SummarySustained fetal hyperglycemia was produced in eight chronically catheterized fetal lambs (seven twins, one singleton) by means of direct fetal glucose infusion. In twin preparations, only one twin was infused, the noninfused twin serving.~;~simultaneous in utero control. Glucose infusions lasted 7.6 +t M8 days and resulted in significant fetal hyperglycemia (from 20.3 + 1.1 mg/dl to 58.2 + 4.7 mg/dl, P < 0.001). The magnitude of the hyperglycemia was linearly related to the glucose infusion rate. Elevations of fetal plasma glucose and glucose infusion rate were associated with a significant fall in fetal arterial oxygen content (P < 0.001). In twin preparations studied, these relationships remained when the simultaneously sampled, noninfused twin was used as control. The fetal glucose-induced hypoxemia was not associated with fetal acidosis (tissue hypoxia) until the arterial oxygen content fell below 30% of baseline (mean base deficit in acidotic fetuses = 11.2 +-2.2 meq/liter). Although Paoz fell in hypoxemic fetuses (from 13.5 + 1.2 mmHg to 9.7 f 1.2 mmHg), the difference was not significant. Fetal plasma insulin rose during hyperglycemia from 10.2 + 3.1 pU/ml to a peak concentration of 26.2 +-3.3 pU/ml, but this response was blunted in markedly hypoxemic fetuses. Neither fetal anemia nor hemoconcentration were evident in these preparations to account for the fall in fetal oxygen content. SpeculationGlucose-induced hypoxemia may be the result of accelerated fetal and/or uteroplacental oxygen consumption. In utero hypoxemia in the fetus of the pregnant diabetic may present a unifying hypothesis linking the known clinical findings of increased fetal red blood cell production, polycythemia, and late fetal demise in fetuses of diabetic mothers.Macrosomia and hyperinsulinism are common features of the fetus of the diabetic mother (FDM), presumably stemming from chronic maternal hyperglycemia and excessive maternal-fetal glucose transfer (5, 19); however, the etiologies behind certain other features seen in the FDM, such as the increased incidences of venous polycythemia and late fetal demise (4, 11) are less evident. Experimentally induced fetal hyperglycemia has been associated with both fetal acidosis and fetal death (1,22,25). Some authors (5, 17) have suggested that chronic in utero fetal hypoxemia induced by maternal diabetes offers a unifying explanation linking excessive red blood cell production, fetal acidosis and excessive stillborn rates in this disorder; however, in at least one study, fetal lamb oxygenation during glucose infusion, as assessed by blood gas analysis, was normal despite the development of metabolic acidosis (22). With the aid of chronically catheterized singleton and twin fetal sheep, the effects of chronic isolated fetal hyperglycemia upon fetal oxygenation, insulin secretion, and fetal metabolism were explored. Because of the relatively steep oxyhemoglobin dissociation curve, fetal blood oxygen content was determined in addition to blood gas analysis to provide a better estimat...

(2, 28) have shown that certain adult glucagon secretogogues such as arginine or epinephrine could produce a significant fetal hyperglucagonemia. Recent work (13) suggests that elevation in fetal glucagon concentration may accompany prolonged maternal fasting.The physiologic function of fetal hyperglucagonemia is also open to question. A hyperglycemic response to pharmacologic injection has been suggested in in vivo preparations (6). In order to clarify the role of glucagon as a possible fetal metabolic regulatory hormone, we utilized the chronically catheterized fetal sheep as our model. Varying degrees of hyperglucagonemia were induced and alterations in fetal glucagon, insulin, glucose and ketone concentrations as well as umbilical glucose and ketone uptakes then noted. Summary SpeculationThe fetus in late gestation may respond to substrate deprivation by secretion of glucagon. If so, a modest but significant hyperglycemia would result, presumably the result of acute fetal glycogenolysis. The acute fetal metabolic adaptation to maternal starvation, however, if modified by glucagon, does not include utilization of ketones as alternate substrates.Acute glucagon injections were performed in chronically catheterized fetal lambs in late gestation to assess the fetal metabolic response to exogenous glucagon infusion. Glucagon dosages between 1 p,g/kg and 1 mg/kg induced significant fetal hyperglycemia by 15-30 min postinjection, with peak glucose values 130-180% of control. Increasing responsivity to the same