help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jackson, L.
Right arrow Articles by Hume, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jackson, L.
Right arrow Articles by Hume, R.
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6251-6256
Copyright © 2004 by The Endocrine Society

Plasma Catecholamines and the Counterregulatory Responses to Hypoglycemia in Infants: A Critical Role for Epinephrine and Cortisol

Lesley Jackson, Fiona L. R. Williams, Ann Burchell, Michael W. H. Coughtrie and Robert Hume

Maternal and Child Health Sciences (L.J., A.B., R.H.), Community Health Sciences (F.L.R.W.), and Pathology and Neurosciences (M.W.H.C.), University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Professor Robert Hume, Maternal and Child Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, United Kingdom. E-mail: r.hume{at}dundee.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The purpose of this study was to define plasma catecholamine responses as part of the counterregulatory hormonal reaction to hypoglycemia in infants after a regular 3- to 4-h feed was omitted. Hormone levels were assessed once, at the end of the fast or at hypoglycemia. The 121 infants were subdivided into three groups for analysis: normoglycemia (n = 94, 78%); transient hypoglycemia (n = 11, 9%); or severe and persistent hypoglycemia (n = 16, 13%). The severe and persistent hypoglycemic group had significantly higher levels of cortisol and epinephrine than the normoglycemic group. Norepinephrine and glucagon levels did not differ between the groups. Human GH levels were higher in the transiently hypoglycemic group but not in the severe and persistent hypoglycemic group. Prefeed blood lactate levels differed significantly among the groups and were highest in the severe and persistent groups. Multiple regression analysis showed that cortisol levels were significantly higher in infants who had severe and persistent hypoglycemia. The counterregulatory hormonal response in infants to severe and persistent hypoglycemia was limited to elevations in only cortisol and epinephrine levels but did not involve glucagon or human GH. This limited hormonal response may also contribute to the frequent occurrence of hypoglycemia in these infants.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE HUMAN BRAIN is dependent on a continuous supply of glucose for energy needs. It is essential that blood glucose levels be always maintained within a controlled range as the brain has minimal glycogen reserves and a limited supply of alternative substrates.

The fetus in utero is supplied with a constant transplacental source of maternal glucose. At birth this supply is abruptly terminated, and the infant must adapt to a state of independent and appropriate blood glucose homeostasis. In the immediate newborn period, the maintenance of blood glucose levels is dependent on mobilization of liver glycogen stores, the establishment of adequate nutritional intakes, and the maturation of key liver enzyme systems controlling gluconeogenesis and glycogenolysis (1). Hepatic glucose-6-phosphatase (G-6-Pase) is the common terminal enzymatic step for the pathways of glycogenolysis and gluconeogenesis (2), and genetic deficiencies of hepatic G-6-Pase (type I glycogen storage diseases) are severe metabolic disorders characterized by fasting hypoglycemia (3). Hepatic G-6-Pase activity is expressed at only low levels in the human fetus in utero (4). Most term infants increase hepatic G-6-Pase activities to adult levels within a few days of birth (4). In many preterm infants this increment in enzyme activity fails to occur (5, 6). This delayed postnatal appearance of hepatic G-6-Pase and glucose production (7) in preterm infants makes them potentially susceptible to repeated hypoglycemic episodes. This may result in cerebral damage and puts them at risk of sudden and unexpected death (8, 9, 10, 11, 12).

We have shown previously that 18% of a consecutive series of preterm infants at the time of discharge home were unable to maintain normal concentrations of blood glucose after a single routine feed was omitted (13). Cortisol, corticotropin, and blood lactate levels were higher in infants with severe and persistent hypoglycemia but insulin, glucagon, and human GH (hGH) did not differ from infants who remained normoglycemic (13). These results appear to indicate that the counterregulatory hormonal response to hypoglycemia was limited to activation of the hypothalamic-pituitary-adrenocortical axis, but the contribution of catecholamines to glucose homeostasis in these infants was not explored.

Catecholamines have important roles in the regulation of blood glucose levels in adult humans (e.g. Ref.14) and to adaptations of glucose homeostasis to extrauterine life in animal studies (15, 16). Their role in the regulation of glucose homeostasis in infants has not been extensively defined (17, 18), and indeed plasma catecholamines levels and their metabolites have not previously been studied in infants after the first postnatal week (19, 20, 21, 22, 23).

