Our aim was to assess the magnitude of peripheral insulin resistance and whether changes in hepatic insulin action were evident in a canine model of late (3rd trimester) pregnancy. A 3-h hyperinsulinemic (5 mU·kg Ϫ1 ·min Ϫ1 ) euglycemic clamp was conducted using conscious, 18-h-fasted pregnant (P; n ϭ 6) and nonpregnant (NP; n ϭ 6) female dogs in which catheters for intraportal insulin infusion and assessment of hepatic substrate balances were implanted ϳ17 days before experimentation. Arterial plasma insulin rose from 11 Ϯ 2 to 192 Ϯ 24 and 4 Ϯ 2 to 178 Ϯ 5 U/ml in the 3rd h in NP and P, respectively. Glucagon fell equivalently in both groups. Basal net hepatic glucose output was lower in NP (1.9 Ϯ 0.1 vs. 2.4 Ϯ 0.2 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.05). Hyperinsulinemia completely suppressed hepatic glucose release in both groups (Ϫ0.4 Ϯ 0.2 and Ϫ0.1 Ϯ 0.2 mg·kg Ϫ1 ·min Ϫ1 in NP and P, respectively). More exogenous glucose was required to maintain euglycemia in NP (15.2 Ϯ 1.3 vs. 11.5 Ϯ 1.1 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.05). Nonesterified fatty acids fell similarly in both groups. Net hepatic gluconeogenic amino acid uptake with high insulin did not differ in NP and P. Peripheral insulin action is markedly impaired in this canine model of pregnancy, whereas hepatic glucose production is completely suppressed by high circulating insulin levels. insulin resistance; hepatic glucose production; lipolysis; ketogenesis; gluconeogenesis LATE PREGNANCY IS ACCOMPANIED by alterations in many metabolic processes, involving multiple maternal tissues, that allow the mother to balance her own nutritional needs with the increasing requirements of utero-placental-fetal tissues (14, 21). In the basal state, hepatic glucose production and ketogenesis are increased, indicating altered basal liver function, and fat and protein metabolism are clearly affected (1, 6 -8, 14, 21, 23, 24). Pregnancy is accompanied by the development of marked whole body insulin resistance in a variety of species (2,4,5,18,20,26,27,32,33). Use of the hyperinsulinemic euglycemic clamp technique in pregnant women revealed a marked reduction in the glucose infusion rate (up to ϳ24%) required to maintain euglycemia compared with nonpregnant controls, even with pharmacological elevation of insulin to levels of ϳ600 U/ml (33). Similar results obtained in clamp studies utilizing very high insulin levels in the pregnant rat (26) and rabbit (18) specifically revealed the significant attenuation of insulin's ability to stimulate glucose uptake in peripheral tissues in pregnancy.The techniques necessary to make thorough assessments of hepatic substrate metabolism are too invasive for use in pregnant women. We recently described a conscious canine model of pregnancy (8) that employs chronic catheterization techniques to make such assessments. We showed that this canine model has basal characteristics similar to those of pregnant women, indicating that it would be useful for studying the regulation of metabolic changes during pregnancy. The aims of the present study were to fur...