Effect of somatostatin infusion on intermediary metabolism and entero-insular hormone release in infants with hyperinsulinaemic hypoglycaemia

The hypoglycaemia of infantile hyperinsulinism is often exceedingly difficult to control. The use of somatostatin has been advocated recently in such infants because of its effect on inhibiting insulin release, but nothing is known of the wider effects of this potent hormone in the young child. Two infants presenting at 9 weeks and 5 days of age with severe hyperinsulinaemic hypoglycaemia were studied during an infusion of somatostatin. In both infants normoglycaemia was restored with suppression of insulin secretion. An increase in blood ketone bodies occurred, but no change was seen in blood pyruvate, lactate or alanine concentrations. The plasma concentrations of glucagon, cortisol, growth hormone, motilin, pancreatic polypeptide, gastric inhibitory of polypeptide, neurotensin, gastrin and vasoactive intestinal peptide decreased markedly during the somatostatin infusion. No consistent change occurred in plasma enteroglucagon or secretin values. We conclude that somatostatin effectively suppresses abnormal insulin secretion in infants, but it has profound effects on the release of nine other hormones. Further studies are needed to define the consequences of suppressing the release of these hormones before somatostatin can be used routinely in the management of infantile hyperinsulinism.     

DEVELOPMENTAL ASPECTS OF GASTRIC INHIBITORY POLYPEPTIDE (GIP) AND ITS POSSIBLE ROLE IN THE ENTEROINSULAR AXIS IN NEONATES

Abstract. Lucas, A., Sarson, D. L., Bloom, S. R. and Aynsley-Green, A. (University Department of Paediatrics, John Radcliffe Hospital, Oxford and Hammersmith Hospital, London, England). Developmental aspects of gastric inhibitory polypeptide (GIP) and its possible role in the enteroinsular axis in neonates. Acta Paediatr Scand, 69: 321, 1980.—Little is known on the development of the release of gastric inhibitory polypeptide (GIP) in neonates or on its potential role in the enteroinsular axis. Using cross-section data collection we studied: ( a ) 100 preterm neonates either at birth (cord blood), or before or after a feed on the sixth or 24th day and ( b ) 63 term neonates at birth or on the sixth day. Blood samples were assayed for GIP, insulin and glucose. At birth plasma GIP concentrations were low compared with fasting adults ( p > 0.01). Basal plasma levels were significantly higher at six days in fed infants, but not in a group of sick preterm infants who had never been fed orally. On sixth day there was no GIP response to a feed, but by 24th day there was a marked postprandial elevation ( p > 0.01). In preterm infants the insulin response was 68 % greater at 24 days than at six days in spite of a similar glycaemic response. We hypothesize that this increasing postnatal insulin response to enteral feeding may be due to the commencement of the postprandial release of GIP, thought to be an important effector in the enteroinsular axis.     

PLASMA PANCREATIC POLYPEPTIDE IN THE HUMAN NEONATE

Abstract. Lucas, A., Adrian, T. E., Bloom, S. R. and Aynsley-Green, A. (University Department of Paediatrics, John Radcliffe Hospital, Oxford and Hammersmith Hospital, London). Plasma pancreatic polypeptide in the human neonate. Acta Paediatr Scand, 69: 211, 1980.—Plasma pancreatic polypeptide (PP) concentrations have been studied in 197 healthy term and preterm infants. At birth plasma concentrations were lower than those found in the young fasting adult ( p > 0.01), but by the sixth postnatal day in both term and preterm infants basal concentrations had risen to adult levels. In preterm infants, who were studied at two further postnatal ages, 13 and 24 days, basal plasma PP concentrations peaked at 13 days with levels that were over twice those seen in fasting adults ( p > 0.005). However, the marked PP elevations following feeding that have been reported in adults, were not seen in any of the groups of neonates studied. PP physiology thus appears to differ in neonates and adults. These findings may be relevant to adaptation to postnatal life.     

Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.     

Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade.

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological ''nesidioblastosis'' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child''s tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.     

