Postnatal surges in plasma gut hormones in term and preterm infants

Using sensitive radioimmunoassays we have measured and compared plasma concentrations of motilin, gastrin, enteroglucagon, neurotensin, gastric inhibitory polypeptide and pancreatic polypeptide in (a) 53 healthy, preterm infants at birth or preprandially at 2.5, 6, 13 or 24 days; (b) 45 normal, breast-fed, term infants at birth or preprandially at 6 or 16 days, and (c) 12 healthy fasting adults. Plasma concentrations of all six hormones rose during the neonatal period in both preterm and term infants, the first four of these hormones reaching levels which exceeded those seen in healthy fasting adults. The rate of increase and the magnitude of the changes were less in term infants than preterm infants. These changes in plasma hormone concentrations may be the result of enteral feeding. Gut hormones exert important effects on gut growth, secretion and motility and on intermediary metabolism, and the postnatal hormonal surges observed may play a key role in the postnatal adaptions to enteral feeding.     

METABOLIC AND ENDOCRINE CONSEQUENCES OF DEPRIVING PRETERM INFANTS OF ENTERAL NUTRITION

ABSTRACT. Plasma enteroglucagon, pancreatic polypeptide, gastrin, motilin, neurotensin, gastric inhibitory polypeptide, secretin, vasoactive intestinal peptide and blood glucose, alamine, ketone bodies, lactate and pyruvate were measured on the sixth postnatal day in ( a ) a group of 10 preterm infants who on account of hyaline membrane disease had not received enteral feeding since birth and ( b ) before and at 55, 90, and 120 minutes after feeding in a group of healthy preterm infants fed three-hourly on human milk. Gut hormones were also measured in umbilical venous cord blood. The infants receiving regular boluses of milk from birth demonstrated postnatal surges in preprandial concentrations of gut hormones together with cyclical hormonal responses to feeding. None of these changes were seen in infants receiving intravenous fluids. The latter infants also had lower concentrations of blood alanine, glycerol and hydroxybutyrate and lacked the phasic changes in intermediary metabolites seen in the infants receiving enteral boluses of milk. Thus deprivation of enteral feeding results in a profound alteration of the metabolic and endocrine milieu which may have important effect on the process of adaptation to postnatal life.     

Heart rates of breast-fed and formula-fed infants.

Heart rates of 46 breast-fed and formula-fed infants were monitored continuously for approximately 18 h at 1 or 4 months of age. Heart rate differed significantly by age (1 month greater than 4 months; p less than 0.001) and feeding mode (breast-fed less than formula-fed; p less than 0.001). Approximately 58% of the variability in heart rate could be attributed to feeding mode, sex, and age. Heart rate was correlated significantly with energy intake (r = 0.60; p less than 0.001), but not sleeping metabolic rate or total daily energy expenditure. Energy intake accounted for none of the variability in heart rate beyond that explained by feeding mode, sex, and age.     

Gut regulatory peptides and intestinal permeability in acute infantile gastroenteritis.

The plasma concentrations of seven gut regulatory peptides were measured in 11 infants suffering from acute gastroenteritis. Samples were taken at the time of the acute illness, upon reintroduction of feeding, and three months after recovery. These results were compared with controls. In the infants with diarrhoea, a massive increase in the fasting plasma mean (SEM) concentrations of enteroglucagon was found at the time of illness (1292 (312) v 79 (27) pmol/l), with concentrations of pancreatic glucagon, peptide tyrosine tyrosine, and motilin also being increased (17.8 (3.1) v 6.3 (1.1) pmol/l, 114.6 (15.2) v 37.0 (11.0) pmol/l, 217.6 (44.1) v 98.5 (18.3 pmol/l) respectively). The preprandial concentrations of motilin were found to be still increased at recovery (183.9 (35.4) pmol/l), but the concentrations of the other three peptides had returned to normal values. No differences in plasma concentrations of vasoactive intestinal polypeptide, neurotensin, or pancreatic polypeptide were found. An increased intestinal permeability was demonstrated at the time of diarrhoea by the urinary ratio of lactulose to mannitol, suggesting simultaneous gut damage. The effects of regulatory peptides may be relevant to the pathophysiology of gastroenteritis in infants.     

