了两种品系的 HGP。与 NMRI 对照组相比，妊娠期 NZO 小鼠的肝细胞葡萄糖摄取（HGU）显着降低，而 E2 刺激则降低了这种差异。与 NMRI 对照组相比，妊娠期 NZO 肝细胞的糖原含量降低，环腺苷酸（cAMP）水平升高，AKT 激活减少。这些差异在 E2 刺激后被消除。总之，我们的数据表明，E2 稳定并防止糖尿病前期 NZO 小鼠的代谢状态恶化。E2 特别增加 GSIS，并在较小程度上改善肝葡萄糖利用。
