The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 8 3715-3723
Copyright © 2003 by The Endocrine Society
Spontaneous Hypoglycemia in Childhood Is Accompanied by Paradoxically Low Serum Growth Hormone and Appropriate 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 WC1N 3JH, United Kingdom; and Institute of Child Health, University College London, London WC1N 1EH, United Kingdom
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 WC1N 1EH, United Kingdom. E-mail: k.hussain{at}ich.ucl.ac.uk.
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Abstract
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Hypoglycemia is a potent stimulus for GH and cortisol secretion. The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol responses from the hypothalamic-pituitary-adrenal axis. The serum GH and cortisol responses to spontaneous hypoglycemia in 22 children were compared with those of 16 children undergoing an ITT for diagnostic purposes. The mean serum GH and cortisol concentrations 1 h before spontaneous hypoglycemia were 6.9 ± 1.1 mU/liter and 424 ± 51 nmol/liter, respectively, and at the time of spontaneous hypoglycemia they were 6.7 ± 1.3 mU/liter and 601 ± 66 nmol/liter, respectively. The mean serum GH and cortisol values at +10, +20, +30, +40, and +50 min from the time of hypoglycemia were 5.4 ± 1.0, 4.7 ± 0.7, 4.6 ± 1.0, 5.4 ± 1.4, and 5.5 ± 1.3 mU/liter and 633 ± 69, 645 ± 71, 668 ± 70, 680 ± 72, and 662 ± 77 nmol/liter, respectively. There was no significant difference between any of these means for GH secretion. In contrast, in the ITT the mean serum GH concentration before hypoglycemia was 5.1 ± 1.3 mU/liter, and at the time of hypoglycemia it was 29.2 ± 7.30 mU/liter. The difference between these means was highly significant (P < 0.01, by t test). There was no significant difference between the cortisol response to spontaneous hypoglycemia and that to the ITT. Physiological changes in the serum nonesterified fatty acid concentration had no significant effect on serum GH secretion. In conclusion, the mechanism(s) of the serum GH response to spontaneous hypoglycemia is different from that due to the ITT. A low GH level detected at the time of spontaneous hypoglycemia does not necessarily imply GH deficiency or GH as a cause of the hypoglycemia.
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Introduction
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THE SECRETION OF GH and cortisol from pituitary somatotrophs and corticotrophs, respectively, is controlled by a complex interaction of factors. Two neuropeptides, GHRH and somatostatin (SS), interact to control the release of GH. GHRH is stimulatory whereas SS is inhibitory to the somatotrophs. It is thought that pulses of GHRH are secreted into the hypophysial portal blood during troughs of SS release (1), but the main determinant of pulsatile GH release is the GHRH pulse occurring at the times of a nadir in SS release (2). Recently, a novel stomach-derived peptide called ghrelin has been shown to be an important endogenous regulator of GH secretion (3).
The secretion of cortisol from the adrenal gland is regulated by ACTH. The release of ACTH from the anterior pituitary is, in turn, regulated by CRF from the hypothalamus. ACTH is secreted in regular pulses of variable amplitude over 24 h, with most secretion occurring during the night; this forms the basis for the circadian rhythm for cortisol secretion (4). Cortisol feedback occurs at the level of the pituitary, with high serum concentrations inhibiting further ACTH secretion.
A number of provocation tests are available for assessing the function of the anterior pituitary axis (5). Each of these tests involves administering a certain stimulus and measuring the hormonal response produced to that stimulus. For assessment of serum GH and ACTH secretion and hence cortisol, the insulin-induced hypoglycemia test (ITT) is most often used. Stress resulting from the hypoglycemia induced by this test is the stimulus for the release of GH and ACTH.
During the ITT, significant changes in the serum concentrations of GH and cortisol occur at or just after the hypoglycemic stimulus is achieved, some 20–30 min after the administration of insulin. As yet, the precise mechanism by which the ITT stimulates GH and cortisol release is not clear.