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.     

Hyperinsulinaemic hypoglycaemia in small for dates babies.

Blood glucose concentrations were measured prospectively in 27 small for dates infants in the first 48 hours after birth: 10 infants became hypoglycaemic. Of these, five had inappropriately raised plasma insulin concentrations. Plasma free fatty acids were lower and carbohydrate intake higher in these five infants, further supporting the diagnosis of hyperinsulinism. The hypoglycaemia recurred in four of the five hyperinsulinaemic infants, but in none of those who were not hyperinsulinaemic. Hyperinsulinism is common in small for dates babies. It is important to recognise this because hypoglycaemia is likely to recur and appropriate treatment is needed to prevent long term sequelae.     

PLASMA SECRETIN IN NEONATES

Abstract. Lucas, A., Adrian, T. E., Bloom, S. R. and Aynsley-Green, A. (University Department of Paediatrics, John Radcliffe Hospital, Oxford and Hammersmith Hospital, London). Plasma secretin in neonates. Acta Paediatr Scand, 69: 205, 1980.—Plasma secretin has been measured in 96 normal 6-day-old term infants and in 158 healthy preterm infants whose mean post-partum ages were 2½, 6, 13 or 24-days. At birth, plasma secretin levels in both term and preterm infants were high compared with those seen in healthy fasting adults ( p > 0.001), but subsequently declined towards adult values. In contrast, preterm infants who had not been fed for the first 6 days of life, had presistently high basal plasma secretin values. In term infants at 6 days of age and in preterm infants up to 13 days, there was no se-cretin response to a feed. However, by 24 days, preterm infants showed a marked post-prandial secretin elevation ( p > 0.02). No correlations were found between plasma secretin concentrations and either blood glucose or plasma insulin concentrations following a feed. Significant adjustments in plasma secretin levels occur in the early weeks of life which may be influenced by enteral feeding.     

Surgical treatment of hyperinsulinaemic hypoglycaemia in infancy and childhood.

Despite a greater awareness of hyperinsulinaemic hypoglycaemia, one in three patients has some degree of mental retardation by the time the diagnosis is made. The diagnosis is established by demonstrating high plasma insulin concentrations during an episode of hypoglycaemia. Twenty one hyperinsulinaemic infants and children were referred for surgical treatment after failing to respond to medical management. The surgical procedure of choice is a 95% pancreatectomy. Recurrence of the hypoglycaemia may develop after less radical resections as occurred in one patient who then underwent an extended resection 72 hours postoperatively. Patients who fail to respond to optimal medical treatment should be referred for surgery early and not as a last resort if permanent neurological damage is to be avoided.     

GROWTH and METABOLIC and HORMONAL PROFILES DURING TRANSPYLORIC and NASOGASTRIC FEEDING IN PRETERM INFANTS

Abstract. Milner, R. D. G., Minoli, I., Moro, G., Rubecz, I., Whitfield, M. F. and Assan, R. (Department of Paediatrics, University of Sheffield, England; Unita Neonatale di Terapia Intensiva, Istituto Ospedaliero Provinciate per la Maternita, Milan, Italy and Hotel Dieu, Paris, France). Growth and metabolic and hormonal profiles during transpyloric and nasogastric feeding in preterm infants. Acta Paediatr Scand, 70:9, 1981. The effect of transpyloric and nasogastric feeding on the blood concentration of glucose, lactate, pyruvate, glycerol, hydroxybutyrate, acetoacetate, alanine, insulin, pancreatic and total glucagon was determined in 20 preterm infants. The babies were studied on the last day of transpyloric feeding and the first and fifth days of ensuing nasogastric feeding. In 9 infants hourly measuer-ments of hormones and metabolites were made at 1000,1100,1200,1300 and 1400 hours. The blood concentrations of glucose, alanine, pancreatic and total glucagon were stable, the concentration of the other metabolites and insulin, less so. No significant difference in mean metabolite or hormone concentration was noted by time of day or type of feeding. Measurements made on the fifth day of nasogastric feeding showed no significant differences from those at the time of changeover. The infants were clinically well and growing normally at the time of study, but had low plasma insulin and high plasma glucagon concentrations. We conclude (i) the site of presentation of milk in the gastrointestinal tract has no effect on the circulating concentration of selected metabolites and hormones in the preterm infants, (ii) the preterm infant grows at a normal rate with a plasma insulin/glucagon ratio that in the adult would be expected to favour catabolism.     

