The present study was undertaken to test the hypothesis that high ketone body concentrations suppress endogenous production of glucose and in pregnant sheep facilitate development of pregnancy toxemia. Rates of endogenous glucose production [mmol.min(-1)], and rate constants of glucose turnover [min(-1)] were measured in seven 12-h fasted sheep in the presence of normo- and hyperketonemia by use of D-2-[(3)H]-glucose. The measurements were carried out in the same sheep during the nonpregnant nonlactating state, during late pregnancy (10 +/- 7 d antepartum) and during lactation (19 +/- 6 d postpartum). Hyperketonemia (5 to 7 mmol.L(-1)), similar to that present in spontaneous ovine pregnancy toxemia, was induced by continuous intravenous 4-h infusions of DL-beta-hydroxybutyrate (DL-BHB). Glucose turnover [mmol.min(-1)] in the same 7 nonpregnant nonlactating, late pregnant, and lactating sheep was significantly greater during normoketonemia (0.80, 1.16, 1.76) than during hyperketonemia (0.66, 0.92, 1.16, respectively). The rate constants of glucose turnover were not altered by elevation of the BHB concentration. The results demonstrated that high BHB concentrations significantly suppressed endogenous glucose production but showed no effect on glucose utilization. The suppressive effect of hyperketonemia on hepatic glucose production resulted in a significant reduction of plasma glucose concentration and was qualitatively the same in all three reproductive states. The results indicate that hyperketonemia, which is regularly present in late twin pregnant hypoglycemic sheep contributes significantly to the reduction of available glucose. This effect of hyperketonemia may invoke sustained hypoglycemia and may render the ewe into a vicious cycle that probably makes the animal refractory to treatment in most cases.