As hypoglycemia is a potent stimulus for the release of serum GH and cortisol, both counterregulatory hormones would be expected to increase in response to spontaneous and ITT-induced hypoglycemia. Morris et al. (6) reviewed all of the diagnostic fasts performed in a tertiary referral center over a 2.5-yr period and found that there was poor correlation of GH response to spontaneous hypoglycemia. Although the serum GH response to ITT-induced hypoglycemia is well documented, the reasons for the observed lack of GH response to spontaneous hypoglycemia are unclear. It may be due to the pulsatile nature of GH secretion or the time of blood sampling. We have investigated the serum GH and cortisol responses to spontaneous hypoglycemia (before, during, and after the hypoglycemic stimulus) in 22 children and compared their serum GH and cortisol responses to those observed in 16 children undergoing ITT.
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Subjects and Methods
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A total of 80 children were referred for investigation of hypoglycemia to a tertiary referral center over an 18-month period. Children with a diagnosis of GH or cortisol deficiency or insufficiency, those with any evidence of midline anatomical lesions, those with psychological dwarfism, and neonates were excluded from the study. The study received 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 80 children referred, 20 were excluded because of the above exclusion criteria. Of the remaining 60 children, 13 were neonates with hyperinsulinism of infancy (HI) who were also excluded from the study and formed part of a separate study. Hence, 47 children were recruited into the final study. Each of the enrolled children underwent a diagnostic fast, the length of which was determined by a set unit protocol. The diagnostic fast involved stopping all of the enteral and iv feeds. Blood glucose concentrations were measured hourly during the fast. The diagnostic fast was terminated if the laboratory plasma glucose concentration was 2.6 mmol/liter or if the child became symptomatic. The hypoglycemic event was then treated with either iv fluids (1 ml/kg 10% dextrose) or if the child tolerated enteral feeds. Each child had blood withdrawn for the measurement of serum GH and cortisol concentrations through an indwelling iv catheter at hourly intervals throughout the fast. Blood samples for serum GH and cortisol measurements were then taken at the time of hypoglycemia and, once the hypoglycemic event was treated, at 10-min intervals for 50 min after the fast was terminated. This sampling interval of 10 min was chosen to detect pulses of GH secretion. The GH and cortisol blood samples were centrifuged and separated for immediate storage at -20 C until they were ready to be analyzed. The other metabolites measured at the commencement of the fast and at the time of hypoglycemia were serum nonesterified fatty acids (NEFA) and serum ketone bodies (acetoacetate and 3ß-hydroxybutyrate). The acetoacetate was precipitated by the bedside by the addition of perchloric acid. Of the 47 children enrolled into the study, 22 became hypoglycemic during the study. None of these children had any hypoglycemic episodes 5 d before the diagnostic fast. All of these children had normal growth velocity and normal height for age. Sixteen separate children underwent the ITT for diagnostic purposes. These children were fasted overnight and had a standard ITT test in the morning (0.1 U/kg bolus of insulin). Blood glucose concentrations were measured at -30 min, 0, 20, 30, 45, and 60 min. The test was terminated when the blood glucose concentration decreased to 2.6 mmol/liter or the child became symptomatic. Blood samples for the measurement of serum GH and cortisol concentrations were taken at 0 and 30 min. The ages, heights, weights, and body surface area of the two groups and the diagnostic categories causing hypoglycemia are shown in Tables 1
and 2, respectively.
Assays
Serum GH concentrations were measured using an immunoradiometric assay (Tandem-R HGH, Hybritech, Leige, 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 (1 ng/ml = 2.6 mU/liter). This assay is highly specific for the 22-kDa form of GH with very little cross-reactivity.
Serum cortisol concentrations were measured using the Coat-A-Count cortisol RIA (Diagnostic Products, Los Angeles, CA). The coefficient of variation for the intraassay was between 3.0–5.1%, and that for the interassay was between 4.0–6.4%. This procedure can detect as little as 0.2 µg/dl cortisol (1 µg/dl = 28.8 nmol/liter). 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.
Glucose and NEFA measurements
The plasma glucose concentration was measured using the standard glucose oxidase method.
The plasma concentration of NEFA was determined using the Cobras Mira Plus Analyzer (Roche, Indianapolis, IN). The principle of the method is based on the fact that NEFA, when reacted with acyl-coenzyme A (CoA) synthase in the presence of AMP, magnesium cations, and CoA, form thiol esters of CoA known as acyl CoA as well as the by-products of AMP and pyrophosphate. In the second part of the reaction, the acyl CoA is oxidized by added acyl-CoA oxidase to produce hydrogen peroxide, which in the presence of added peroxidase allows the oxidative condensation of 3-methyl-N-ethyl-N-(ß-hydroxyeth)-aniline with 4-aminoantipyrine to form a purple adduct with an absorption maximum of 550 nm. The amount of NEFA in the sample can be determined from the OD measured at 550 nm.