The aim of our study was to further define the roles of epinephrine and norepinephrine in the counterregulatory responses to spontaneous hypoglycemia occurring in infants when a single routine feed was omitted.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We recruited a cohort of preterm infants (64 infants, 24–36 wk gestation) who were admitted to the neonatal intensive care unit, Ninewells Hospital and Medical School, Dundee, and who survived to discharge home at 37 wk mean corrected gestation. There were no exclusion criteria. Infants were on no medications at the time of the study apart from routine iron and vitamin supplementations. A cohort of term infants was also recruited (57 infants, 37–42 wk gestation) primarily on the basis of small for gestational age, birth weight less than the 10th centile. These criteria were set because these infants could be potentially vulnerable to hypoglycemia. The study period was June 2000 to March 2002. The Tayside Medical Research Ethics Committee approved the study protocol. Informed written parental consent was obtained.

Neonatal blood glucose measurements, over the first 5 d, were taken on all infants in the study, and the number of episodes of blood glucose levels less than 2.6 mmol/liter was recorded and defined as neonatal hypoglycemic episodes.

Preterm infants were studied at the time of discharge home and term infants at 14 postnatal days. Extensive epidemiological data were collected on each infant; this included maternal health, both generally and in pregnancy; prescribed medication in pregnancy; disorders of pregnancy; details of delivery and resuscitation; neonatal morbidity; and any medications prescribed (24). Birth weight ratios (25) and study weight ratios (13) were calculated for each infant. These ratios are standardized to the Scottish mean birth weight for each gestational week and for males and females separately. Anthropometric measurements recorded included crown-heel length; crown-rump length; occipital-frontal circumference; midarm and leg circumferences; and waist, chest, and hip circumferences. Ponderal indices, midarm circumference, and occipitofrontal circumference ratios were calculated. Skin-fold thickness was measured using Holtain calipers, using a standardized technique (26) and only one operator (L.J.), at the following sites: biceps, triceps, anterior and posterior thigh, suprailiac crest ,and infrascapular; the z score of the sum of these measurements was used as a proxy for total body fat.

It is standard practice in the United Kingdom to measure blood glucose levels in the early newborn period in all infants admitted to neonatal units and to feed preterm infants initially by the parenteral route or by continuous or frequent bolus nasogastric milk feeds, usually hourly. Thereafter when blood glucose levels are apparently stable, it is not normal practice to routinely measure blood glucose concentrations, and most infants will advance to an increased reliance on enteral nutrition and a progression from hourly to 4-h feeds. Blood glucose levels are measured in term infants with identifiable risk factors for hypoglycemia, and they are discharged when normoglycemic. On the study day, all infants were on regular 3- to 4-h feeds. An in-dwelling venous cannula for blood sampling was sited at around 3 h from the start of the last feed. Blood glucose and lactate concentrations were measured 4 h from the start of the last feed. The next scheduled feed was omitted, and blood glucose and lactate concentrations were measured 2 and 4 h later. The infants were studied immediately before their intended discharge home. This study design was selected because it mimics the natural progression in feeding patterns toward longer intervals and omission of a feed, which would be expected for many infants post discharge home. Hypoglycemia was predefined as a blood glucose concentration less than 2.6 mmol/liter. The study was discontinued if two consecutive blood glucose levels were less than 2.6 mmol/liter. Insulin, glucagon, cortisol, hGH, and a range of catecholamines were measured at the end of the infant’s fast (prefeed); the state of arousal of the infant at the time of blood sampling was recorded (sleeping, fractious, or crying). Transient hypoglycemia was defined as one measurement recorded less than 2.6 mmol/liter with spontaneous recovery. Severe and persistent hypoglycemia was defined as at least two episodes recorded less than 2.6 mmol/liter.

All blood glucose and lactate samples were analyzed on-site using the 2300 Stat plus glucose analyzer (Yellowsprings Inc., Yellow Springs, OH). Three plasma hormones levels were measured by the Department of Biochemical Medicine, Ninewells Hospital and Medical School: cortisol using ADVIA Centaur assay (Bayer Diagnostic, Leuverkusen, Germany) and hGH using IMMULITE assay (Olympus Diagnostic System, Southall, UK). Insulin was measured using the IMx system (Abbott Laboratories, Diagnostic Division, Tokyo, Japan). N-terminal glucagon levels were determined by RIA at the Metabolic Laboratory, Royal Victoria Hospital, Belfast, Northern Ireland.

