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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4342-4347
Copyright © 2003 by The Endocrine Society

Neonates with Symptomatic Hyperinsulinemic Hypoglycemia Generate Inappropriately Low Serum Cortisol Counterregulatory Hormonal Responses

K. Hussain, P. Hindmarsh and A. Aynsley-Green

London Center for Pediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children, National Health Service Trust, London, United Kingdom WC1N 3JH; and Institute of Child Health University College, London, United Kingdom WC1N 1EH

Address all correspondence and requests for reprints to: Dr. K. Hussain, Department of Biochemistry, Endocrinology, and Metabolism, Institute of Child Health, University College London, 30 Guilford Street, London, United Kingdom WC1N 1EH. E-mail: k.hussain{at}ich.ucl.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Serum cortisol plays an important role in counterregulation to hypoglycemia. It antagonizes the peripheral effects of insulin and also directly influences glucose metabolism. Classically serum cortisol concentrations rise in response to hypoglycemia, but the response in neonates with hyperinsulinemic hypoglycemia is unclear. To investigate the serum cortisol responses in neonates with hyperinsulinemic hypoglycemia, 13 neonates (34–40 wk gestation; male/female ratio, 7/6) with hyperinsulinemic hypoglycemia underwent diagnostic fasts. The serum cortisol concentration was measured before the commencement of the fast and at the time of hyperinsulinemic hypoglycemia. The hypoglycemia was then treated with iv glucose (1 ml/kg bolus of 10% dextrose), and serum cortisol concentrations were measured at 10-min intervals for a total of 50 min. Six of the 13 neonates had plasma ACTH concentrations measured at the time of hypoglycemia and then received a 62.5-µg iv bolus injection of Synacthen. The mean (±SEM) serum cortisol concentration 15 min before the hypoglycemic episode was 156 ± 24 nmol/liter, and that at the time of hypoglycemia was 182 ± 28 nmol/liter. Mean cortisol concentrations at 10, 20, 30, 40, and 50 min for the first seven neonates who were not given Synacthen at the time of hypoglycemia were 213 ± 44, 223 ± 48, 209 ± 49, 228 ± 46, and 252 ± 30 nmol/liter, respectively. The six neonates who received an iv bolus dose of Synacthen had significantly greater (P < 0.01) serum cortisol concentrations at the same time points, 208 ± 39, 219 ± 46, 378 ± 139, 664 ± 57, 905 ± 121, 1048 ± 247, and 1192 ± 105 nmol/liter, respectively. Plasma ACTH levels were inappropriately low in all six neonates at the time of hypoglycemia (mean plasma ACTH concentration, 13.2 pg/ml). Neonates with hyperinsulinemic hypoglycemia fail to generate an adequate serum cortisol counterregulatory hormonal response. This appears to be related to the lack of drive from the hypothalamic-pituitary axis, with inappropriately low plasma ACTH concentrations at the time of hypoglycemia. The normal serum cortisol response to an iv bolus injection of Synacthen suggests that this is a centrally mediated phenomenon and does not imply that these patients have adrenal insufficiency.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE COUNTERREGULATORY hormone cortisol plays an essential role in the maintenance of a normal blood glucose concentration. Cortisol has numerous effects on glucose metabolism, the most important of which include the stimulation of gluconeogenesis and antagonizing the actions of insulin. The glycemic threshold, that is, the concentration of blood glucose that stimulates the release of cortisol, lies just within the physiological range of plasma glucose and is thought to be about 3.5 mmol/liter in adults (1). This glycemic threshold for the release of cortisol is higher than the threshold for symptoms (1).

Although cortisol is released at the glycemic threshold level, the physiological effects of cortisol on glucose metabolism generally take several hours to become manifest (2). The effects of cortisol on glucose production occur earlier than its effects on glucose utilization (2).

At birth, mixed cord blood cortisol concentrations are relatively high (~880 nmol/liter) (3); this reflects the maternal transfer of steroids and the stress of delivery. By 24 h of age, cortisol concentrations fall rapidly to about 270 nmol/liter (3), and by d 3 of life the normal cortisol values range between 46.9 and 385.4 nmol (4). From birth, both cortisol and ACTH are released in a pulsatile fashion, with secretory bursts at intervals of 1–2 h. Initially these secretory bursts have a high frequency, low amplitude pattern, followed by a low frequency, high amplitude pattern. The circadian rhythm of ACTH and cortisol release is not established until about 3 months of age (5).

Neonates can generate adequate serum cortisol concentrations in response to stress. A study by Anand et al. (6) demonstrated that neonates undergoing cardiac surgery have cortisol responses in excess of 750 nmol/liter. Another study by Hughes et al. (7) demonstrated that preterm neonates undergoing intensive care have serum cortisol concentrations above 2200 nmol/liter. As hypoglycemia is considered to be a severe form of a stressful stimulus (8) neonates with hypoglycemia would be expected to show a significant cortisol response to hypoglycemia. In neonates, as in adults, a serum cortisol response to the stressful stimulus of hypoglycemia is defined as adequate if serum cortisol concentrations rise above 500 nmol/liter at the time of hypoglycemia (9, 10, 11, 12).

Hyperinsulinism in infancy (HI) is the most common cause of recurrent and persistent hypoglycemia in the neonatal period (13). It is characterized by the inappropriate and excessive secretion of insulin from the pancreatic ß-cells. The most common cause of HI is due to mutations in the genes regulating the function of the KATP channel located on the ß-cell membrane (14). The KATP channels are composed of two proteins, SUR 1 and KIR6.2, and play a unique role in stimulus secretion coupling whereby they link the metabolism of glucose to regulated insulin secretion (15). Neonates with HI have been shown to generate the poorest serum cortisol responses to hyperinsulinemic hypoglycemia (16). Whether this poor serum cortisol response is related to lack of drive from the hypothalamic-pituitary-adrenal axis, in some way to the central actions of insulin, or to the timing of sample collection is not clear.

To address these possibilities we studied the serum cortisol, ACTH, and GH responses to hyperinsulinemic hypoglycemia in 13 neonates with HI.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A total of 20 neonates were referred for investigation and management of hyperinsulinemic hypoglycemia to a tertiary referral center over an 18-month period. Neonates with a diagnosis of cortisol deficiency or insufficiency, those with any evidence of a midline anatomical lesion, those receiving hydrocortisone or diazoxide therapy, those subjected to perinatal asphyxia, and infants of diabetic mothers were excluded from the study. The study had ethical approval from the ethics committee of Great Ormond Street Hospital and the Institute of Child Health, and written informed consent was obtained from the parents or guardians.

Of the seven neonates that were excluded, two had cortisol deficiency (due to septo-optic dysplasia), four were already commenced on diazoxide and hydrocortisone at the referring hospital, and one infant did not have secure central venous access for blood sampling. The gestational age of the patients ranged between 34–42 wk, birth weight ranged from 2.0–5.6 kg, and the maximum glucose infusion rate was between 12 and 23 mg/kg·min.

Each of the enrolled neonates underwent a diagnostic fast. No child was hypoglycemic 72 h before commencement of the fast. Normoglycemia was maintained during these 72 h by continuous iv infusion of glucose through a central indwelling catheter. The controlled diagnostic fast involved stopping all enteral feeding and iv glucose. Blood glucose concentrations were measured at 10- to 20-min intervals before and during the fast. The diagnostic fast was terminated when the laboratory plasma glucose concentration was 2.6 mmol/liter or earlier if the child became symptomatic. All patients developed hypoglycemia within 1 h of stopping the iv glucose infusion (range, 30–60 min). The hypoglycemic event was then treated with either iv glucose (1 ml/kg of a 10% dextrose bolus), followed by a continuous infusion of glucose. Each child had blood withdrawn for measurement of the serum cortisol concentration through an indwelling iv catheter at baseline and then at 15-min intervals throughout the fast at the time of hypoglycemia and once the hypoglycemic event was treated at 10-min intervals for 50 min after the fast was terminated. In six neonates, blood samples for plasma ACTH were collected at the time of hypoglycemia. This group of neonates then received a 62.5-µg bolus injection of iv Synacthen (Alliance Pharmaceuticals, Ltd., Chippenham, Wiltshire, UK) (17) at the time of hypoglycemia, and blood was sampled again for serum cortisol measurements at 10-min intervals for 50 min. The other hormones and intermediary metabolites measured at baseline and at the time of hypoglycemia were serum insulin, serum GH, serum nonesterified fatty acids, and serum ketone bodies (acetoacetate and 3ß-hydroxybutyrate). All 13 neonates became hypoglycemic during the study, and all demonstrated symptoms (drowsy, sweating, and tachycardia) of hypoglycemia. Throughout the fast the patients were monitored and assessed by the principal investigator (K.H.) and a nurse.

Hormonal assays

Blood samples for the measurement of serum cortisol were centrifuged and separated for immediate storage at -20 C until they were ready to be analyzed. Serum cortisol measurements were performed on 20 µl plasma using a Coat-A-Count cortisol RIA (Diagnostic Products, Los Angeles, CA). The coefficient of variation for the intraassay was 3.0–5.1%, and that in the interassay was 4.0–6.4%. This procedure can detect as little as 0.2 µg/dl cortisol. The antiserum is highly specific for cortisol, with very low cross-reactivity to other compounds that might be present in the patients’ samples. This assay has a cross-reactivity of 0.94% with corticosterone, 0.98% with cortisone, and 0.26% with 11-deoxycorticosterone.

Plasma ACTH and insulin concentrations were measured using the Immulite system (Diagnostic Products). The Immulite Automated Immunoassay Analyzer is a continuous random access instrument that performs automated chemiluminescent immunoassays.

Serum GH concentrations were measured using an immunoradiometric assay (Tandem-R HGH, Hybritech Assay, Liege, Belgium). The Hybritech assay is highly specific for GH, with a cross-reactivity of less than 1% with other hormones. The sensitivity of the assay was 0.2 ng/ml. This assay is highly specific for the 22-kDa form of GH, with very little cross-reactivity.

Statistics

The serum cortisol, GH, and ACTH results are expressed as the mean ± SEM. Mean values were compared using the standard t test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The hormone and intermediary metabolite results at the time of hyperinsulinemic hypoglycemia are shown in Table 1Go. The mean serum cortisol concentration was 156 ± 24 nmol/liter for the whole cohort before the hypoglycemic episode and 182 ± 28 nmol/liter at the time of hyperinsulinemic hypoglycemia. There was no significant difference between these means. The individual serum cortisol responses at the time of hypoglycemia are shown in Fig. 1Go. All 13 neonates showed inappropriately low serum cortisol responses for the degree and severity of hypoglycemia. In contrast, all 13 neonates showed elevated serum GH responses (Fig. 2Go).


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  		TABLE 1. Results of the diagnostic fast showing the hormones and intermediary metabolites at the time of hyperinsulinemic hypoglycemia

 


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  		FIG. 1. Serum cortisol response to hyperinsulinemic hypoglycemia.

 


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  		FIG. 2. Serum GH response to hyperinsulinemic hypoglycemia.

 
The mean serum cortisol concentrations at 10, 20, 30, 40, and 50 min for the first seven neonates who were not administered iv Synacthen at the time of hyperinsulinemic hypoglycemia were 213 ± 44, 223 ± 48, 209 ± 49, 228 ± 46, and 252 ± 30 nmol/liter, respectively, and those for the six neonates who received Synacthen at the time of hypoglycemia were 208 ± 39, 219 ± 46, 378 ± 139.1, 664 ± 57, 905 ± 121, 1048 ± 247, and 1192 ± 105 nmol/liter, respectively. There was a significant difference (P < 0.01) between the mean serum cortisol concentrations in the Synacthen group and those in the non-Synacthen group. Figures 3Go and 4Go show the different serum cortisol responses in the two groups of neonates.



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  		FIG. 3. Serum cortisol changes in babies not given Synacthen.

 


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  		FIG. 4. Serum cortisol changes in babies given 62.5 µg Synacthen.

 
Plasma ACTH concentrations were inappropriately low in all six neonates (mean concentration at the time of hyperinsulinemic hypoglycemia, 13.2 pg/ml; Fig. 5Go).



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  		FIG. 5. ACTH levels at the time of hypoglycemia.

 
GH data were analyzed for 12 infants because 1 infant did not have enough serum for analysis. The mean serum GH was 50.7 ± 9.5 mU/liter before hypoglycemia and 55.7 ± 10.0 mU/liter at the time of hyperinsulinemic hypoglycemia. The mean serum GH values at 10, 20, 30, 40, and 50 min posthypoglycemia were 69.8 ± 10.5, 74.4 ± 12.2, 81.7 ± 12.3, 77.1 ± 13.1, and 69.2 ± 12.3 mU/liter, respectively. Serum GH levels were elevated even before the onset of hypoglycemia, with no significant incremental rise at the time of hypoglycemia or for 50 min posthypoglycemia. Figure 6Go shows the sequential changes in the serum GH response.



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  		FIG. 6. Serum GH changes at the time of hyperinsulinemic hypoglycemia.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
These data demonstrate that neonates with hyperinsulinemic hypoglycemia have inappropriately low serum cortisol responses. This inappropriately low serum cortisol response was maintained over the period of sampling for 50 min in the group that was not administered Synacthen at the time of hypoglycemia. In the group that was administered an iv bolus dose of Synacthen at the time of hypoglycemia, there was a significant (P < 0.01) increase in the mean serum cortisol concentrations by 20 min. The serum cortisol concentration continued to increase up to the end of the sampling period. In the six neonates in whom plasma ACTH was measured at the time of hypoglycemia, it was inappropriately low for the degree and severity of hypoglycemia.

Neonates with hyperinsulinemic hypoglycemia require large amounts of dextrose to maintain normoglycemia. The normal glucose requirement of 4–6 mg/kg·min is significantly increased, sometimes up to 20 mg/kg·min (18). During the diagnostic fast these neonates can become hypoglycemic rapidly (within 30 min) when the iv fluids are stopped. Hence, one possibility for why they may be mounting such a poor serum cortisol counterregulatory response is related to the rapidity with which the blood glucose concentration drops, not allowing the counterregulatory drive to switch on. There may well be a time lag before serum cortisol is released, because serum cortisol release is dependent on ACTH. The continuation of sampling for serum cortisol for 50 min posthypoglycemia in this study should detect any delayed serum cortisol response. The inappropriately low plasma ACTH concentration at the time of hypoglycemia suggests that the mechanism for the poor serum cortisol response may well be located at the level of the pituitary or hypothalamus.

As babies with HI are subject to recurrent hypoglycemic episodes, it could be argued that previous episodes of hypoglycemia alter the counterregulatory hormonal responses to subsequent episodes of hypoglycemia. Studies in adults, for example, show that acute (19) or intermittent (20) hypoglycemia may modulate counterregulatory hormonal responses to subsequent hypoglycemic events. Prior recurrent or persistent hypoglycemic episodes reduced serum cortisol responses compared with a single hypoglycemic event (19). Possible explanations for this include central nervous system adaptation to hypoglycemia or hormonal depletion due to repeated episodes of hypoglycemia. The former hypothesis is supported by studies in which rats rendered either continuously (insulinoma or insulin pump) or intermittently (daily insulin injections) hypoglycemic for 4 d were found to have an increase in blood brain glucose transport (21). In our patients with HI there was no hypoglycemia in the preceding 72 h before the fast was commenced, and we were able to demonstrate adequate serum cortisol responses upon ACTH administration. These patients were not cortisol depleted, but lacked the drive from ACTH stimulation. In contrast, all 13 neonates showed appropriate and, in some cases, exaggerated GH responses to the stimulus of hypoglycemia. The fact that serum GH was elevated at the time of hypoglycemia makes it unlikely that recurrent or intermittent hypoglycemia 72 h before the fast is responsible for the low serum cortisol response.

Babies with HI have inappropriately high insulin levels in relation to their blood glucose concentration, and hence, insulin per se may have a role in modulating the counterregulatory hormonal responses to hypoglycemia. It is now clear that insulin has access to the blood-brain barrier and can exert widespread modulatory influences on a number of important neuronal pathways (22). Insulin receptors are localized in the hypothalamus, and insulin-sensitive neurons are present in other parts of the central nervous system (23, 24). It has been shown that intrahypothalamic hyperinsulinism in newborn rats causes malformations and morphological alterations in hypothalamic nuclei, especially ventromedial (VMN) and lateral hypothalamic area (LHA) nuclei, which are thought to play an important role as glucosensors (25). The fact that the ACTH level is inappropriately low for the degree of hypoglycemia suggests that there may be a central component to this poor cortisol response.

Further compelling evidence that insulin itself may modulate the counterregulatory hormonal response is provided by a study by Davis et al. (26). In this study an adult patient with insulinoma showed a 63% reduction in the cortisol counterregulatory hormonal response to hypoglycemia. After resection of the insulinoma, cortisol counterregulatory responses normalized.

It is well established that the VMN and LHA areas of the brain are the glucose-responsive regions (25). The specialized neurons in these regions respond to changes in extracellular glucose as a result of KATP channel expression (27). As in the pancreatic ß-cell, these channels link cell excitability with the metabolic status of the cell. The KATP channel in the VMN region is thought to be similar to the pancreatic ß-cell, with SUR-1 and KIR 6.2 components, and to be responsive to diazoxide as well as tolbutamide (28). Hence, theoretically, babies with HI who have mutations in the genes encoding SUR-1 and KIR6.2 may also have impaired function of the glucose-responsive neurons in the hypothalamic area.

In conclusion, neonates with symptomatic hyperinsulinemic hypoglycemia fail to generate an adequate serum cortisol counterregulatory hormonal response. This appears to be related to the lack of drive from the hypothalamic-pituitary axis, with inappropriately low plasma ACTH concentrations at the time of hypoglycemia. The normal serum cortisol response to iv bolus injection of Synacthen suggests that this is a centrally mediated phenomenon and does not imply that these patients have adrenal insufficiency. As KATP plays a key role as the glucose sensor in VMN and LHA, further studies are needed to determine whether patients with defects in pancreatic KATP channels have impaired counterregulatory hormonal responses.


   Footnotes
 
Some of this work was undertaken by Great Ormond Street Hospital for Children National Health Service Trust, who received a proportion of its funding from the National Health Service Executive. The views expressed in this publication are those of the authors and are not necessarily those of the National Health Service Executive.

Abbreviations: HI, Hyperinsulinism in infancy; LHA, lateral hypothalamic area; VMN, ventromedial nucleus.

Received January 27, 2003.

Accepted June 4, 2003.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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