To evaluate the effects of streptozocin on maternal pancreatic beta-cell function, we administered the agent to 14 pregnant ewes at 85 to 90 days' gestation on two occasions, 4 days apart. Intravenous glucose tolerance tests were performed before the initial administration, before the second dose, and 4 weeks after the final dose of streptozocin. There was a significant elevation in maternal fasting blood glucose (82 +/- 8.1 mg/dl before streptozocin and 102.6 +/- 6.8 mg/dl after streptozocin, p less than 0.05). Five late-gestation ewes were used as controls, and a significant elevation in fasting plasma glucose levels was found in the streptozocin-treated animals (71.4 +/- 7.1 mg/dl control vs 102.6 +/- 6.8 mg/dl after streptozocin, p less than 0.05). The glucose tolerance test curves showed a significant elevation 4 weeks after streptozocin compared with before streptozocin (p less than 0.05). The maternal insulin response to streptozocin demonstrated a loss of the second-phase insulin response to the glucose load after one dose of streptozocin and loss of the first phase after two doses. The fetuses of the streptozocin-treated ewes showed a significant elevation in plasma glucose level compared with that of controls (13.3 +/- 0.8 mg/dl, n = 5) vs 42.1 +/- 8.1 mg/dl, n = 10; p less than 0.05, control vs streptozocin, respectively). There was a consistent trend to fetal hyperinsulinemia in the fetuses of the streptozocin-treated ewes, although this did not achieve statistical significance (3.3 +/- 0.8 microIU/ml, n = 5 vs 9.6 +/- 2.5 microIU/ml, n = 10; p = 0.06, control vs streptozocin, respectively). The fetal insulin/glucose ratio was preserved in the streptozocin-treated ewes. Comparison of fetal weights between the control and diabetic ewes showed a significant increase in fetal weight in the fetuses of diabetic ewes (3280 +/- 46 gm in control fetuses vs 3710 +/- 54 gm in diabetic fetuses, p less than 0.05). The alterations in the maternal glucose and insulin response resulting from streptozocin-induced pancreatic beta-cell destruction combined with elevations in fetal glucose, insulin, and weight provides a large animal model suitable for investigation of gestational diabetes in pregnancy.