Norepinephrine (NE), norepinephrine sulfate (NE sulfate), epinephrine (EPI), epinephrine sulfate (EPI sulfate), dihydroxyphenylglycol (DHPG), and DHPG sulfate were measured after extraction from plasma using an alumina extraction procedure and then separated and quantified by liquid chromatography with electrochemical detection (27). The interassay coefficients of variation within and above the normal range were for EPI 10.4–18.5% and 3.6–6.5% and for NE 3.0–4.3% and 1.8–4.6%, respectively. Interassay coefficient of variation for DHPG was 8.6%. Intraassay coefficients of variation were EPI 13.4%, NE 6.8%, and DHPG 4.8%.

Plasma amino acids, free fatty acids, 3-hydroxybutyrate, urinary amino acids, and organic acids were also measured (by the Department of Biochemical Medicine, Ninewells Hospital and Medical School using routine procedures) in hypoglycemic infants so that recognized metabolic disorders could be excluded.

Statistical analysis

Means and SDs were calculated for all the variables; one extreme measurement for glucagon of 2000 ng/liter in one infant was excluded from statistical analysis. Differences between and within groups were found by ANOVA and by using the t test for unequal variance for determining the specific differences. The association among: EPI, NE, and metabolites; cortisol; glucagon; and hGH was quantified in a correlation matrix (Spearman’s rho).

Logistic regression analysis was used to determine the influence of various factors (explanatory variables) on glycemic status (Table 1Go). The explanatory variables were derived from the significant results of the bivariate analysis. The Wald {chi}2 and the odds ratios (with 95% confidence intervals) were used to assess the importance of each explanatory variable, adjusted for the other factors in the model.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Characteristics (±SD) of the infant study groups with differences between hypoglycemic groups assessed by one-way ANOVA

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
One hundred twenty-one infants were recruited into the study. After the controlled fast, 94 infants remained normoglycemic throughout (lowest blood glucose values of 3.07 ± 0.32 mmol/liter), 11 were transiently hypoglycemic (lowest blood glucose values of 2.39 ± 0.15 mmol/liter), and 16 had severe and persistent hypoglycemia (lowest blood glucose values of 1.97 ± 0.41 mmol/liter). There were no differences among the groups in gestation at delivery, birth weight, or birth weight ratios (Table 1Go). All infants were studied at a similar corrected gestational age. The infant weight at the time of study was lower in the severe and persistently hypoglycemic group (Table 1Go) than in the normoglycemic group. The study weight ratio showed the same trend. Cortisol levels and the mean number of neonatal hypoglycemic episodes were significantly higher in the severe and persistent hypoglycemic group, compared with the normoglycemic group (Table 1Go). hGH levels were higher in the transiently hypoglycemic group but not in the severe and persistent hypoglycemic group (Table 1Go). Glucagon levels did not differ among the groups (Table 1Go). Prefeed blood glucose levels, which were taken immediately before the feed at the end of the fast, were significantly lower in the transient and severe and persistent hypoglycemic groups. Between-group differences were evident for prefeed blood lactate levels, which were taken immediately before the feed at the end of the fast, with the severe and persistent group having the highest levels (Table 1Go).

NE levels did not differ among the groups. DHPG levels were marginally raised in the severe and persistent hypoglycemic group, compared with the normoglycemic group (Table 2Go). EPI levels were significantly higher in the severe and persistent hypoglycemic group, compared with the normoglycemic group (Table 2Go).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Levels of catechols and their metabolites (mean ± SD) of the infant groups at the time of study, with differences between hypoglycemic groups assessed by one-way ANOVA

 
Analysis of the associations among the levels of catechols, cortisol, hGH, glucagon, prefeed blood glucose, and blood lactate resulted in many significant correlations (Table 3Go). Cortisol levels were positively and significantly associated with EPI, EPI sulfate, NE, DHPG, DHPG sulfate, and prefeed blood lactate levels but negatively associated with hGH and prefeed blood glucose levels. EPI levels were positively associated with cortisol, NE, DHPG, and prefeed blood lactate levels. NE was positively associated with DHPG and prefeed blood lactate levels (Table 3Go).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Significant correlations (Spearman’s rho) between catechols and their metabolites, cortisol, human GH, glucagon, and prefeed blood glucose levels (significance taken as P < 0.005 using Bonferroni correction for multiple testing)