dose/kg was noted to parallel increasing gestational age. In selected preparations in which umbilical venous catheters were implanted, glucagon injection caused an acute fall in the glucose/oxygen quotient and net umbilical glucose consumption. The fall in glucose consumption to 8% of control values occurred within 15 min of injection and suggests acute fetal glucose excretion, probably secondary to hepatic glycogenolysis. Glucagon injection in the neonatal lamb caused qualitatively similar increases in plasma glucose concentration but the quantitative responses were considerably greater. No change in fetal ,B-hydroxybutyrate (,B-ORD) concentration was noted after injection; nor did the fetal uptake or excretion of this ketone change. The neonatal ,B-ORD concentration was significantly different (P < 0.001) from fetal concentrations and did rise 14% above control after glucagon injection; thus, elevation of plasma glucagon in the fetus causes an acute hyperglycemia but, unlike the adult, does not induce a significant ketogenesis.Experimental design. Eleven pregnant ewes between 118-149 days of gestation were studied (Table 1). Term gestation in the sheep is 147 days. All but two had singleton fetuses. Intravenous sodium pentobarbital and spinal anesthesia were administered to each animal preoperatively. Polyvinyl catheters were then placed in a fetal pedal artery and vein as well as the maternal femoral artery for purposes of sampling and infusion. In five of the fetal lambs umbilical venous catheters were als...

Devices and methods for long term intravenous insulin infusion in ambulatory patients have recently been developed. With informed consent we studied 7 non-obese uncomplicated Type I diabetics (aged 15-17y) who received insulin for 14-23 days by central venous infusion (CVII). All subjects were studied in hospital with otherwise unrestricted activity and received 3 daily meals and an evening snack of constant caloric content. Under local anesthesia, a thin silicone rubber catheter was inserted into a branch of the external jugular vein, advanced to the SVC and tunnelled subcutaneously to exit in the supramammary region, where it was connected to the portable system consisting of a small peristaltic pump, a flow rate controller and a reservoir of soluble insulin. Insulin was infused a t a constant basal rate of 17+3 mU/min. The rate was increased 15 minutes from the start of a m e d 4-5 fold for 60-120 min then returned,to the basal rate in a 2 step fashion over 40-120 min. Fasting plasma glucose (mean+SEM) was 262+40 prior to infusion and fell to 92+9 mg/dl on CVII with increases during-mealtimes from 80+3 to 115+3 mildl a t 41+3 min pc. Mean urinary glucose excretion of 55g/day fellto 1.9 during C~I I and fasting serum cholesterol of 220+28 and triglycerides of 281594 fell to 138213 and 115524 mg/dl respecfively. Mean HgbAl (N:6.5 -8.5%) fell from 14.8 to 10.7% by the end of the study period. All indices of control showed improvement with p <0.05. There were no catheter related complications and the system was well accepted by all subjects. We conclude that in ambulatory adolescent diabetics continuous central venous insulin infusion without continuous glucose sensing is feasible for the prolonged normalization of glycemia and other indices of metabolic control. Prolonged f e t a l hyperglycemia has previously been shown t o cause metabolic acidosis but the mechanism involved i s unclear. EFFECTSChronic f e t a l glucose (G) infusions (mean: 8.322.6 d, range 3-17d) were performed i n 5 f e t a l lambs. Infusions were varied t o achieve plasma G of 2-3x basal concentration. In 4 of 5 preparat i o n s twins were used with t h e noninfused twin serving a s internal control. Plasma G increased from 16.521.9 t o 58.124.7 mg/dl during infusion. Plasma i n s u l i n ( I ) increased from 1223 t o 27+4 pu/ml (p<.02). Fetal a r t e r i a l O2 content (02) f e l l from 6.720.9 t o 4.121.0 m1/100 m l (p<.01). Although not related t o changes i n I , the O2 decrement was l i n e a r l y related t o the A plasma G from basal and, i n the twins, t o the difference i n G between infused and control lambs (p<.001). O2 decrement was r e l a t e d nonlinearly t o the G infusion r a t e (G.I.R.) w i t h a sign i f i c a n t (p<.01) change noted i n O2 above G . I . R . of 10 mg/kg/min. In twins, a t G . I . R . of 10-15 mg/kg/min, O2 content of the infused twin f e l l t o 50215% (p<.01) of the simultaneously sampled control twin. Despite the r e l a t i v e hypoxemia, metabolic acidosis (base d e f i c i t >5) was not observed u...

