ABSTRACT. Glucose and insulin clamp experiments were performed in vivo in chronically catheterized, late-gestation fetal lambs to quantify the effects of glucose and insulin on fetal glucose metabolism. Fetal glucose uptake from the placenta via the umbilical circulation (umbilical glucose uptake) was measured by application of the Fick principle, and fetal glucose utilization rate (GUR) was measured using [U-'4C]glucose tracer. Fetal plasma insulin concentrations ranged from 2 to 119 fiU.ml-' and fetal blood glucose concentrations ranged from 7.3 to 62.6 mg.dl-I. GUR varied from 2.82 to 15.12 mg/min/kg and the exogenous glucose entry rate (umbilical glucose uptake + glu- tration and plasma insulin concentration of 20.6 mg/dl and 10 wU/ml, respectively. According to this model, the glucose and insulin effects were additive. Furthermore, change in GUR was not proportionate to change in glucose concentration, accounting for a decreasing metabolic clearance rate at higher glucose concentrations. These results demonstrate the three-dimensional nature of the simultaneous additive effects of glucose and insulin on glucose utilization. These results also serve to emphasize that comparative studies of insulin and glucose metabolism in fetal lambs must be conducted at similar concentrations of glucose to avoid inaccurate estimates of the magnitude of insulin effect on glucose metabolism. (Pediatr Res 23: 381-387, 1988) Abbreviations 38Recently, we demonstrated that the maximum response of the fetal lamb to insulin infusion was a doubling of fetal glucose utilization rate (4). These studies were camed out using a glucose clamp technique in which individual fetuses were studied at "euglycemia," defined as the control (preinsulin) level of glucose. These glucose concentrations covered the normal range of glucose concentrations for well-fed Columbia-Rambouillet sheep, 15-25 mg/dl whole blood. Over this range of glucose concentration, glucose utilization rate was positively correlated with glucose concentration both at normal and high levels of insulin. These results strongly suggested that ovine fetal glucose metabolism could be more fully characterized according to effects of both insulin and glucose concentrations. To date, however, there has been little direct experimental evidence provided to complete such characterization of fetal insulin and glucose effects. As a result, the response of fetal glucose metabolism to changes of fetal glycemia and fetal insulinemia, produced by changes in maternal glucose concentration that occur with important clinical problems such as diabetes mellitus or fasting-induced hypoglycemia, have not been adequately quantified.Therefore, the present studies were conducted to measure glucose metabolism in the fetal lamb at different levels of plasma insulin and blood glucose concentration in order to provide a more complete description of how insulin and glucose act together to regulate fetal glucose metabolism. In these studies, glucose and insulin clamp experiments were performed in vivo i...

SUMMARYIn order to measure the effect of hyperinsulinaemia on fetal glucose metabolism and oxygen consumption, we applied the glucose-clamp technique to experiments in fifteen late-gestation, unstressed, chronically catheterized fetal lambs. In a control period, and immediately thereafter following 2 h of hyperinsulinaemia, we measured fetal glucose utilization and oxidation rates (radioactive tracer methodology) and net fetal uptake rates of exogenous glucose and oxygen uptake rates (Fick principle). During the period of hyperinsulinaemia, fetal glucose concentration was maintained at the average control period value by a variable rate of glucose infusion into the fetus in response to serial 10 min measurements of fetal arterial blood glucose concentration. Hyperinsulinaemia in the fetus (12-12 + 1 -92 ng . ml-' (mean + S.E.M.) arterial plasma) resulted in a 13% increase in net fetal oxygen uptake rate (0-310+0-011 to 0-349+0-012 mmol.min -1 .kg-'), a 106% increase of fetal glucose uptake rate (4-54 + 0-43 to 9-35 + 0-50 mg . min-' . kg-') and an 83 % increase of fetal glucose utilization rate (4-94 + 0-43 to 9-05 + 0-83 mg. min-' -kg-'). Fetal glucose uptake and utilization rates were not different from each other during the control and the hyperinsulinaemia periods. The fraction of glucose that was oxidized (0-58+0-05, control; 0-54+0-05, hyperinsulinaemia) did not change significantly; thus the glucose oxidation rate, the rate of entry of glucose into non-oxidative pathways, and the amount of oxygen used for glucose oxidation all increased in proportion to glucose utilization. These results suggest that insulin promotes the entry of glucose into fetal tissues, thereby increasing fetal glucose utilization and oxidation rates and substituting glucose oxidation for that of other substrates. The insulin-enhanced glucose utilization rate also increases slightly fetal metabolic rate.