 
All the variables that were either significantly associated with glycemic status in the bivariate analysis or were supported by the literature were entered into the multiple regression model, they included arousal, study weight ratio, gestation, EPI, DHPG, cortisol, insulin, hGH, and prefeed lactate (Table 4Go). Only cortisol was independently and significantly associated (P < 0.005) with whether the infant was normoglycemic or severe and persistent hypoglycemic.


View this table:
[in this window]
[in a new window]
  		TABLE 4. Multiple logistic regression analysis, dependent variable normoglycemia vs. severe and persistent hypoglycemia

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Overall the results from this study support the findings of a previous study that investigated glycemic status in preterm infants at time of discharge home (13). In that study, the corticotrophin and cortisol levels were elevated in the severe and persistently hypoglycemic group, but insulin, hGH, and glucagon levels were not different, compared with normoglycemic infants. In the present study, similar hormonal results were obtained, but hGH was elevated in the transient hypoglycemic group but not in the severe and persistent hypoglycemic group. Similar to the previous study, cortisol levels were elevated in the severe and persistent hypoglycemic group. For effective counterregulation, cortisol and hGH are both required because an absence of either is not compensated for by larger responses from EPI and glucagon (28). These apparent dissociations of cortisol and hGH levels in response to hypoglycemia in our infants may be a reflection of a developing and as yet not fully coordinated hormonal counterregulatory response to low blood glucose levels. Ethical constraints limit blood volumes sampled from infants. A series of sequential samples could therefore not be obtained to determine the temporal pattern of the counterregulatory response; thus, it is possible that peak levels of hormones were missed.

The blood glucose level of less than 2.6 mmol/liter taken as the definition of hypoglycemia was based on the neuroglycemic responses to induced hypoglycemia (29) and on a study of preterm infants in which values of blood glucose less than 2.6 mmol/liter were associated with abnormal neuromotor and intellectual performance (8). The definition of what constitutes hypoglycemic blood glucose levels in infants remains contentious (e.g. Refs.30, 31), but evidence to support a level higher than 2.6 mmol/liter is lacking.

In adults a blood glucose level of 3.2 mmol/liter is the threshold for the cortisol response (32). A similar threshold is suggested in infants and children older than 6 months who are spontaneously hypoglycemic, but in infants younger than 3 months, there is no difference in cortisol levels between those who are hypoglycemic (<2.5 mmol/liter) and those who are normoglycemic (33). It is possible that with recurrent spontaneous hypoglycemia in these young infants (<3 months) cortisol reserves are depleted (33); in contrast, our hypoglycemic infants have elevated cortisol levels in response to a comparatively short period of hypoglycemia (maximum 2 h). Cortisol depletion cannot be the complete explanation because preterm infants can maintain very high cortisol levels over a prolonged period in response to the stress of illness (34).

hGH levels in our infants are similar to previously fasted normoglycemic and hypoglycemic infants before discharge from the hospital (13) and also to infants younger than 3 months with spontaneous hypoglycemia whether or not hypoglycemic at sampling (33). Although hGH responses to spontaneous hypoglycemia in older infants (>6 months) and children are reduced in magnitude, indirect evidence suggests that the glycemic threshold of 3.7 mmol/liter is similar to that of adults (32, 33).

In adults EPI constitutes more than 80% of adrenal catecholamine secretion (35) and increases more than NE levels in response to stressful conditions such as hypoglycemia, reflecting relatively greater adrenomedullary hormonal than sympathetic neuronal activation (36). Our infants with severe and persistent hypoglycemia show a similar pattern; EPI levels are significantly higher, but NE levels are the same. In a recent large and well-controlled study of nonstressed children (5–17 yr), basal levels of EPI were higher (particularly in boys) than those of adults, but NE levels were similar (37). A similar study is required with comparable data from children who are stressed by illness or hypoglycemia.

