Figure 8. Summary of the proposed mechanism explaining how gestational diabetes mellitus (GDM) may lead to cognitive impairment and ovarian aging later in maternal life. Our high-fat diet (HFD) mouse model exhibited the pathophysiological phenotype that resembles GDM, including hyperglycemia, being overweight, and experiencing insulin resistance during pregnancy. After delivery, all mice were reverted back to a standard diet. In the postpartum period, the blood glucose level and body weight returned to normal, but insulin resistance persisted and reduced cognitive function was observed at 12 months of age. A reduced progesterone level was also observed; an early indication of perimenopause. Through metabolome profiling of the hypothalamus, pituitary gland, and ovarian (HPO) axis, a downstream dysregulation of the HPO axis was revealed. In particular, ovarian fatty acid levels were reduced. All these adverse outcomes were prevented when insulin resistance during pregnancy was treated with metformin. These phenotypes were not directly associated with hyperglycemia or high-fat diet during gestation, nor differences in bodyweight after pregnancy. Based on these observations, we hypothesize that persistent insulin resistance postpartum is the primary cause of GDM-related cognitive impairment and accelerated ovarian decline.