Folate nutrition is optimal in exclusively breast-fed infants but inadequate in some of their mothers and in formula-fed infants

Plasma concentrations of folate were studied in a group of exclusively breast-fed infants and their mothers (their numbers gradually decreased from 200 at birth to 7 at 12 months) and in infants completely weaned to a cow's milk formula (containing 35 micrograms of folate/L) and solid foods. The exclusively breast-fed infants were in no danger of folate deficiency; their plasma levels were elevated after the age of 2 months and, on average, were 2.0-3.3-fold higher than maternal levels throughout the study. None of these infants had an inadequate plasma concentration, whereas up to 5% of the mothers had values less than or equal to 3 micrograms/L, despite supplementation during lactation with 0.1 mg folate/day. In the formula-fed infants, 69-94% of the plasma folate concentrations lay below the lowest concentration for the breast-fed infants. Although no infant had signs of anemia or macrocytosis in red cell indices, the infants weaned earliest had the lowest hemoglobin concentrations (p = 0.09) and the highest mean corpuscular volume (MCV) values (p = 0.06) at 9 months of age. Thus, an infant fed a formula containing the recommended amount of folate runs a risk of folate deficiency.     

Feeding premature infants with human milk or preterm milk formula. Effects on postnatal growth and on circulating concentrations of intermediary metabolites, amino acids, and regulatory peptides

Results of a comprehensive longitudinal study comparing the effects of feeding healthy preterm infants with human milk or a specially adapted formula designed for the preterm infant are reported. 10 healthy infants were given human milk from birth, and 9 similar infants were given a formula which contained 80 kcal, 1.8 g protein, and 4.5 g fat per 100 ml. Anthropometric measurements were made weekly as were routine haematological and biochemical variables together with plasma amino acid and gastrointestinal regulatory peptide levels and metabolic fuel concentrations. Infants receiving the formula demonstrated a significantly greater growth velocity compared with infants receiving human milk. There were no significant differences between the two groups in routine haematological or biochemical variables measured nor in plasma insulin or blood glucose, lactate, pyruvate, or ketone body concentrations. Plasma amino acid profiles, however, did demonstrate some significant differences between the two groups with higher methionine and threonine levels in the formula-fed infants. Plasma motilin, enteroglucagon, neurotensin, cholecystokinin, gastric inhibiting polypeptide, and pancreatic polypeptide levels all demonstrated significant postnatal surges, with significant differences between the two groups in plasma gastric inhibiting polypeptide and pancreatic polypeptide concentrations.     

Age and diet effects on fecal bile acids in infants

Fecal bile acid patterns and concentrations have been determined for 28 infants who were followed from average ages of 3-11 months. Half were solely breast-fed and half were solely formula-fed at the beginning of the study. Breast-fed infants were found to have significantly (p less than 0.05) lower concentrations of cholic acid than the formula-fed group, up to an average age of 5 months. Concentrations of deoxycholic and lithocholic acids were directionally lower in breast-fed infants at all ages. Concentrations of chenodeoxycholic acid were similar for both groups throughout the study. At the end of the study, breast-fed infants were excreting 17% of their total bile acids in the form of secondary acids, compared to 33% for formula-fed infants. This pattern persisted long after the infants began weaning. Formula-fed infants were found to have lithocholic acid in their stools at a significantly (p less than 0.05) earlier age than breast-fed infants. Appearance of deoxycholic acid was at similar ages for both groups. Both of these secondary acids were found to occur at much younger ages (approximately 2 months) than has been previously reported. These observed differences are attributed to the distinct intestinal microbial populations encouraged by the different diets.     

Functional enteroinsular axis in full-term newborn infants

The term "enteroinsular axis" refers to the enhancement of insulin release by hormones secreted from the gut. Gastric inhibitory polypeptide (GIP) is one of the major hormones that mediates this function. The purpose of the present study was to examine whether the enteroinsular axis is functional in newborn infants born at term gestation. Between d 2 and d 4 of life, glucose was infused for 2 h intravenously or orogastrically to 44 fullterm newborn infants, of whom 18 were appropriate for gestational age, nine large for gestational age, eight small for gestational age; nine infants were born to diabetic mothers. Glucose was infused at either 8 mg/kg/min intravenously or 16 mg/kg/min orogastrically to achieve similar plasma glucose concentrations. Plasma insulin and GIP concentrations were compared. Plasma GIP concentration increased significantly with enteral glucose administration in all infants but remained unchanged with parenteral glucose infusion. The responses of plasma insulin and the insulin/glucose ratio were significantly greater in infants receiving enterally than parenterally infused glucose. However, when glucose was infused orogastrically at a lower rate (8 mg/kg/min), plasma GIP concentrations rose, but no enhancement of insulin response was detected, suggesting the importance of the role of circulating glucose in the "enteroinsular axis". The infants of diabetic mothers and the large-for-gestational-age infants had more rapid insulin response to orogastrically administered glucose, but their GIP responses were similar to that of normal infants. These findings suggest that, at term gestation, the newborn infants have a "functional" enteroinsular axis in response to glucose, i.e. the rising plasma GIP contributed in part to the enhanced insulin response to enterally infused glucose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma amino acids after a feed of human milk or formula at three months of age