In normal adults EPI transiently increases hepatic glycogenolysis followed by a sustained increase in hepatic and renal gluconeogenesis (38, 39). Lactate is the predominant gluconeogenic substrate of EPI-stimulated gluconeogenesis in both liver and kidney (40), with glycerol, alanine, and glutamine of lesser importance (40, 41). In our study there was a significant trend toward higher lactate levels in infants with severe and persistent hypoglycemia, as in our previous study (13). This suggests increased EPI levels are affecting a compensatory metabolic response but with insufficient glucose production to correct the hypoglycemia, but other gluconeogenic substrates or hepatic glycogen levels were not determined to assess sufficiency for glucose synthesis.

Glucagon and EPI are important in limiting the glucose nadir and promoting rapid recovery from transient hypoglycemia of rapid onset in adults (42) and also in countering slow-onset but progressive hypoglycemia (43). This study confirmed our previous observations (13) that increases in plasma glucagon are not a feature of our infants with severe and persistent hypoglycemia. Glucagon release by pancreatic {alpha}-cells is stimulated directly by low blood glucose levels (44) or indirectly by autonomic inputs from sympathetic (NE) and parasympathetic (acetylcholine) innervations as well as adrenal medulla (EPI) (45). Glucagon release is inhibited by local insulin production (45). Regulation of glucagon release is complex, but the nature of the failed response to low blood glucose levels in our infants is not obvious. There is also a very limited glycemic response to exogenous glucagon stimulation in such infants (46), which is also present in the early neonatal period in preterm infants (van Kempen, A., personal communication), but not later in infancy (47). These data suggest that, during the developmental phase of our study, EPI rather than glucagon is the major acute regulator of glycogenolysis and gluconeogenesis.

Cortisol and EPI are interrelated in a number of ways. High intraadrenal steroid levels are required for production of catecholamines in the human adrenal medulla (e.g. Ref.48), and plasma EPI levels in many situations vary more closely with those of corticotropin than those of NE (49). Cortisol and EPI levels were both elevated in our infants with severe and persistent hypoglycemia, and cortisol levels were significantly correlated to not only EPI levels but also NE.

In diabetes mellitus antecedent hypoglycemia causes defective glucose counterregulation, in particular a reduction in the EPI response and an absent glucagon response, (e.g. Ref.50); these changes may be mediated by elevations in cortisol levels (51, 52, 53). In healthy adults, antecedent hypoglycemia reduces EPI, NE, and glucagon responses to subsequent hypoglycemia, with GH and cortisol responses reduced or unaltered (51, 54, 55). It is standard practice to monitor blood glucose levels in the early neonatal period in preterm and other vulnerable infants and, once these levels are apparently stable, to discontinue further monitoring and progress feeding to 4-h intervals. However, the number of hypoglycemic episodes during the first five postnatal days reflects the glycemic status at the time of study; suggesting an underlying developmental disorder in glucose homeostasis. It is possible, particularly in our group with severe and persistent hypoglycemia, that some infants had episodes of low blood glucose in the days before the test. If infants respond to antecedent hypoglycemia in the same manner as adults, this may have modified the hormonal responses to the controlled test fast.

Insulin inhibits gluconeogenesis and acts predominantly by suppressing the expression of the genes for the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and G-6-Pase. The expression of the genes for G-6-Pase and phosphoenolpyruvate carboxykinase is induced by glucagon, glucocorticoids, and catecholamines (see review in Ref.56). The molecular bases of delayed postnatal development of hepatic G-6-Pase in infants are not known, but dysfunctional postnatal endocrine regulation is likely to be a contributory factor. Our preterm infants were studied at between 1 and 13 wk of age. Severe and persistent hypoglycemia was associated with elevated plasma EPI concentrations. This is contrary to previous studies in the early neonatal period (17, 18). These differences suggest that ontogenic studies of catecholamine responsiveness to glycemic status are required in preterm infants and that these studies are related to gestational and postnatal age.

Infants with severe and persistent low blood glucose values are not sufficiently distinctive from normoglycemic infants to identify them accurately on clinical grounds. This is our second series of preterm infants we have described in which asymptomatic hypoglycemia is common at the time of discharge home; we now show the same phenomenon in growth-restricted term infants. Until this work is repeated by other researchers in other populations and it is determined whether this observed hypoglycemia is detrimental to neurodevelopmental outcome, we recommend that the feeding regimen in preterm and growth-restricted term infants be frequent and regular with a low threshold for readmission at times of metabolic stress.


