Endogenous inhibitors of the Na/K-ATPase (NKA) and diabetes mellitus (DM) are both risk factors for preeclampsia and NaCl sensitive hypertension. Our goal was to test the hypothesis that NaCl supplementation, induces preeclampsia-like symptoms in pregnant rats with DM via stimulation of marinobufagenin (MBG), a natriuretic and vasoconstrictor inhibitor of the NKA. Type 2 DM in female Sprague-Dawley rats was induced by administration of 65mg/kg streptozotocin at day 4 post-partum. In intact rats, pregnancy was associated with a twofold increase in MBG levels and a mild impairment in glucose tolerance. Pregnant rats with DM exhibited fetal macrosomia, greater impairment of glucose tolerance, and higher levels of MBG as compared to that in normal pregnant rats. As compared to intact pregnant rats, NaCl supplementation of diabetic pregnant rats (drinking 1.8% NaCl during days 12-19 of pregnancy) was associated with an increase in systolic blood pressure, decreased fetal and placental weight, fivefold elevation of MBG excretion, and 42% inhibition of NKA in erythrocytes. In nonpregnant rats, in vivo pretreatment with anti-MBG antibody produced an exaggerated response of plasma levels of glucose and insulin in oral glucose tolerance test. These results suggest that MBG is a common factor in the pathogenesis of DM and preeclampsia, and that regulation of glucose tolerance may be one of the physiological functions of endogenous cardiotonic steroids.