Glucose and insulin clamp experiments were performed in late-gestation fetal lambs to quantify the separate and combined effects of physiological concentrations of fetal glucose (G; 7.3-62.6 mg/dl) and insulin (I; 2-119 uU/ml) on fetal glucose metabolism and O2 consumption. Fetal glucose utilization rate (GUR) varied from 2.82 to 15.12 mg.min-1.kg-1. Fetal CO2 production from fetal glucose carbon oxidation (CO2Pr) varied from 32 to 234 mumol.min-1.kg-1 and was directly related to G and I [CO2Pr = -0.00868 + 0.00578 (G) + 0.000901 (I) - 0.0000619 (G)2, r = 0.88] and to GUR (CO2Pr = 0.0159 GUR - 0.0130, r = 0.89). CO2Pr accounted for 54.7% of the mean GUR and for 35.9% of the mean umbilical O2 uptake (UO2U), ranging from 26.0% in the control studies to 36.5% in hyperinsulinemic-euglycemic studies and to 45.1% in hyperinsulinemic-hyperglycemic studies. UO2U varied from 0.200 to I [UO2U = 0.303 + [0.000813 (G)] + [0.0000461 (I)], r = 0.89] and to GUR (UO2U = 0.0098 GUR + 0.275, r = 0.91). These results define independent (additive) effects of G and I on glucose oxidation in the late gestation fetal lamb and demonstrate the necessity for considering the levels of both G and I when studying these aspects of fetal metabolism.

SUMMARYFructose disposal and oxidation rates were measured in fetal lambs receiving a constant intravenous infusion of D-[U-'4C]fructose. Approximately 60 % of the infused tracer entered the placenta, but loss of fructose into the maternal circulation was negligible. Fructose was metabolized to lactate and CO2 in both the placenta and fetus, whereas there was no detectable conversion to glucose. In well-fed ewes the fetal disposal and utilization rates of fructose were 2-41 + 017 and 097 + 0-09 mg/min.kg, respectively. The umbilical excretion rate of CO2 originating from the oxidation of fetal fructose was 18-1 + 13 1smol/min.kg or 5-3 % of total fetal CO2 production. This excretion rate is one-fifth of the CO2 excretion rate from fetal glucose carbon. In four ewes comparison of fructose metabolism in the fed and fasted states showed a significant decrease of fructose production and oxidation with fasting. Although fructose is present in high concentrations in the fetal blood of ungulates, its contribution to fetal oxidative metabolism is relatively small in comparison to glucose.

Glucose clamp experiments were performed in 27 chronically catheterized, lategestation fetal lambs in order to measure the effect of fetal insulin concentration on fetal glucose uptake at a constant glucose concentration. Fetal arterial blood glucose concentration was measured over a 30-min control period and then maintained at the control value by a variable glucose infusion into the fetus while insulin was infused at a constant rate into the fetus. Plasma insulin concentration increased from 21 ± 10 (SO) to 294 ± 179 (SD) JLU -mr'.The exogenous glucose infusion rate necessary to maintain constant glycemia during the plateau hyperinsulinemia averaged 4.3 ± 1.6 (SO) mg-min-I. kg". In a subset of 13 animals, total fetal exogenous glucose uptake (FGU; sum of glucose uptake from the placenta via the umbilical circulation plus the steady-state exogenous glucose infusion rate) was measured during the control and hyperinsulinemia period. FGU was directly related to insulin concentration (y = 4.24 + 0.07x) at insulin levels < 100 JLU/ml and increased 132% above control at insulin 557