Hyperaminoacidemia due to the accumulation of gluconeogenic amino acid precursors in hypoglycemic small-for-gestational age infants.

The postnatal (3 to 12 hours) plasma amino acid patterns of normal full-term, nonhypoglycemic, and hypoglycemic small-for-gestational age infants were compared. Seventeen amino acid were separated by automatic column chromatography. It was found that hypoglycemia in SGA newborn infants was associated with a marked increase in total serum amino acid concentrations. This hyperaminoacidemia, which was mainly due to the increase in concentrations of alanine, glycine, proline, and valine, apparently reflected a decreased heapatic gluconeogenic capacity. A significant inverse correlation was observed between concentration of blood glucose and the accumulation of gluconeogenic amino acids. The proportionate accumulation of alanine, glycine, proline, and valine suggests a closely interrelated production and release of these amino acids from the peripheral pools. It is concluded that the changes in concentrations of plasma amino acids occurring in hypoglycemic SGA infants can be helpful in understanding the relative contribution of individual amino acids to gluconeogenesis in the human infant.     

The effect of birth asphyxia on plasma free amino acids in preterm newborn infants

The postnatal plasma amino acid pattern was compared in 16 asphyxiated and 13 non-asphyxiated preterm newborn infants. The lactic acidosis induced by asphyxia was associated with a marked rise in the total amino acid content of the plasma. Among the 17 individual amino acids determined the concentrations of alanine, proline, taurine, glutamate, valine, methionine and lysine were significantly elevated. The accumulation of alanine was particulary marked and its concentration showed a significant linear correlation with that of lactate (p less 0.001). A similar relationship was observed between other potentially glucogenic amino acids and lactate. It is suggested that an impaired gluconeogenesis may be responsible for the accumulation of glucogenic amino acids. The response of the plasma aminogram to asphyxia resembles that associated with hypoglycaemia in the small-for-gestational-age infant, where a delay in the maturation of key gluconeogenic enzymes seems to account for the reduced hepatic disposal of glucose precursors.     

Amino Acid Studies during Complete Intravenous Feeding of Small Premature Infants

Kellerman, G. M., MacMahon, R. A., Leber, M. H. and James, B.E. (1976). Aust. Paediat. J. , 12, 255–260. Amino acid studies during complete intravenous feeding of small premature infants. Serum and urine amino acid concentrations were measured during complete intravenous feeding of small premature, infants weighing less than approximately 1 kg at birth, and compared with data from milk-fed babies. Serum and urine levels of amino acids supplied in the D-L form were higher in treated infants than in controls. Serum levels of amino acids supplied in the L-form were lower than normal in treated infants, the only exception being L-arginine. Serum glycine concentrations were increased 3-fold in treated infants but serum levels of amino acids not supplied in the infusion were lower than normal in treated babies. The total urinary amino acid concentration in intravenously-fed infants was up to approximately 20 times that in controls. Improved amino acid solutions are needed to avoid potentially serious developmental problems in these patients.     

The metabolic effects of glucagon infusion in normoglycaemic and hypoglycaemic small-for-gestational-age infants. II. Changes in plasma amino acids.

Altogether 17 individual amino acids were determined before and during glucagon infusion in normoglycaemic and hypoglycaemic SGA infants. The magnitude and time course of the response in total plasma amino acids to glucagon infusion (0.2 microng/kg/min for four hours) differed in the two groups: while in the normoglycaemic SGA infants a significant hypoaminoacidaemia was noted by the second hour of glucagon infusion, in the hypoglycaemic newborns no appreciable changes were observed. In the former group altogether twelve amino acids showed a progressive and significant decline. The fall of three important gluconeogenic amino acids alanine, glycine,proline, and that of three branched chain amino acids was particularly striking. In contrast, in the hypoglycaemic infants the amino acids were not significantly affected by glucagon infusion. This unresponsiveness of plasma amino acids was probably transient as judged from the moderate hypoaminoacidaemia noted by the end of the infusion period. The observations seem to have important implications regarding the influence of glucagon on hepatic glucose production, and its possible therapeutic importance in the management of hypoglycaemic intrauterine malnourished infants.     