Prefeeding plasma amino acid concentrations were higher and glycine-to-valine ratios lower in formula-fed infants as compared to breast-fed infants at 3 months of age. After a human milk meal (true protein, 0.8 g/100 ml) or formula meal (1.5 g/100 ml), all essential and several nonessential amino acids peaked at 30-60 min. The postprandial increments were greater and lasted longer after formula, reflecting the amounts of individual amino acids in the feeds. The changes resembled those seen in adults, and were smaller than those observed in these infants at 1 week of age. These data indicate that gastrointestinal, hepatic, and endocrine responses to a meal are immature at the age of 3 months.     

Levels of serum ferritin and total body iron among infants with different feeding regimens

The levels of serum ferritin and total body iron of healthy infants were analyzed to evaluate iron status among infants with different feeding regimens. The results showed that the levels of serum ferritin and total body iron were lower in breast-fed infants than in partially breast-fed or formula-fed infants at late infancy and 18 months of age.     

Glucose kinetics in glucose-infused small for gestational age infants

To evaluate the maturation of glucose homeostasis in the small for gestational age (SGA) neonate, glucose kinetics were measured with 78% enriched D-[U-13C]glucose by the prime plus constant infusion technique in nine SGA infants and compared with the rate obtained in seven term appropriate for gestational age infants and 13 preterm appropriate for gestational age infants. All of the infants had received glucose intravenously from birth and continued to receive the glucose infusion throughout the study. Fasting plasma glucose and plasma insulin concentrations and plasma [13/12C]ratios were measured during the steady state turnover period. From this data, the glucose production rate was derived. During the turnover period, the SGA and both groups of appropriate for gestational age infants had similar average plasma glucose, plasma insulin, plasma glucagon concentrations, and similar persistent rates of glucose production during glucose infusion. We conclude that under stimulation of glucose infusion, the SGA infant and his AGA counterpart have similar hormonal regulatory responses as well as functional integrity in handling glucose during the second day after birth.     

Tryptophan fortification of adapted formula increases plasma tryptophan concentrations to levels not different from those found in breast-fed infants.

Several recent studies have demonstrated significantly lower plasma total tryptophan concentrations in formula-fed than in breast-fed infants. We have measured preprandial plasma amino acid concentrations in infants breast-fed or fed a formula with a protein concentration of 1.57 g/dl and with a whey/casein ratio of 60:40 or a formula with a protein concentration of 1.37 g/dl and a whey/casein ratio of 40:60 and fortified with 10 mg/dl (15 mg/100 kcal) of tryptophan. Healthy term infants (10 per group) were either breast-fed from birth or randomly assigned to one of the two study formulas. At 4 and 12 weeks of age, anthropometric measurements were performed and blood samples were obtained. During the study period of 12 weeks, all infants showed normal growth (weight, length, and head circumference) and there were no statistically significant differences between the groups. The plasma concentrations of the essential amino acids phenylalanine, threonine, valine, and lysine were significantly lower in the breast-fed group than in both formula-fed groups. For tyrosine, methionine, leucine, histidine, isoleucine, and arginine, no significant differences could be found between the feeding groups. Concentration of total plasma tryptophan was significantly higher in the breast-fed group than in the group fed the tryptophan-unfortified formula, but no statistically significant difference could be found between the plasma tryptophan concentration in the breast-fed group versus the group fed the tryptophan-fortified formula. The results indicate that tryptophan fortification of adapted formula is necessary to achieve plasma total tryptophan concentrations similar to those found in breast-fed infants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Iron status in low birth weight infants on breast and formula feeding

