Estradiol (E2) Improves Glucose-Stimulated Insulin Secretion and Stabilizes GDM Progression in a Prediabetic Mouse Model

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.