   Acknowledgments
 
The authors thank the parents of participating infants and the staff of the neonatal unit for their enthusiastic support. We thank Truc Huynh for help with the catechols assays and Graeme Eisenhofer for his considerable help in the preparation of the manuscript. We acknowledge the assistance of the Department of Biochemical Medicine in sample preparation under the supervision of Judith Strachan.


   Footnotes
 
This work was supported by Tenovus (Scotland) and Paediatric Metabolic Fund.

Abbreviations: DHPG, Dihydroxyphenylglycol; EPI, epinephrine; G-6-Pase, glucose-6-phosphatase; hGH, human GH; NE, norepinephrine.

Received March 22, 2004.

Accepted September 21, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Aynsley-Green A, Soltesz G 1985 In: Aynsley-Green A, Chambers TL, eds. Hypoglycaemia in infancy and childhood. Current reviews in paediatrics. Edinburgh: Churchill Livingstone
  2. Burchell A, Allan BB, Hume R 1994 The endoplasmic reticulum glucose phosphatase proteins. Mol Membr Biol 11:217–227[Medline]
  3. Chen Y-T, Burchell AM 1995 Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill; 935–965
  4. Burchell A, Gibb L, Waddell ID, Giles M, Hume R 1990 The ontogeny of the human hepatic glucose-6-phosphatase proteins. Clin Chem 36:1633–1637[Abstract/Free Full Text]
  5. Hume R, Lyall H, Burchell A 1992 Impairment of the activity of the microsomal glucose-6-phosphatase system in premature infants. Acta Paediatr 81:580–584[Medline]
  6. Hume R, Burchell A 1993 Abnormal expression of glucose-6-phosphatase in preterm infants. Arch Dis Child 68:202–204[Abstract/Free Full Text]
  7. van Kempen AAMW, Romijn JA, Ruiter AFC, Endert E, Weverling GJ, Kok JH, Sauerwein HP 2003 Alanine administration does not stimulate gluconeogenesis in preterm infants. Metabolism 52:945–949[CrossRef][Medline]
  8. Lucas A, Morley R, Cole TJ 1988 Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. BMJ 297:1304–1308
  9. Lyall H, Burchell A, Howie PW, Ogsten S, Hume R 1994 Early detection of metabolic abnormalities in preterm infants impaired by disorders of blood glucose concentration. Clin Chem 40:526–530[Abstract/Free Full Text]
  10. Duvanel CB, Fawer C-L, Cotting J, Hohlfeld P, Matthieu J-M 1999 Long-term effects of neonatal hypoglycaemia on brain growth and psychomotor development in small-for-gestational-age preterm infants. J Pediatr 134:492–498[CrossRef][Medline]
  11. Cowett RM 1999 Neonatal hypoglycaemia: a little goes a long way. J Pediatr 134:389–391[CrossRef][Medline]
  12. Burchell A, Lyall H, Busuttil A, Bell J, Hume RM 1992 Glucose metabolism and hypoglycaemia in SIDS. J Clin Pathol 45(11 Suppl):39–45
  13. Hume R, McGeechan A, Burchell A 1999 Failure to detect preterm infants at risk of hypoglycemia before discharge. J Pediatr 134:499–502[CrossRef][Medline]
  14. Cryer PE 1997 Hypoglycemia. pathophysiology, diagnosis and treatment. New York: Oxford University Press; 85–125
  15. Sperling MA, Ganguli S, Leslie N, Landt K 1984 Fetal-perinatal catecholamine secretion: role in perinatal glucose homeostasis. Am J Physiol 247:E69–E74
  16. Padbury JF, Martinez AM 1988 Sympathoadrenal system activity at birth: integration of postnatal adaptation. Semin Perinatol 12:163–172[Medline]
  17. Hawdon JM, Weddell A, Aynsley-Green A, Ward Platt MP 1993 Hormonal and metabolic response to hypoglycaemia in small for gestational age infants. Arch Dis Child 68:269–273[Abstract/Free Full Text]
  18. Ekblad H, Kero P, Korvenranta H, Scheinin M 1992 Sympathoadrenal activity in preterm infants during the first five days of life. Biol Neonate 61:294–301[Medline]
  19. Lagercrantz H, Bistoletti P 1977 Catecholamine release in the newborn infant at birth. Pediatr Res 11:889–893[Medline]