The role of parenteral lipids in supporting gluconeogenesis in very premature infants

We have previously demonstrated that very premature infants receiving glucose at 17 micromol/kg min plus appropriate supply of parenteral lipids (Intralipid) and amino acids (TrophAmine) maintained normoglycemia by glucose produced primarily via gluconeogenesis. The present study addressed the individual roles of parenteral lipids and amino acids in supporting gluconeogenesis. Fourteen premature infants (993 +/- 36 g 27 +/- 1 wk) (mean +/- SE) were studied for 8 h on d 5 +/- 1 of life. All infants were receiving standard TPN prior to the study. At start of study, the glucose infusion rate was decreased to approximately 17 micromol/kg min and either Intralipid (g + AA; n = 8) or TrophAmine (g + IL; n = 6) was discontinued. Data from 14 previously studied infants receiving glucose (approximately 17 micromol/kg min) + TrophAmine + Intralipid (g + AA + IL) are included for comparison. Gluconeogenesis was measured by [U-13 C]glucose, (g + AA) and (8 infants of the g + AA + IL group) or [2-13C]glycerol, (g + IL) and (6 infants of the g + AA + IL group). Infants studied by the same method were compared. Withdrawal of Intralipid resulted in decreased gluconeogenesis, 6.3 +/- 0.9 (g +AA) vs. 8.4 +/- 0.7 micromol/kg min (g + AA + IL) (p = 0.03). Withdrawal of TrophAmine affected neither total gluconeogenesis, 7.5 +/- 0.8 vs. 7.9 +/- 0.9 micromol/kg min nor gluconeogenesis from glycerol, 4.4 +/- 0.6 vs. 4.9 +/- 0.7 micromol/kg min (g+ IL and g + AA + IL groups, respectively). In conclusion, in parenterally fed very premature infants, lipids play a primary role in supporting gluconeogenesis.     

Glucagon,Insulin, and Growth Hormone Response to Exchange Transfusion in Premature and Term Infants

Exchange transfusions were performed on premature or term infants using blood preserved with acid citrate and glucose. The plasma concentrations of glucose, free fatty acids, insulin, glucagon, and growth hormone were measured in the donor blood and in blood from the infant at different times during the transfusion. The total amounts of metabolite and hormone infused and removed from the infant were calculated. The exchange transfusion caused a larger rise in plasma glucose of premature infants than of term infants, due in part to a higher plasma glucose in the donor blood used for premature infants. Despite the higher plasma glucose levels, the premature infants secreted less insulin in response to the glucose challenge, as judged by the rise in plasma insulin and the insulin balance. The transfusions were associated with increased growth hormone secretion in both groups. Premature infants secreted more growth hormone per kg bodyweight than term infants. Plasma glucagon levels in term and premature infants before transfusion were higher than those found in normal infants under comparable conditions. The transfusion caused a similar fall in plasma concentration and a similar negative balance of free fatty acids and glucagon in each group.     

The metabolic and endocrine milieu of the human fetus and mother at 18-21 weeks of gestation. I. Plasma amino acid concentrations

Plasma levels of 17 amino acids were measured in 10 conscious mothers and their minimally stressed fetuses (mean body weight 302 g) at 18-21 wk gestation. Simultaneous blood samples were taken from the maternal antecubital vein, and from the fetal umbilical vein and artery by fetoscopy prior to termination of pregnancy. The mean concentrations of all amino acids were significantly higher in the fetal (2.26 mmol/liter) than in the maternal (0.96 mmol/liter) circulation, the total molar concentration of amino acids was 2.4 times greater in fetal than in maternal plasma. There was a significant positive relationship between maternal and fetal levels for most amino acids; the mean umbilical concentration difference was significantly positive for glycine, alanine, isoleucine, leucine, phenylalanine, and histidine.     

Metabolic fuel and hormone responses to fasting in newborn infants.

To examine why newborn infants frequently cannot maintain adequate levels of plasma glucose in the interval between delivery and the time they are first fed, circulating metabolic fuel and regulatory hormone concentrations were determined in 44 healthy infants at the end of an eight-hour postnatal fast. Plasma glucose fell below 40 mg/100 ml prior to eight hours in four of 24 term-appropriate-for-gestational-age (AGA), two of nine preterm-AGA, five of six term-small-for-gestational-age (SGA), and three of five preterm-SGA infants. Fuel and hormone patterns in the premature and SGA infants were not different from those found in term-AGA infants. Results in these neonates differed in two areas from the response to fasting seen later in life. In fasted term-AGA infants, ketones were low (beta-hydroxybutyrate 0.29 +/- 0.04 mM/liter) despite elevated concentrations of fatty acid precursors (1.4 +/- 0.07 mM/liter), and the group of infants studied failed to demonstrate the increase in plasma ketones with lower glucose levels (r = ".23, P = .07) which is found in older children. Levels of glucose precursors were two to three times higher in term-AGA infants (lactate 2.9 +/- 0.2 mM/liter; alanine 0.48 +/- 0.02 mM/liter) than levels found beyond the neonatal period and, in contrast to older children and adults, were not diminished in infants with lower plasma glucose (lactate, r = -.28, P less than .035; alanine, r = -33, P less than .02). These differences between the responses to postnatal fasting and those seen beyond the neonatal period suggest that the capacity for both hepatic ketone synthesis and gluconeogenesis is not fully developed at birth.     