Beta-blocking agents are among the most frequently prescribed medications. To investigate the factors that influence their use we analysed the practices of 25 medical residents who provided longitudinal care in the out-patient clinics of a teaching hospital. A computer-based audit identified the 349 patients treated with one of four beta-blocking agents during a 4-month period. The most frequently prescribed was atenolol (48%), followed by metoprolol (28%), propranolol (20%), and nadolol (4%). Ease of use and compliance and continuation of a beta-blocker prescribed by a previous physician emerged as the most influential factors. In contrast, cost of drugs, manufacturers' promotions and advertisements had no significant influence on beta-blocker selection.

P e d i a t r i c s , Farmington, CT. The a b i l i t y of t h e human placenta t o t r a n s p o r t amino a c i d s from t h e mother t o f e t u s i s well documented. Net synthesis of c e r t a i n amino a c i d s such a s alanine (A) v i a transamination i s known t o occur i n such t i s s u e s a s muscle but it is unclearwhether t h i s capacity is shared by p l a c e n t a l t i s s u e . Five human placentas were obtained a f t e r e l e c t i v e caesarean section. Plac e n t a l fragments were incubated i n a bicarbonate-buffered E a r l e ' s solution enriched with oxygen. Placental A production was assessed during a 45 min incubation period by observing t h e net change i n A i n t i s s u e and media before and a f t e r incubation. Plac e n t a l glucose (G) consumption was measured u t i l i z i n g a s i m i l a r method. Net p l a c e n t a l A production was 0.42f0.10 pmoles/gm wet weight/45 min (p<.01). When adjusted f o r t o t a l p l a c e n t a l and f e t a l weights a n e t p l a c e n t a l production of 1.56f0.34 pmoles/kg fetus/min is evident. This represents approximately 1/3 of the A uptake i n the f e t a l sheep. Placental G consumption varied between placentas (mean 4.54f0.78 pmoles/gm/45 min) b u t was not r e l a t e d t o A production. Neither t h e addition of pyruvate nor i n s u l i n a l t e r e d A production o r G consumption. Incubations of 15, 30 and 45 minutes revealed a l i n e a r r e l a t i o n s h i p between incubation time and A production, evidence a g a i n s t a simple leachi n g phenomenon. These d a t a suggest t h e p o s s i b i l i t y of i n t r a p l ac e n t a l nitrogen t r a n s f e r with n e t synthesis of alanine, a potent i a l f e t a l f u e l a s well a s p r o t e i n c o n s t i t u e n t . MATERNAL-FETAL COORDINATION OF CIRCADIAN RHYTHMICITYMass. General Hospital, Children's Service, Boston MA. Maternal coordination of t h e f e t a l b i o l o g i c a l clock was examined. Pregnant r a t s were housed i n diurnal l i g h t i n g (LD 12:12) from mating u n t i l 2 d p r i o r t o b i r t h when they were t r a n s f e r r e d t o darkness and t h e pups were born and reared i n darkness. Circadian output was monitored i n 10-d-old pups by measuring t h e rhythm i n p i n e a l N-acetyltransferase (NAT) a c t i v i t y . Analysis of NAT i n the pups revealed a l a r g e d a i l y rhythm i n a c t i v i t y (0.1 n m l / g / h t o 20 nmol/g/h) which was coordinated by the light-dark c y c l e during pregnancy. To determine whether the f e t u s could d i r e c t l y perceive a l t e r a t i o n s i n l i g h t i n g , 2 groups of pregnant r a t s were raised i n diurnal l i g h t i n g u n t i l day 7 of pregnancy. A t t h a t time one group was blinded and both groups were subjected t o a phase s h i f t i n l i g h t i n g u n t i l a reversed l i g h t i n g cycle (DL 12:12) was a t t a i n e d . A l l were maintained i n reversed l i g h t i n g from day 14 of pregnancy u n t i l 2 d p r i o r t o b i r t h when a l l were placed i n d...