Iron status in 15 low birth weight infants, 1000–2499 g, on breast feeding was studied longitudinally for the first 6 months of age, and the findings compared to those of 30 low birth weight infants receiving a proprietary iron-fortified formula. The two groups received no iron supplement until they developed iron deficiency. The incidence of iron deficiency at 6 months was significantly greater in the breast-fed group than in the formula-fed group (86% v 33%). The breast-fed group had significantly lower serum ferritin and hemoglobin values after 4 months of age. The findings indicate that breast-fed low birth weight infants have a higher risk of developing iron deficiency and should receive iron supplementation from 2 months of age.Abbreviations TIBC total iron-binding capacity - MCV mean corpuscular volume     

Effects of soy formulas on mineral metabolism in term infants

We studied 40 healthy term infants who received a soy-based formula containing either a single carbohydrate (glucose polymers) or dual carbohydrates (glucose polymers and sucrose). Ten exclusively breast-fed infants served as controls for the first four months of the study. All infants were studied at 2 weeks, 2 months, and 4 months of age for anthropometric development, biochemical values, and bone mineral content. There were no differences among the three groups in weight, length, or head circumference gains. Serum levels of calcium, phosphorus, magnesium, copper, 25-hydroxycholecalciferol, and alkaline phosphatase were also similar. However, at 4 months of age, the breast-fed group had a higher plasma zinc level than both formula-fed groups, and at 2 and 4 months of age, it had higher bone mineral content and bone density.     

Responses of gastrointestinal peptides and motor activity to milk and water feedings in preterm and term infants.

Because duodenal motor activity differs between preterm and term infants during fasting, this study evaluated the responses of motor activity and peptide release in response to feeding. In the first study, fasting concentrations of gastrin, gastric inhibitory peptide, neurotensin, and peptide YY (PYY) were determined in 53 preterm and 20 term infants. Plasma concentrations of gastrin and neurotensin were significantly lower in preterm infants than in healthy adults reported previously by our lab (p less than 0.01). Plasma concentration of gastric inhibitory peptide and PYY were higher than in healthy adults (p less than 0.01). Gastrin concentrations in preterm and term infants varied directly with gestational age (p less than 0.005); PYY varied inversely with gestational age (p less than 0.005). In a secondary study, intestinal manometry was recorded and serial peptide concentrations were determined in 43 preterm babies who were given their first enteral feeding intraduodenally with formula or sterile water. Although none of the four peptide plasma concentrations changed in response to feeding with water, plasma concentrations of gastric inhibitory peptide, neurotensin, and PYY significantly increased with formula feedings (p less than 0.05 or less). In addition, plasma gastrin increased significantly in seven infants fed milk compared with eight fed water by orogastric tube (p less than 0.01). In contrast to the peptide response to feeding, motor activity changed in response to feeding with either water or milk; motility indices increased and periods of motor quiescence decreased significantly during feeding as compared with fasting (p less than 0.02). Responses of both motor activity and peptides to feeding were time related.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma gastrin and somatostatin levels in newborn infants receiving supplementary formula feeding

Plasma gastrin and somatostatin concentrations were measured by radioimmunoassay in exclusively formula-fed infants and in breast-fed infants receiving supplementary formula during the first five postnatal days. Infants exclusively formula fed had a progressive increase in mean plasma gastrin concentration from 109±42 pmol/l (mean±SD) on the first day to 236±103 pmol/l on the fifth day after birth ( p = 0.0001). Breast-fed infants receiving supplementary formula had similar hormone concentrations as formula-fed infants of corresponding postnatal age and they also had a significant increase in hormone levels from the first to the fifth day ( p = 0.0001). A positive relationship was found between gastrin concentration and ingested milk volume: Rs = 0.51, n = 105, p = 0.0001. The high gastrin concentrations most probably reflect enhanced hormonal release from the gastrin-producing cells in response to increasing volumes of milk ingested by the infant. The mean plasma somatostatin concentration on the first day after birth was 18 ± 6 pmol/l. No significant change occurred during the first five postnatal days, independent of feeding type.     