The metabolic effects of cold exposure in the newborn rabbit.

Blood glucose, lactate, plasma free fatty acid and plasma and tissue individual free amino acid levels were followed in newborn rabbits exposed for 10 h to an environmental temperature of 25 degrees C. Severe hypothermia developed with an increase of blood lactate and accumulation of total free amino acids in plasma and liver. Alanine, isoleucine, leucine, valine, phenylalanine, tyrosine, ornithine and taurine were elevated in the plasma; alanine and ornithine in the liver; leucine and isoleucine in the muscle.     

PLASMA FREE AMINO ACID LEVELS DURING THE INITIAL REHABILITATION OF PROTEIN-ENERGY MALNUTRITION WITH PROTRACTED DIARRHOEA USING A FREE AMINO ACID-GLUCOSE DIET

ABSTRACT. This study intends to assess, by ion-exchange chromatography of free amino acid levels of peripheral blood plasma, the amino acid absorption of severely growth retarded infants with protracted diarrhoea, during the initial period of rehabilitation. Eleven infants from a very low socio-economic group of a developing country, with nutritional marasmic growth retardation and prolonged diarrhoea, were treated for a period of 10 days with a commercially available free amino acid–glucose diet (Vivonex®, Pfrimmer Co., Erlangen, Germany). Excessive hyperprolinaemia characterized the plasma aminogram before treatment. After initial rehabilitation with this diet, the plasma analyses showed very low branch-chained and cystine levels, and marginally high alanine, glycine, and proline levels. It seemed that the free amino acids could not be absorbed quickly enough to meet with the high supply of glucose. Furthermore, this investigation supports the assumption that cystine is an essential amino acid in malnourished infants. In spite of normal or high human growth hormone levels, somatomedin was not detectable in pooled samples from these severely growth retarded infants.     

Preserved fetal plasma amino acid concentrations in the presence of maternal hypoaminoacidemia

The effects on the conceptus of persistently decreased maternal plasma amino acid concentrations were studied in pregnant rats by the infusion of glucagon (0.21 mg/day) to the mother from day 14 to 20 of gestation with a subcutaneous, osmotically driven minipump. Controls received diluent. The experimental animals either had normal caloric intake and weight gain, or diminished caloric intake with no weight gain. Both experimental groups exhibited a decrease in plasma total amino acid concentration of approximately 50%. Maternal plasma glucose and insulin concentrations were unaffected except for slight decreases in the low weight gain group. At cesarean section on day 20, fetal weight was unaffected in the normal weight gain group, while the low weight gain animals exhibited intrauterine growth retardation. Fetal plasma glucose and insulin concentrations were unaffected. Despite the marked decrease in maternal plasma total amino acid concentration, fetal plasma total amino acid concentration was unaffected. Individual plasma amino acid concentrations in the normal weight gain mothers and fetuses revealed a spectrum of changes. Some maternal amino acids were decreased by more than 60% (alpha-aminobutyric acid, asparagine, threonine, glutamine, alanine) while others were unaffected (tyrosine, tryptophan, phenylalanine, histidine). In general, amino acids that were decreased in the mother exhibited no change or a lesser decrease in fetal plasma concentration, while those that were unaffected in the mothers showed increased fetal concentrations. Fetuses from the low weight gain mothers had plasma amino acid profiles that were similar to those of the normal weight gain mothers.(ABSTRACT TRUNCATED AT 250 WORDS)     

PLASMA NORADRENALINE AND ADRENALINE IN INFANTS OF DIABETIC MOTHERS AT BIRTH AND AT TWO HOURS OF AGE

ABSTRACT. Plasma noradrenaline and adrenaline in the umbllical artery were very high in many infants of both diabetic mothers (IDM) and non-diabetic mothers (controls) compared to values obtained in adults. Blood pH was slightly but significantly lower in IDM than in controls at delivery. There was a significant negative correlation between plasma noradrenaline and blood pH in IDM at birth, but no correlation between plasma noradrenaline and blood glucose, birth weight and Apgar scores. Plasma noradrenaline decreased significantly from birth to two hours of age both in IDM and controls. At two hours of age plasma noradrenaline and adrenaline were significantly greater in IDM compared to controls whereas blood glucose concentration was lower in the former group. There was a close inverse correlation between plasma noradrenaline and adrenaline, respectively, and blood glucose in IDM at two hours of age but not in controls. The elevated plasma noradrenaline at delivery in IDM may be explained by clinically undetectable acidosis whereas elevated plasma catecholamines at two hours are probably due to hypoglycaemia.     