Statistics
Mean serum GH and cortisol concentrations at various time points were compared by Student’s t test and ANOVA. P < 0.01 was considered significant.
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Results
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Serum GH responses to spontaneous and ITT-induced hypoglycemia
The serum GH and cortisol concentrations before, at, and after spontaneous hypoglycemia are shown in Table 3. The serum GH and cortisol concentrations in response to ITT-induced hypoglycemia are shown in Table 4.
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TABLE 3. Serum GH/cortisol concentrations at different time points and plasma glucose concentration at the time of hypoglycemia (1 ng/ml = 2.6 mU/liter)
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The serum GH concentrations at the time of hypoglycemia in both the spontaneous and ITT groups are shown in Fig. 1. An appropriate serum GH response to spontaneous hypoglycemia was defined as a rise in the serum GH concentration greater than 15 mU/liter. The mean serum GH concentration at the time of spontaneous hypoglycemia was 6.7 ± 1.3 mU/liter. Only one child in the spontaneous hypoglycemia group had a significant serum GH response to hypoglycemia.
In contrast, in the ITT group all children tested had a serum GH concentration greater than 15 mU/liter at the time of hypoglycemia (Fig. 1
). The mean serum GH value at the time of hypoglycemia induced by the ITT was 29.2 ± 7.30 mU/liter. There was no correlation (r = -0.27) between the blood glucose concentration and the serum GH concentration in the ITT group. One child had a blood glucose concentration of 2.9 mmol/liter yet generated an adequate serum GH response to the hypoglycemic stimulus. Blood glucose concentrations achieved at the time of hypoglycemia were otherwise comparable to those in the group with spontaneous hypoglycemia.
The serum GH profiles over time in response to spontaneous hypoglycemia and ITT-induced hypoglycemia are shown in Figs. 2 and 3, respectively. The mean serum GH values in children with spontaneous hypoglycemia at 10, 20, 30, 40, and 50 min after hypoglycemia were 5.4 ± 1.0, 4.7 ± 0.7, 4.6 ± 1.0, 5.4 ± 1.4, and 5.5 ± 1.3 mU/liter, respectively. There was no significant difference between these mean serum GH values (range of P values, 0.37–0.9) over the period of sampling.
The baseline mean serum GH value in the ITT group was 5.1 ± 1.3 mU/liter. This reflects the serum GH response to an overnight fast. These children maintained normal blood glucose concentrations throughout the overnight fast. Hypoglycemia was then induced by the administration of insulin, and the mean serum GH concentration rose to 29.2 ± 7.3 mU/liter at 30 min. There was a significant difference between these means (P < 0.01).
Influence of physiological NEFA concentrations on serum GH responses
The effect of the NEFA concentration generated by spontaneous hypoglycemia on serum GH levels is shown in Fig. 4. The lowest NEFA concentrations were seen in the children with HI, whereas the highest NEFA concentrations were present in the children with a fatty acid oxidation disorder. Regression analysis showed no correlation between the serum GH level and changes in the serum NEFA concentration (r = -0.06). These results suggest that physiological changes in serum NEFA concentrations do not have any significant effect on serum GH secretion.
Serum cortisol response to spontaneous and ITT-induced hypoglycemia
The serum cortisol responses to spontaneous and ITT-induced hypoglycemia are shown in Fig. 5. Eight children with spontaneous hypoglycemia had a serum cortisol response less than 500 nmol/liter. These eight children included five children with hyperinsulinism. One of these children with hyperinsulinism had the lowest serum cortisol level (116 nmol/liter) in the entire cohort. The other three children included two with ketotic hypoglycemia and one with glycogen storage disease 1A. The mean serum cortisol value for the entire cohort at the time of spontaneous hypoglycemia was 601 ± 66 nmol/liter. In the ITT group only one child had a serum cortisol concentration less than 500 nmol/liter. The mean serum cortisol value at the time of hypoglycemia induced by the ITT was 778 ± 66 nmol/liter.