  20. Eliot RJ, Lam R, Leake RD, Hobel CJ, Fisher DA 1980 Plasma catecholamine concentrations in infants at birth and during the first 48 hours of life. J Pediatr 96:311–315[CrossRef][Medline]
  21. Eichler I, Eichler HG, Rotter M, Kyrle PA, Gasic S, Korn A 1989 Plasma concentrations of free and sulfoconjugated dopamine, epinephrine, and norepinephrine in healthy infants and children. Klin Wochenschr 67:672–675[CrossRef][Medline]
  22. Ratge D, Knoll E, Wisser H 1986 Plasma free and conjugated catecholamines in clinical disorders. Life Sci 39:557–564[CrossRef][Medline]
  23. Schwab KO, Breitung B, von Stockhausen HB 1996 Inappropriate secretion of umbilical plasma catecholamines in preterm compared to term neonates. J Perinat Med 24:373–380[Medline]
  24. Burchell A, McGeechan A, Hume R 2000 Therapeutic insulin and hepatic glucose-6-phosphatase enzyme activity in preterm infants. Arch Dis Child Fetal Neonatal Ed 82:F228–F232.
  25. Morley R, Brooke OG, Cole TJ, Powell R, Lucas A 1990 Birthweight ratio and outcome in preterm infants. Arch Dis Child 65:30–34[Abstract/Free Full Text]
  26. Oakley JR, Parsons RJ, Whitelaw AG 1977 Standards for skinfold thickness in British newborn infants. Arch Dis Child 52:287–290[Abstract/Free Full Text]
  27. Eisenhofer G, Goldstein DS, Stull R, Keiser HR, Sunderland T, Murphy DL, Kopin IJ 1986 Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clin Chem 32:2030–2033[Abstract/Free Full Text]
  28. Bolli GB, Fanelli CG 1999 Physiology of glucose counterregulation to hypoglycemia. Endocrinol Metab Clin North Am 28:467–493[CrossRef][Medline]
  29. Koh THHG, Aynsley-Green A, Tarbit M, Eyre JA 1988 Neural dysfunction during hypoglycaemia. Arch Dis Child 63:1353–1358[Abstract/Free Full Text]
  30. Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R, Kalhan SC 2000 Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics 105:1141–1145[Abstract/Free Full Text]
  31. Schwartz RP 1997 Neonatal hypoglycaemia: how low is too low? J Pediatr 131:171–173[Medline]
  32. Schwartz NS, Clutter WE, Shah SD, Cryer PE 1987 Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 79:777–781
  33. Crofton PM, Midgley PC 2004 Cortisol and growth hormone responses to spontaneous hypoglycaemia in infants and children. Arch Dis Child 89:472–478[Abstract/Free Full Text]
  34. Hughes D, Murphy JF, Dyas J, Robinson JA, Riadfahmy D, Hughes IA 1987 Blood spot glucocorticoid concentrations in ill preterm infants. Arch Dis Child 62:1014–1018[Abstract/Free Full Text]
  35. Eisenhofer G, Rundquist B, Aneman A, Friberg P, Dakak N, Kopin IJ, Jacobs MC, Lenders JW 1995 Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines. J Clin Endocrinol Metab 80:3009–3017[Abstract/Free Full Text]
  36. Goldstein DS, Spanarkel M, Pitterman A, Toltzis R, Gratz E, Epstein S, Keiser HR 1982 Circulatory control mechanisms in vasodepressor syncope. Am Heart J 104:1071–1075[CrossRef][Medline]
  37. Weise M, Merke DP, Pacak K, Walther MM, Eisenhofer G 2002 Utility of plasma free metanephrines for detecting childhood pheochromocytoma. J Clin Endocrinol Metab 87:1955–1960[Abstract/Free Full Text]
  38. Sacca L, Vigorito C, Cicala M, Corso G, Sherwin R 1983 Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans. Am J Physiol Endocrinol Metab 245:E294–E302
  39. Gerich J, Meyer C, Woerle HJ, Stumvoll M 2001 Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24:382–391[Abstract/Free Full Text]
  40. Meyer C, Stumvoll M, Welle S, Woerle HJ, Haymond M, Gerich J 2003 Relative importance of liver, kidney, and substrates in epinephrine-induced increased gluconeogenesis in humans. Am J Physiol Endocrinol Metab 285:E819–E826