Plasma free amino acid levels during the initial rehabilitation of protein-energy malnutrtion with protracted diarrhoea using a free amino acid--glucose diet.

This study intends to assess, by ion-exchange chromatography of free amino acid levels of peripheral blood plasma, the amino acid absorption of severely growth retarded infants with protracted diarrhoea, during the initial period of rehabilitation. Eleven infants from a very low socio-economic group of a developing country, with nutritional marasmic growth retardation and prolonged diarrhoea, were treated for a period of 10 days with a commercially available free amino acid--glucose diet (Vivonex, Pfrimmer Co., Erlangen, Germany). Excessive hyperprolinaemia characterized the plasma aminogram before treatment. After initial rehabilitation with this diet, the plasma analyses showed very low branch-chained and cystine levels, and marginally high alanine, glycine, and proline levels. It seemed that the free amino acids could not be absorbed quickly enough to meet with the high supply of glucose. Furthermore, this investigation supports the assumption that cystine is an essential amino acid in malnourished infants. In spite of normal or high human growth hormone levels, somatomedin was not detectable in pooled samples from these severely growth retarded infants.     

Cerebrospinal fluid amino acid levels in newborn infants with intracranial hemorrhage

Cerebrospinal fluid (CSF) amino acid levels including excitatory amino acids (i.e. glutamate and aspartate) in 25 preterm and 18 full-term newborn infants with no serious disease except intracranial hemorrhage (ICH) were measured. ICH was detected in 13 preterm and six full-term infants on the basis of the clinical, lumbar puncture (LP) and cranial ultrasonography (CraUSG) findings. Twelve preterm and 12 full-term infants who were neurologically healthy comprised the control group. The mean concentration of CSF amino acids did not differ between preterm and full-term infants. The CSF concentrations of taurine, threonine, glycine, alanine, valine, isoleucine, leucine, tyrosine and phenylalanine in preterm infants, and threonine, aspartic acid and alanine in full-term infants were significantly elevated in infants with ICH. These abnormalities, especially in preterm infants, are probably related to cerebral hypoxia in CSF amino acid concentrations in newborn infants with ICH.     

NEONATAL HOMEOSTASIS: THE ROLE OF DIETARY COMPOSITION, GROWTH AND RENAL REGULATION

The relative importance of growth, composition of the diet, and renal function in maintaining internal stability during the first 2 critical weeks when the newborn baby is endeavouring to adapt to his new environment has been investigated. The technique used was serial daily metabolic balance studies in normal premature babies, in oedematous premature babies, oedematous premature babies with respiratory distress, dysmature babies, infants of diabetic mothers, and full term infants fed pooled human milk.     

LOW CONCENTRATION OF PLASMA AMINO ACIDS IN NEWBORN BABIES OF DIABETIC MOTHERS

Abstract Plasma amino acid concentrations were measured in maternal peripheral vein and in umbilical vein and artery at birth (caesarean section) in 6 diabetic and 5 non-diabetic pregnancies. The mean birth weight in the control group amounted to 3.9 kg as oversize of the foetus in three cases contributed to the indication for caesarean section. The infants in the diabetic group consisted of "small for gestational age" babies (mean weight 2.8 kg). Free amino acid levels in the normal group and in diabetic maternal blood were in agreement with previous investigations. No difference in amino acid concentrations in the maternal plasma was found, but the concentrations of the umbilical vein plasma were significantly lower in the diabetic group. Foetal hyperinsulinaemia may be a cause of the low amino acid concentrations. Besides, abnormalities of the placenta and maternal vascular complications increase and the mean birth weights decrease significantly through the White classes. Conditions of impairment of placental transfer of amino acids may thus be present. Characteristic features of the foetus may be consistent with the hypothesis as follows: The foetus in diabetic pregnancy is in varying degree exposed to an oversupply of glucose, hyperinsulinaemia, imbalanced uptake and a slightly diminished supply of amino acids.     