The hyperinsulinaemic hypoglycaemias in infancy: a study of six cases

The aim of the present study was to evaluate various functional tests for the differentiation of hyperinsulinaemic hypoglycaemia. The pathophysiological and histological findings in six infants, aged 2–7 months, with persistent hyperinsulinaemic hypoglycaemia are described. Islet cell adenoma was found in four infants and pancreatic nesidioblastosis in two others. Circulating levels of blood glucose (BG), immunoreactive insulin and C-peptide immunoreactivity were measured under basal conditions and during both stimulation and suppression. The diagnosis of hyperinsulinaemia was made by estimation of the BG/serum insulin ratio, which was the most important diagnostic criterion of hyperinsulinism. Control subjects of comparable age showed a ratio of 8.3±4.4 (range 4.1–13.3), whereas the six patients had values between 0.3 and 5.1. At least four determinations with ratios lower than 2.6 were necessary for confirming the diagnosis. Preoperatively we performed oral glucose tolerance, diazoxide infusion, somatostatin infusion and C-peptide suppression tests. It is suggested that the various function tests, especially the suppression tests, do not differentiate hyperinsulinism caused by an adenoma from that caused by diffuse pancreatic nesidioblastosis.Abbreviations IRI Immunoreactive insulin - BG blood glucose - CPR C-peptide immunoreactivity - HCP human C-peptide - BW body weight     

FEEDING AND THE DEVELOPMENT OF ENTEROINSULAR HORMONE SECRETION IN THE PRETERM INFANT: EFFECTS OF CONTINUOUS GASTRIC INFUSIONS OF HUMAN MILK COMPARED WITH INTERMITTENT BOLUSES

ABSTRACT. Preterm infants receive gastric milk feeds as continuous infusions or intermittent boluses. It is not known whether these feeding methods have different effects on the development of digestive metabolism. We have measured plasma levels of insulin, pancreatic polypeptide (PP), gastric inhibitory polypeptide (GIP), gastrin, motilin, enteroglucagon (EG) and neurotensin (NT) in 19 preterm infants (28-34 weeks gestation) tolerating full enteral feeding from birth. 7 infants received human milk by continuous infusion, 12 infants were bolus fed. Hormones were measured in cord blood and at 6 and 13 days of age; samples were drawn preprandially in bolus fed infants. Both groups showed similar significant increases in plasma motilin, PP, NT and EG levels. At 13 days infusion fed infants had higher insulin. GIP and gastrin levels. No difference in rate of weight gain was seen in the two groups of infants. We conclude that both methods of feeding induce progressive changes in circulating enteroinsular hormone levels. However, the endocrine milieu is different in the two groups, particularly since bolus-fed infants experience marked cyclical surges in hormones after boluses of milk by 13 days of age. These differences in hormone release may affect metabolic homeostasis.     