METABOLIC AND ENDOCRINE RESPONSES TO A MILK FEED IN SIX-DAY-OLD TERM INFANTS: DIFFERENCES BETWEEN BREAST AND COW'S MILK FORMULA FEEDING

ABSTRACT. Lucas, A., Boyes, S., Aynsley-Green, A. (Department of Paediatrics, John Radcliffe Hospital, Oxford) and Bloom, S. R. (Hammersmith Hospital, London, England). Metabolic and endocrine responses to a milk feed in six-day-old term infants: JMfferences between breast and cow's milk formula feeding. Acta Paediatr Scand, 70:195, 1981. – There is little information on the metabolic and endocrine responses to milk feeding in the neonatal period particularly in relation to the mode of nutrition and composition of the milk. Plasma concentrations of insulin, glucagon and gastric inhibitory polypeptide (GIP) together with blood levels of glucose, ketone bodies, pyruvate, lactate and glycerol were measured pre- and post-prandially in 79 healthy six-day-old term infants who had been either breast fed or fed on a modified cow's milk formula (Cow and Gate Premium) from birth. Formula fed infants had a greater insulin and GIP response to feeding and their basal and postprandial blood ketones were considerably lower than in breast fed infants. In addition a significantly greater post feed rise in both lactate and pyruvate concentrations was observed with formula feeding. These results may have significant implications regarding infant feeding and postnatal metabolism.     

Protein and Energy Intake during Weaning

ABSTRACT. Preprandial plasma amino acid concentrations were measured at 5 and 6 months of age in 30 healthy term infants who were either breast-fed ad libitum or fed one of two different formulas (1.9 g of protein per 100 ml with a whey: casein ratio of 50:50; 2.9 g of protein per 100 ml with a whey: casein ratio of 20:80) ad libitum, plus the same supplementary food regimen. The mean plasma concentrations of total amino acids and especially total essential amino acids were higher in the formula-fed infants. Those fed formula also had plasma concentrations of methionine, isoleucine, phenylalanine, leucine, valine, threonine, aspartate, proline, lysine, tyrosine, histidine that exceeded plasma concentrations of breast-fed infants by 2 or more standard deviations. Concentrations of arginine, glutamic acid, glutamine, ornithine, serine, cystine did not differ and taurine was higher in the breast-fed infants. The data indicate that formulas in common use today during weaning (4–6 months) provide excessive protein intakes when compared to the breast-fed control infants. A lowering of protein concentration and a further manipulation of the whey: casein ratio is necessary if plasma amino acid patterns similar to those found in breast-fed infants is to be achieved with artificial feeding.     

Protein and energy intake during weaning. III. Effects on plasma amino acids

Preprandial plasma amino acid concentrations were measured at 5 and 6 months of age in 30 healthy term infants who were either breast-fed ad libitum or fed one of two different formulas (1.9 g of protein per 100 ml with a whey:casein ratio of 50:50; 2.9 g of protein per 100 ml with a whey:casein ratio of 20:80) ad libitum, plus the same supplementary food regimen. The mean plasma concentrations of total amino acids and especially total essential amino acids were higher in the formula-fed infants. Those fed formula also had plasma concentrations of methionine, isoleucine, phenylalanine, leucine, valine, threonine, aspartate, proline, lysine, tyrosine, histidine that exceeded plasma concentrations of breast-fed infants by 2 or more standard deviations. Concentrations of arginine, glutamic acid, glutamine, ornithine, serine, cystine did not differ and taurine was higher in the breast-fed infants. The data indicate that formulas in common use today during weaning (4-6 months) provide excessive protein intakes when compared to the breast-fed control infants. A lowering of protein concentration and a further manipulation of the whey:casein ratio is necessary if plasma amino acid patterns similar to those found in breast-fed infants is to be achieved with artificial feeding.     

Early-life patterns of plasma gut regulatory peptide levels in calves: effects of the first meals.

The effects of the first meals on the release of seven gut regulatory peptides were studied in newborn calves fed colostrum either at serial intervals during the first day of life or at 28 h only. Fasted animals showed no significant variation of plasma peptides until the first feed, except for somatostatin, which peaked at 4-5 h and declined thereafter. As assessed before and 1 h after feeding, the first meal tended to induce rises in plasma gastrin, cholecystokinin and pancreatic polypeptide, while the other peptides were unaffected. Repeated colostrum feeds induced marked increases in plasma gastrin, cholecystokinin, secretin and vasoactive intestinal peptide from 10 h on. Pancreatic polypeptide was transiently increased from 4 to 16 h. Feeding was followed by a transitory reduction of plasma somatostatin and by a prolonged decrease of plasma motilin. We conclude that colostrum feeding potently modulates the release of several regulatory peptides shortly after birth in calves. These responses may be important for the adaptation of gut growth, secretions and motility to food ingestion in the neonatal period.