Plasma amino acids in diabetic pregnant rats and in their fetal and adult offspring

Amino acid profiles and total amino-acid concentrations are established in nonfasting plasma of pregnant control, mildly diabetic and severely diabetic rats, and of their fetal and adult offspring. In pregnant rats at day 20 of gestation plasma amino acids can be regarded as normal in mildly diabetic mothers, but are significantly decreased in severely diabetic mothers. In fetuses of control rats, amino acid levels are twice as high as in the mother (fetomaternal ratio 2.0); in the fetuses of mildly diabetic mothers they are significantly lower than normal (fetomaternal ratio 1.3); in the fetuses of severely diabetic mothers they are also significantly lower than normal but with a normal fetomaternal ratio (fetomaternal ratio 2.0). In adult offspring of mildly diabetic mothers the concentration of almost all amino acids as well as that of total amino acid pool is significantly lower than in the controls; in the offspring of severely diabetic mothers they can be regarded as normal. No specific amino acid or group of amino acids can be held responsible for any of these changes, since all differences with control values display an overall effect, involving all or almost all amino acids.     

Neonatal hypoglycaemia in infants of diabetic mothers

OBJECTIVE: To determine whether umbilical cord blood glucose correlates with subsequent hypoglycaemia after birth in infants of well-controlled diabetic mothers. METHODOLOGY: Thirty-eight term infants of well-controlled diabetic mothers were enrolled. Five mothers had pre-existing diabetes. Of the 33 gestational diabetic mothers, 16 were managed on insulin and 17 on diet. Maternal blood glucose was maintained between 4 and 8 mmol/L during labour and delivery. Infants' plasma glucose levels were measured from venous cord blood and serially, at less than 30 min, 1 h and 2 h of life by glucose hexokinase method. Blood glucose levels were further monitored by bedside Dextrostix for 24 h. RESULTS: Eighteen (47%) infants developed hypoglycaemia (blood glucose level less than 2 mmol/L) during the first 2 h of life. There was no difference in the cord blood glucose levels between infants with or without hypoglycaemia (3.7 +/- 1.1 vs 4.5 +/- 1.1 mmol/L, respectively). Infants of mothers with diabetes diagnosed prior to 28 weeks gestation were at a higher risk of developing hypoglycaemia (8 of 10 vs 10 of 28, OR 7.2, 95%CI 1.3-40.7). Hypoglycaemic infants were of significantly higher birthweight, and were more likely to be born to Caucasian mothers and by Caesarean section. Raised maternal fructosamine blood level, the need for insulin treatment or the infant's haematocrit were not different between infants with or without hypoglycaemia. CONCLUSIONS: In well-controlled diabetic mothers, the incidence of early hypoglycaemia in infants is still high, particularly in those mothers who had a longer duration of diabetes. Cord blood glucose level did not identify the infants with hypoglycaemia.     

Long term postnatal development of insulin secretion in early premature infants

The postnatal development of insulin secretion was studied in a group of premature infants (26-30 weeks gestation at birth) for periods up to 110 days after birth and in a small group of full-term infants (38-42 weeks gestation) for up to 47 days after birth. Circulating insulin levels were measured before, and at 30 min after the commencement of a glucose infusion given either parenterally or enterally depending on conceptual age and the mode of nutrition of the infant. The insulin response was assessed as the ratio of the increase in plasma insulin concentration to the increase in blood glucose concentration at 30 min. There was a small insulin response to glucose on day 1 in the premature infants and this increased slowly over the remainder of the study period regardless of the route of administration of glucose or of the mode of nutrition. The full-term infants were more responsive over the seven postnatal weeks in which they were studied. It is concluded that early premature infants can take up to eighteen weeks to develop an ability to respond fully to hyperglycaemia with insulin secretion even though full oral nutrition had been established over the last twelve weeks.     

Growth hormone levels during the first week of life in full-term normal infants, infants of diabetic mothers and in premature infants

Growth hormone levels during insulin- and glucose load have been studied, in normal infants, infants of diabetic mothers and in premature infants during the first week of life.
Base levels of HGH were elevated in all patients when compared to older infants. The highest levels were present on the first day of life. Lower levels were found in infants of diabetic mothers than in the other patients studied.
Insulin-induced hypoglycaemia increased HGH levels in all patients. The increase was more pronounced at the age of one day as compared, to 5—6 days if the absolute levels were compared. The increase was more moderate in infants of diabetic mothers. If the response to hypoglycaemia is expressed as the per cent maximal increment from basic levels no difference in response can be shown between the first day of life and the age of 5—6 days or between normal infants and infants of diabetic mothers. For premature infants the response in per cent increment was more pronounced at the end of the first week and of much higher degree than for other infants studied.
Hyperglycaemia induced an increase in HGH levels comparable to that found during hypoglycaemia. The differences between the groups studied are the same as for hypoglycaemia.