HYPERGLYCEMIA-INDUCED HYPERINSULINEMIA DECREASES MATERNAL AND FETAL PLASMA-PROTEIN-C CONCENTRATION DURING OVINE GESTATION

To determine effects of diabetic gestation on plasma concentration of the coagulation regulatory protein, protein C, pregnant ewes were give n glucose infusions to raise plasma glucose to twice baseline concentr ation or insulin infusions to lower glucose concentration to half base line value. Control animals received no infusions. Concentrations of p rotein S, factor X, and antithrombin III were determined for compariso n. Concentrations of glucose, insulin, and those above were determined thrice weekly for 2-9 wk. Short-term (8-12 h) infusions of glucose or insulin were performed to isolate their effects on concentration of p rotein C. Results were analyzed using a two-tailed t test, and protein C concentrations were further analyzed using a full linear mixed-effe cts model. In long-term infusions, hyperglycemia-induced hyperinsuline mia (mean insulin concentration 141 mu U/mL) exerted negative effects on maternal concentrations of protein C [0.69 U/mL, n (number of sampl es) = 32, experimental versus 0.97 U/mL, n = 157, control], protein S (0.86 U/mL, n = 31, experimental versus 1.04 U/mL, n = 109, control), and factor X (0.89 U/mL, n = 31, experimental versus 1.08 U/mL, n = 10 9, control); it exerted no effects on antithrombin III (1.05 U/mL, n = 23, experimental versus 1.04 U/mL, n = 32, control). The fetal lamb d id not respond to chronic moderate hyperglycemia (mean 33 mg/dL) with a consistent change in insulin concentration (mean 10 versus 9 mu U/mL ): no coagulation protein changed. In contrast, fetal hypoglycemia res ulted in decreased fetal plasma insulin (5 mu U/mL versus 10 mu U/mL) and a corresponding increase in protein C (0.56 U/mL, n = 17, experime ntal, versus 0.48 U/mL, n = 180, control) protein S (0.65 U/mL, n = 17 , experimental versus 0.44 U/mL, n = 87, control), factor X (0.31 U/mL , n = 16, experimental versus 0.24 U/mL, n = 86, control), and antithr ombin III (0.96 U/mL, n = 14, experimental versus 0.84 U/mL, n = 32, c ontrol). Insulin concentration varied inversely with protein C concent ration when all groups were considered together and accounted for 12% of the variability of protein C concentration in control ewes. Glucose was not found to exert an independent effect on protein C concentrati on within any study group but was significant when all groups were con sidered together. Short-term studies confirmed the long-term infusion findings in the maternal group with hyperglycemia-induced hyperinsulin emia. These studies indicate that hyperglycemia-induced hyperinsulinem ia may predispose to hypercoagulability and thrombosis in the diabetic ewe and her fetus.