  41. Stumvoll M, Meyer C, Perriello G, Kreider M, Welle S, Gerich J 1998 Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity. Am J Physiol Endocrinol Metab 274:E817–E826
  42. Cryer PE, Gerich J 1983 Relevance of glucose counter-regulatory systems to patients with diabetes: critical roles of glucagon and epinephrine. Diabetes Care 6:95–99[Abstract]
  43. De Feo P, Perriello G, De Cosmo S, Ventura MW, Campbell PJ, Brunetti P, Gerich JE, Bolli GB 1986 Comparison of glucose counter-regulation during short-term and prolonged hypoglycemia in normal humans. Diabetes 35:563–569[Abstract]
  44. Pipeleers DG, Schuit FC, Van Schravendijk CF, Van de Winkel M 1985 Interplay of nutrients and hormones in the regulation of glucagon release. Endocrinology 117:817–823[Abstract/Free Full Text]
  45. Taborsky Jr GJ, Ahrén B, Havel PJ 1998 Autonomic mediation of glucagon secretion during hypoglycemia implications for impaired-cell responses in type 1 diabetes. Diabetes 47:995–1005[Abstract]
  46. Jackson L, Burchell A, McGeechan A, Hume R 2003 An inadequate glycaemic response to glucagon is linked to insulin resistance in preterm infants? Arch Dis Child Fetal Neonatal Ed 88:F62–F66
  47. Chanoine J-P, Rebuffat E, Kahn A, Bergmann P, Van Vleit G 1995 Glucose, growth hormone, cortisol, and insulin responses to glucagon injection in normal infants, aged 0.5–12 months. J Clin Endocrinol Metab 80:3032–3035[Abstract/Free Full Text]
  48. Weise M, Mehlinger SL, Drinkard B, Rawson E, Charmandari E, Hiroi M, Eisenhofer G, Yanovski JA, Chrousos GP, Merke DP 2004 Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high-intensity exercise. J Clin Endocrinol Metab 89:591–597[Abstract/Free Full Text]
  49. Goldstein DS, Eisenhofer G, Kopin IJ 2003 Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther 305:800–811[Abstract/Free Full Text]
  50. Cryer PE 2001 Hypoglycemia-associated autonomic failure in diabetes. Am J Physiol Endocrinol Metab 281:E1115–E1121
  51. Davis SN, Shavers C, Costa F, Mosqueda-Garcia R 1996 Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. J Clin Invest 98:680–691[Medline]
  52. Galassetti P, Mann S, Tate D, Neill RA, Costa F, Wasserman DH, Davis SN 2001 Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab 280:E908–E917
  53. McGregor VP, Banarer S, Cryer PE 2002 Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia. Am J Physiol Endocrinol Metab 282:E770–E777
  54. Davis SN, Shavers C, Davis B, Costa F 1997 Prevention of an increase in plasma cortisol during hypoglycemia preserves subsequent counterregulatory responses. J Clin Invest 100:429–438[Medline]
  55. Heller SR, Cryer PE 1991 Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in nondiabetic humans. Diabetes 40:223–226[Abstract]
  56. Barthel A, Schmoll D 2003 Novel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 285:E685–E692



This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
P. J. Rozance, S. W. Limesand, J. S. Barry, L. D. Brown, S. R. Thorn, D. LoTurco, T. R. H. Regnault, J. E. Friedman, and W. W. Hay Jr.
Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1{alpha} mRNA and phosphorylated CREB in fetal sheep
Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E365 - E370.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
K. Hussain, J. Bryan, H. T. Christesen, K. Brusgaard, and L. Aguilar-Bryan
Serum Glucagon Counterregulatory Hormonal Response to Hypoglycemia Is Blunted in Congenital Hyperinsulinism
Diabetes, October 1, 2005; 54(10): 2946 - 2951.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jackson, L.
Right arrow Articles by Hume, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jackson, L.
Right arrow Articles by Hume, R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals