INSULIN AND GLUCAGON RESPONSE TO ARGININE INFUSION IN CYSTIC FIBROSIS

Abstract Redmond, A. O. B., Buchanan, K. D. and Trimble, E. R. (The Royal Belfast Hospital for Sick Children, Belfast, and The Department of Medicine, Queen's University, Belfast). Insulin and glucagon response to arginine infusion in cystic fibrosis. Acta Paediatr Scand, 66:199, 1977.—The glucagon and insulin responses to intravenous arginine were studied in 17 children with cystic fibrosis and in 9 control children. It was found that the overall secretion of insulin was diminished; however, four of the CF children did have a normal output. The glucagon responses did not parallel those of insulin. The glucagon output varied in the CF children—seven had normal, four excessively high and six low output. Three of the four children with extremely high output had more severe disease and were below the third centile on the weight chart. These four had a fasting hypoglycaemia and also a very low glucose and insulin response. We have confirmed diminished insulin secretion in cystic fibrosis, but diminished glucagon secretion was only noted when some insulin secretion was preserved. The high levels of glucagon seen in the most insulin deficient subjects may be derived from extrapancreatic sources, or may be associated with 'stress' reaction in these patients who also had most severe pulmonary involvement. The data would be consistent with diminished glucagon and insulin secretion from the pancreas but as the disease progresses an excessive secretion of extra pancreatic glucagon results.     

BLOOD GLUCOSE and PLASMA INSULIN and GLUCAGON RESPONSE DURING INTRAVENOUS GLUCOSE TOLERANCE TEST IN NEWBORN INFANTS AFFECTED BY ERYTHROBLASTOSIS FOETALIS

Abstract. Massi-Benedetti, F., Marini, A., Caccamo, M. L. and Falorni, A. (Paediatric Clinic of the University of Perugia and the Service of Neonatal Pathology of the University of -Milan, Italy). Blood glucose and plasma insulin and glucagon response during intravenous glucose tolerance test in newborn infants affected by erythroblastosis foetalis. Acta Paediatr Scand, 64:113, 1975.–Intravenous glucose injection (1 g/kg b.w.) was performed in eight newborn infants affected by erythroblastosis foetalis (IEF) and in seven controls during the first day of life in order to study insulin and glucagon response. The IEF infants were affected by mild or moderate hemolytic disease and their blood glucose values and plasma insulin concentrations before and throughout the test did not differ significantly from those of the controls. After the glucose injection the plasma glucagon concentrations showed great variations in both groups. The control infants did not show any significant changes; in the IEF infants, significant decreases were seen at 3 and 20 min of the test. These data seem to indicate that the alpha-cell sensitivity to glucose is greater in IEF than in normal infants and is not dependent on the development of the glucose-mediated insulin release mechanism.     

EFFECT OF INTRAVENOUS L-ALANINE ADMINISTRATION ON PLASMA GLUCOSE, INSULIN AND GLUCAGON, BLOOD PYRUVATE, LACTATE AND BETA-HYDROXYBUTYRATE CONCENTRATIONS IN NEWBORN INFANTS Study in Term and Preterm Newborn Infants

ABSTRACT. Ten term and eleven preterm newborn infants with appropriate weights for their gestational age were infused for one minute with L-alanine (150 mg/kg) at the age of 29 to 76 hours (mean 48 hours) and circulating levels of glucose, lactate, pyruvate, d -betahydroxybutyrate ( d -BOHB), insulin and glucagon were monitored. Plasma glucose concentrations increased from 2.7±0.16 (mean±S.E.M.) to 3.7±0.2 mmol/1 after 50 min (p±0.01) in term infants. In preterm infants, after an initial decrease of the glucose level from 3.1±0.16 to 2.6±0.16 mmol/1 (p±0.05), it returned to the baseline level at 50 min: 3.0±0.2 mmol/1. The blood concentration of d -BOHB decreased in term infants from 192±37 to 112±6 μM/1 (p±0.01) after 40 min. In preterms, its decrease was not significant (p±0.05). Plasma glucagon levels rose from 53±5 to 70±8 pmol/1 after ten minutes (p±0.01) in term infants and from 61±6 to 75±9 after 20 min (p±0.01) in preterm infants. There were no significant changes in plasma insulin concentrations in either group. Forty minutes after l -alanine infusion, I/G ratios were lower in preterm infants (1.26±0.14) than in term infants (1.71±0.25) (p±0.01). There was no relationship between the glycemic responses to l -alanine and the basal levels of d -BOHB.
The data suggest that the glycemic effect of l -alanine infusion and circulating glucagon depends upon a specific stage in maturation. The antiketogenic effect of l -alanine infusion is observed in term infants as in adults.     

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.     

PANCREATIC ISLET CELL FUNCTION AND METABOLIC CONTROL IN AN INFANT WITH PERMANENT NEONATAL DIABETES

ABSTRACT. A girl with typical clinical manifestations of neonatal diabetes was observed for 16 months with consecutive evaluations of pancreatic beta and alpha-cell function and metabolic control. At the diagnosis both the plasma immunoreactive insulin (IRI) and C-peptide concentrations were inappropriate for the contemporaneous hyperglycemia. During the follow-up, the C-peptide fell twice below the detection limit but the beta-cell function recovered partially on both occasions. Based on 24-hour urinary C-peptide excretion, the endogenous insulin secretion was less than 10% of that in non-diabetic infants. When diagnosed the patient had plasma immunoreactive glucagon (IRG) and glucagon-like immunoreactivity (GLI) concentrations below the reference range for normal neonates. The IRG normalised within the first month, while the GLI increased to a level exceeding the reference range. Hemoglobin A₁ had already risen at the time of diagnosis and subsequently rose to a level indicating poor metabolic control. The findings indicate an immature function of both beta- and alpha-cells at the diagnosis with the alpha-cells maturing within the first month. The recovery of the beta-cell function, after two failures in this patient with permanent neonatal diabetes, suggests that the beta-cell damage was at least partially reversible.     

INFLUENCE OF LONG TERM GROWTH HORMONE THERAPY ON GLUCOSE TOLERANCE AND INSULIN SECRETION

Daily secretion of growth hormone (GH) in the normal child is unknown and may not be assessable in the near future. The dosage of human growth hormone (HG) commonly used in hypopituitary growth retardation is purely empirical. Growth is in general successfully accelerated by HGH but would presumably be stimulated also by higher than physiological doses. Our study consisted of a longitudinal evaluation of the effects of HGH on glucose tolerance, free fatty acids and immunoreactive insulin in three children with primordial growth retardation and two children with GH deficiency over six to twenty-seven months. Two additional hypopituitary children were studied twelve and eighteen months after onset of HGH therapy. In all patients there was no discernible effect on the parameters studied at the dosage used (HGH (Raben 10 mg/m²/ week in three divided injections). This finding supports the assumption that the dose of HGH commonly used is indeed physiological in regard to carbohydrate metabolism.     

INSULIN AND GROWTH HORMONE SECRETION IN A LEUKAEMIC GIRL WITH HYPOTHALAMIC SYNDROME

Abstract Schilirò, G., Russo, A., Sciotto, A. and Vigo, R. (Paediatric Clinics I and II, University of Catania, Catania, Italy). Insulin and growth hormone secretion in a leukaemic girl with hypothalamic syndrome. Acta Paediatr Scand, 66:261, 1977.—The authors report a girl with acute lymphoblastic leukaemia presenting hypothalamic syndrome characterized by meningeal leukaemia, hyperphagia and obesity. Insulin and growth hormone secretion, studied with arginine and insulin stimulation tests, showed a high peak of serum insulin and no response of growth hormone. Insulin and growth hormone responses to these tests reverted to normal after intrathecal methotrexate.     

IMPORTANCE OF INSULIN ABSORPTION, SUBCUTANEOUS BLOOD FLOW, AND RESIDUAL BETA-CELL FUNCTION IN INSULIN THERAPY

Abstract. Lauritzen, T., Binder, C. and Faber, O. K. (Steno Memorial Hospital, Gentofte, Denmark). Importance of insulin absorption, subcutaneous blood flow, and residual beta-cell function in insulin therapy. Acta Paediatr Scand, Suppl. 283: 81, 1980.—The interaction between variation in insulin absorption and beta-cell function was studied as well as the possible relation between subcutaneous blood flow through the region of injection and the variability in insulin absorption. The results indicate that the dose of insulin, the type of insulin preparation and the local blood flow influence the insulin absorption. Residual endogenous insulin secretion, governed by the blood glucose values, serves as a modulator.     

THE EFFECT OF DIETARY RESTRICTION ON INSULIN SECRETION AND GLUCOSE TOLERANCE IN OBESE CHILDREN

A study of 6 obese children was made to test the effect on glucose tolerance and insulin response to glucose of two diets commonly used in therapy. Glucose tolerance was studied after one week on each of three consecutive regimes, a normal diet, a sugar restricted diet and a severe calorie restricted diet. After a normal diet the obese children had slightly impaired glucose tolerance and a very variable insulin response. After restriction of sugar in the diet, insulin response to glucose was diminished without further impairment of glucose tolerance. After a 300 k calorie diet, the children had severe glucose intolerance associated with increased insulin response, and high plasma insulin levels in the latter part of the test.     

GROWTH, BODY WEIGHT AND INSULIN REQUIREMENT IN DIABETIC CHILDREN

ABSTRACT. The weight and height development of 51 boys and 48 girls who had developed diabetes prior to the age of 15 years was followed for a minimum of 3 years, mean 8.3 years, up to the age of 18 for the girls and 20 for the boys. In addition, the insulin requirements were recorded. Weight and height proved to be within the normal range, and height at onset of diabetes was normal. After a long duration of diabetes, however, there occurred a reduction of height increment of about 1/2 cm/year. This reduction was greater in children who rarely attended as compared with those who frequently attended a sub-specialized clinic. The daily dose of insulin increased with age, the greatest increase coinciding with the growth spurt. During the first 4 years of diabetes the 24-hour dose/kg body weight increased, indicating a decreasing endogenous insulin production. Later it was constant at around 0.9 i.u./kg. Modern management of diabetic children leads to normal adult stature.     

EFFECT OF GLUCAGON ON BLOOD GLUCOSE HOMEOSTASIS IN INFANTS OF DIABETIC MOTHERS

ABSTRACT: Wu, P. Y. K., Modanlou, H. and Karelitz, M. (Department of Pediatrics, University of Southern California School of Medicine, Los Angeles County-University of Southern California Medical Center, Los Angeles, USA). Effect of glucagon on blood glucose homeostasis in infants of diabetic mothers. Acta Paediatr Scand, 64:441, 1975.–Thirty infants of diabetic mothers (IDM) were randomly selected and divided into 3 groups of 10 babies each. Group A were used as controls. Group B received glucagon 300Uµg/kg i.m. and Group C received glucagon 300µg/kg i.v. at birth. Hypoglycemia developed in 6 infants in Group A and 4 infants in Group B. None of the infants in Group C had hypoglycemia. Mean blood glucose was higher in Group C in the first 3 hours than Group A, and higher in Group B in the first 1/2-1 hour. I.v. glucagon, 300µg/kg when given in the first IS minutes after birth prevented hypoglycemia in IDM in the first hours of life.     

THE EFFECT OF FEEDS OF DIFFERING COMPOSITION ON ENTERO-INSULAR HORMONE SECRETION IN THE FIRST HOURS OF LIFE IN HUMAN NEONATES

Abstract. 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.     

Inappropriately high plasma insulin levels in suspected perinatal asphyxia

The aim of this study was to determine differences in levels of the major hormones responsible for glucose homeostasis (insulin and glucagon) in babies with acute neonatal encephalopathy secondary to perinatal asphyxia and to correlate these with outcome. In a prospective observational study, plasma insulin, C-peptide, glucagon and serum glucose levels were determined using standard techniques at specified times in term babies with a diagnosis on admission of perinatal asphyxia or acute neonatal encephalopathy. The setting comprised two university-affiliated, regional, tertiary level neonatal intensive care units. Thirty-one babies with a diagnosis of perinatal asphyxia or acute neonatal encephalopathy were entered into the study over 15 months and neurodevelopmental outcomes at 18 months of age for 28 babies were available for analysis. Babies with a poor neurodevelopmental outcome had significantly higher insulin and C-peptide levels than those who had a good outcome. Glucose delivery, serum glucose and glucagon levels did not differ significantly between the babies with a poor outcome and those with a good outcome. In conclusion, babies with significant foetal or neonatal asphyxia frequently have inappropriately high plasma insulin levels. This, either alone or in combination with other hormonal disturbances, may lead to the hypoglycaemia often associated with severe asphyxia and may predict a poor outcome.     

HUMAN PROINSULIN IN INSULIN-TREATED JUVENILE DIABETICS

Abstract. Human proinsulin was determined in a group of 73 diabetics, aged 5–20 years, with onset of diabetes at the age of 1–16 years and a duration of diabetes of 2–17 years. At the time of the investigation, the patients were receiving conventional 5 times crystallized insulin and all had detectable insulin binding IgC. Because of the binding of human proinsulin to insulin antibodies the serum was extracted with acid ethanol. Proinsulin was then determined in fasting serum after removal of human C-peptide which would have interfered with the proinsulin radioimmunoassay. The detection limit in normal serum not containing antibodies was 0.01 pmol/ml. The detection limit in sera that had to be extracted was approximately 0.05 pmol/ml. 31 of the patients (42 %) had detectable serum proinsulin, ranging from 0.055 to 2.00 pmol/ml. In the same group of patients, 19 (26%) had detectable C-peptide. There was a strong correlation between the concentration of human proinsulin and C-peptide ( P < 0.001). 38 normal fasting sera contained from 0 to 0.033 pmol/ml, mean ±S.D.: 0.009 ± 0.008 pmol/ml. The human proinsulin constituted from 0.1 to 92% of the total immunoreactive insulin (IRI) in the 31 patients with detectable proinsulin (mean: 8.5%). Thus it appears that proinsulin was secreted in 42% of 73 insulin treated juvenile diabetics who had had diabetes for 3–14 years, whereas C-peptide was found in 26% of the patients. The insulin antibodies bind a portion of the secreted proinsulin, prolonging its half-life and increasing its serum concentration. Hence, the levels of proinsulin in patients having insulin antibodies are not comparable to those in persons without antibodies.     

THE ABSORPTION OF INSULIN

Abstract. It is desirable to improve metabolic control in diabetics receiving insulin. Studies on insulin kinetics provide information that may be useful in the optimization of the injection scheme. Absorption has been measured using 1251-insulin as marker and counting the residual activity with a crystal detector. Plasma insulin has been measured (by radio-immunoassay) in the absence of insulin antibodies. The relationship between the rate of absorption and exogenous insulinemia was analyzed using a simple mathematical model. The time course of plasma insulin was calculated for various insulin preparations, including mixtures. The data suggest the significance of the injection site for the effect of insulin, e.g., a more rapid effect atrer injection into the abdominal subcutaneous tissue. The pattern of exogenous insulinemia in patients treated with insulin bears no resemblance to that in normal subjects. The calculated patterns of exogenous plasma insulin aner injection of various preparations suggest that insulin therapy might be improved to obtain a better and more physiological metabolic control.     