GLUCOSE TOLERANCE AND INSULIN SECRETION IN VERY SMALL BABIES

ABSTRACT: Cser, A. and Milner, R. D. G. (Department of Child Health, University of Manchester, St. Mary's Hospital, Manchester M13 OJH, England). Glucose tolerance and insulin secretion in very small babies. Acta Paediatr Scand, 64:457, 1975.–Nineteen exchange transfusions were performed via the umbilical artery using blood preserved with acid-citrate and dextrose in 8 infants of 34–40 weeks gestation (larger infants) and 9 very small infants of 26–33 weeks gestational age. The plasma glucose rise which was similar in both groups stimulated insulin secretion from the larger infants but not the very small infants. No significant differences occurred between the groups in the fall in mean free fatty acid levels or increase in growth hormone secretion. Following transfusion there was a sharp rise in mean plasma insulin concentration in the larger infants and a smaller rise in the very small infants, but the rate of glucose disappearance was greater in the very small infants. A highly significant positive correlation was found between the maximum posttransfusion plasma insulin and the birth weight of the infants. Plasma glucose levels of less than 30 mg/100 ml occurred in 2 larger and 5 very small infants during the first 3 hours after transfusion. One infant of birth weight 0·98 kg received four transfusions; in 2 where he received ACD blood via the umbilical artery or vein, insulin secretion was not stimulated but in the other 2 in which glucagon or arginine was added to the ACD donor blood, insulin secretion was stimulated. Feeding practice should take account of the fact that although very small infants secrete less insulin than larger infants during exchange transfusion they are more likely to become hypoglycaemic in the immediate posttransfusion period.     

DIBUTYRYL CYCLIC 3':5'-ADENOSINE MONOPHOSPHATE IN HYPOPITUITARISM AND SILVER-RUSSELL SYNDROME

Abstract. Vanderschueren-Lodeweyckx, M., Van den Berghe, G., Proesmans, W., Corbeel, L., Eggermont, E. and Eeckels, R. (Department of Paediatrics, Katholieke Universiteit Leuven, Belgium). Dibutyryl cyclic 3':5'-adenosine monophosphate in hypopituitarism and Silver-Russel syndrome. Acta Paediatr Scand 63: 364, 1974.–The effect of the infusion of dibutyryl cyclic 3':5'-adenosine monophosphate (0.2 mg/kg/min during 1 hour) on plasma growth hormone and on glucose, immunoreactive insulin and cortisol was studied in 3 control children, in 2 Silver-Russell patients and in 8 patients with idiopathic hypopituitarism. Upon the infusion of the cyclic nucleotide, plasma glucose and immunoreactive insulin increased markedly. An increased level of plasma cortisol was also observed in all cases except in one hypopituitary patient with associated ACTH deficiency. In contrast to what has been reported in normal subjects and observed in the 3 normal children and the 2 Silver-Russell patients, dibutyryl cyclic 3':5'-adenosine monophosphate failed to increase the level of plasma growth hormone above 1 ng per ml in 7 out of the 8 hypopituitary patients. Exogenous dibutyryl c-AMP may be considered as an alternative test for the study of growth hormone release.     

THYROXINE-BINDING GLOBULIN DEFICIENCY IN EARLY CHILDHOOD

ABSTRACT. Jacobsen, B. B., Hansted, L. C, Brandt, N. J., Haahr, J., Hummer, L., Munkner, T. and Sorensen, S. S. (Department of Paediatrics, Viborg Hospital, Children's Hospital Fuglebakken, Department of Paediatrics, Section of Clinical Genetics and Department of Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark). Thyroxine-binding globulin deficiency in early childhood. Postnatal changes in serum concentrations of thyroid hormones and thyroid hormone-binding proteins. Acta Paediatr Scand, 70:155, 1981. –Serial determinations of serum thyroxine (T4), triiodothyronine (T3), thyrotropin(TSH), thyroid hormone-binding globulin (TBG), prealbumin (TBPA) and albumin were performed in a euthyroid girl with TBG deficiency and in her mother for a period of 22 months after delivery. At 8 days old the child had a serum TBG concentration around 50% of normal level which remained essentially unchanged during infancy. Total serum T4 and T3 concentrations were low, the free serum T4, free serum T3 and serum TSH concentrations were normal. The mother had received thyroid hormone from the age of 15 years. Her serum TBG level at 6 weeks post partum was similar to that of non-pregnant adults but decreased to about 50% of normal level, indicating a TBG deficiency. She remained euthyroid after withdrawal of T4 therapy. Serum TBPA and albumin concentrations were normal in mother and child. An X-linked inheritance of the TBG deficiency was suggested from a study of the family.     