SENSORY NERVE CONDUCTION VELOCITY AND VIBRATORY SENSIBILITY IN JUVENILE DIABETICS

ABSTRACT. Ludvigsson, J., Johannesson, G., Heding, L., Häger, A. and Larsson, Y. (Departments of Paediatrics and Neurophysiology, University Hospital Linköping, Sweden and Novo Research Institute, Bagsvaerd, Denmark). Sensory nerve conduction velocity and vibratory sensibility in juvenile diabetics. Relationship to endogenous insulin. Acta Paediatr Scand, 68: 739, 1979.—Sensory nerve conduction velocity (NCV) and the vibratory sense (biothesiometry) were determined in 67 children and adolescents with insulin dependent diabetes. Age at onset of diabetes varied between 1–14 years (mean ±S.D. 6.5±3.6) and the duration of diabetes between 4–17 years (7.7±3.4). Within ±3 months of the nerve function tests blood was drawn for determination of C-peptide and insulin antibodies (IgG and IRI). A low NCV (<50 m/s) in the sural nerve and/or an abnormal vibratory sense (≥1.0 microns) were found in 34 patients (50.7%). Measurable fasting serum C-peptide 0.04–0.60 pmol/ml (0.17±0.15) was found in 16 patients (23.9%). All but one patients had insulin antibodies with IgG 0.130–11.029 mU/ml (2.957±2.509) and total IRI 10–9120 μU/ml (1204±1723). In multiple regression analysis we did not find any correlation between nerve function and sex, age, or age at onset of diabetes, and there was only a weak relationship between NCV and duration. However, there was a positive correlation between NCV and C-peptide (p<0.001). Vibration sense was also better among patients with C-peptide (p<0.05). The results support the view that insulin deficiency contributes to peripheral diabetic neuropathy.     

C-PEPTIDE IN JUVENILE DIABETES

Abstract. C-peptide can be used as a measure of endogenous insulin secretion in insulin treated diabetics with insulin antibodies. At the onset of juvenile diabetes insulin production is thought to be absent or minimal, but we have found rather high levels of C-peptide, even in ketoacidotic patients. The ketoacidosis does not mean an irreversible beta cell failure. In the postinitial remission period with stable metabolism many patients have normal or almost normal C-peptide levels and their beta cells have the capacity to respond to natural stimulation with an increased insulin secretion. For some unknown reason the metabolism becomes more labile coinciding with decreasing C-peptide values. However, even several years beyond the postinitial remission period many juvenile diabetics have some persistent beta cell function, and it has been shown that even trace remnants of beta cell function are of importance for stabilization of the metabolism. There is no reason to believe that the beta cell failure should be predetermined e.g. by genetic factors. However, little is known how to influence the progression and stop the increasing beta cell failure. Some of our results suggest that an early detection and an intensive treatment of diabetes before severe metabolic disturbances and pronounced insulin deficiency have appeared, may increase the possibility of preserving some beta cell function.     

GROWTH HORMONE SECRETION IN PROTEIN ENERGY MALNUTRITION

ABSTRACT. Günöz, H., Neyzi, O., Sencer, E., Molvalilar, S. and Argun, A. (Departments of Pediatrics and Internal Medicine, Istanbul Faculty of Medicine, University of Istanbul, Turkey). Growth hormone secretion in protein energy malnutrition. Acta Paediatr Scand, 70: 521,.–Plasma hGH levels were assessed in 15 infants with protein energy malnutrition following insulin induced hypoglycemia, arginine and L-Dopa provocation tests and intravenous glucose tolerance test. Fasting hGH levels were high in 85.7 % of the cases. An adequate hGH response to stimulation was obtained in only 42.8 % of the cases with insulin induced hypoglycemia; in 52.5 % with arginine; in 30.8 % with L-Dopa. Response to at least one type of provocation was obtained in all 5 cases to which all three tests were applied. Exaggerated or delayed response to provocative stimuli was also encountered in a number of the cases. Intravenous glucose tolerance test did not lead to suppression in hGH secretion or to increase in insulin secretion in these subjects. The results indicate that marasmic protein energy malnutrition may lead to defects in the hGH secretory function of the hypothalamopituitary axis.