PLASMA FERRITIN CONCENTRATIONS IN PRETERM INFANTS IN CORD BLOOD AND DURING THE EARLY ANAEMIA OF PREMATURITY

Abstract. Hågå, P. (Department of Paediatrics and Paediatric Research Institute, National Hospital of Norway, and Department of Paediatrics, Oslo City Hospital, Ullevål, Oslo, Norway). Plasma ferritin concentrations in preterm infants in cord blood and during the early anaemia of prematurity. Acta Paediatr Scand, 69: 637, 1980.—Ferritin concentrations in cord blood were determined in 22 normal term and 32 preterm infants (birth weights 600–2000 g). Eight of the preterms were SGA infants. AGA preterm infants had significantly lower concentrations than term infants, and the SGA preterm newborn had even lower levels. Plasma ferritin in cord blood of the term and AGA preterm infants correlated positively with plasma iron and transferrin saturations, but not with the transferrin level, while plasma iron and transferrin concentrations correlated positively. In a longitudinal study, 17 AGA preterm infants (birth wights 850–1500 g) were followed during the early anaemia of prematurity. Iron was supplemented from 4 weeks of age. Plasma ferritin rose rapidly during the first days after birth, peak levels being reached at 1–4 weeks. Thereafter linear falls (semilog) occurred with similar slopes in different infants. Transferrin concentrations showed a slow progressive increase from 0–8 weeks. Plasma ferritin, after reaching the peak value, correlated negatively with weight gain. No infant had low ferritin values indicating iron deficiency during the early anaemia.     

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)     

The effect of feeds of differing composition on entero-insular hormone secretion in the first hours of life in human neonates.

Little is known on the enteral stimuli for gastro-intestinal hormone release in newborn infants. We have compared the effect of the first feed of human breast milk (5 ml/kg) or 10% dextrose (5 ml/kg) on blood glucose and plasma gastrin, enteroglucagon, Gastric Inhibitory polypeptide (GIP), pancreatic glucagon, and insulin in 21 full-term infants at 4--6 hours of age. The first feed of human milk caused a rise in blood glucose and plasma insulin, gastrin and enteroglucagon, but no change occurred in GIP or pancreatic glucagon. The 10% dextrose feed did not stimulate enteroglucagon release, although similar changes occurred in blood glucose and plasma insulin and gastrin. We conclude that the composition of the feed influences the pattern of gastro-intestinal hormone release during the first hours of life and that the entero-insular responses to feeding differ in the neonate and the adult.     

Plasma C peptide in hyperinsulinaemic hypoglycaemia.

We describe two children with hypoglycaemia due to pancreatic beta cell hyperactivity. Both had low serum insulin but raised plasma C peptide concentrations when hypoglycaemic. Measurement of C peptide is valuable in the diagnosis of hyperinsulinaemic hypoglycaemia in children.     

Histochemical,clinical, and in vitro β cell responses in a neonate with persistent hyperinsulinaemic hypoglycaemia of infancy

When treatment with diazoxide and somatostatin for persistent hyperinsulinaemic hypoglycaemia of infancy failed, subtotal pancreatectomy was performed on a neonate on day 41. The pancreatic tissue was saved and used for immunohistochemical and cell culture studies. The initial immunohistochemistry of β cells for insulin was negative, using a 1 in 200 dilution of insulin antiserum, but positive results were obtained with an increased concentration of the antiserum.
The insulin to somatostatin cell ratio in islets of Langerhans was about 1:1, with no somatostatin cells outside the islets. Glucose stimulated insulin secretion in a concentration dependent manner in vitro. Isobutyl methyl xanthine doubled insulin secretion, but lithium had no effect. The glucose stimulated insulin secretion was inhibited by somatostatin, epinephrine, and in the absence of Ca²⁺.
In view of the normal in vitro responses of β cells to various secretory analogues, the lack of responsiveness to somatostatin analogue before pancreatectomy may not have been due to deficiency or resistance to somatostatin, but to β cell hyperplasia overwhelming the paracrine regulatory mechanism(s).