Serum cortisol profiles in response to spontaneous and ITT-induced hypoglycemia are shown in Figs. 6 and 7, respectively. The mean serum cortisol concentration at 60 min before the onset of hypoglycemia was 424 ± 51 nmol/liter. The mean serum cortisol concentration at the time of hypoglycemia was 601 ± 66 nmol/liter. The mean serum cortisol concentrations at 10, 20, 30, 40, and 50 min after hypoglycemia were 633 ± 69, 645 ± 71, 668 ± 71, 680 ± 72, and 662 ± 78 nmol/liter, respectively. The changes in the other mean values were not significant. Of the eight patients with a serum cortisol level less than 500 nmol/liter at the time of hypoglycemia, only one failed to generate a serum cortisol above 500 nmol/liter at 30 min. The increase in serum cortisol persisted for the entire period of sampling. These results suggest that the maximum incremental rise in serum cortisol in response to spontaneous hypoglycemia occurs within the first 60 min leading up to the hypoglycemia. The maximal serum cortisol values are reached at 40 min after hypoglycemia. This increase in serum cortisol concentrations continues for at least 50 min from the time of correction of the hypoglycemia.
The mean baseline serum cortisol value before the onset of hypoglycemia induced by ITT was 396 ± 63 nmol/liter. This again reflects the cortisol response to an overnight fast in these children. At the time of hypoglycemia the mean serum cortisol value increased to 778 ± 66 nmol/liter. The difference between these means was highly significant (P < 0.01). These results suggest that the hypoglycemia induced by the ITT is sufficient to generate an appropriate serum cortisol response.
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Discussion
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GH and cortisol play an essential role in glucose counterregulation after an episode of hypoglycemia (7, 8). Although GH and cortisol are released immediately in response to hypoglycemia, the counterregulatory metabolic effects of these hormones do not become manifest for several hours (8).
GH and cortisol have numerous effects on glucose metabolism, including increasing the rates of gluconeogenesis and glycolysis and antagonizing the effects of insulin. In adults, the glycemic thresholds for the activation of glucose counterregulatory hormones such as GH and cortisol lies within or just below the physiological blood glucose concentration and is slightly higher than the threshold for symptoms (9). This implies that GH and cortisol secretion increases in response to blood glucose concentrations within the normoglycemia range, and it is thought that these increases are inversely proportional to the nadir in blood glucose (10).
The lack of a serum GH response to spontaneous hypoglycemia observed in the present study has been noticed previously (11), but the underlying mechanism has not been explored. The present study has also shown that the serum GH responses in spontaneous hypoglycemia are different from those in hypoglycemia induced by the ITT.
The inappropriately low serum GH response observed in spontaneous hypoglycemia could be due to several different factors. Given that GH is secreted in a pulsatile fashion, one possibility is that the pulses of GH secretion may not be detected. This is unlikely, as the sampling interval of 10 min encompasses the half-life of GH, which is approximately 7–15 min (12). Further, the timing of the samples with respect to the point of hypoglycemia ensured that a 50-min posthypoglycemia period was covered.
Another possible reason for the difference in serum GH response to spontaneous hypoglycemia compared with the ITT may be related to the rapidity with which hypoglycemia is achieved. In our cohort of children with spontaneous hypoglycemia there was a gradual spontaneous reduction in the level of blood glucose concentration (minimum of 1 h in the hyperinsulinemic children to a maximum of 18 h in the ketotic hypoglycemic children), whereas in the ITT the blood glucose was rapidly lowered, with significant hypoglycemia induced within 15–20 min. This suggests that the rate of fall of the blood glucose concentration with respect to time may be an important determinant in signaling GH secretion. Ameil et al. (13) showed, using glucose patch-clamp techniques, that the rate of fall in the blood glucose concentration does not affect the counterregulatory responses to hypoglycemia in normal and diabetic adults. This study suggested that the counterregulatory hormone response to hypoglycemia was triggered by the glucose level per se and not by the rate of fall in blood glucose. No such studies have been performed in children. Studies in children with insulin-dependent diabetes mellitus when hypoglycemic show vigorous GH and cortisol counterregulatory responses (13). The rate of fall in the blood glucose concentration does not affect the hierarchy of the counterregulatory hormonal responses to hypoglycemia (14).
In both the ITT and spontaneous hypoglycemia groups, the levels of hypoglycemia ranged from 1.2–2.9 mmol/liter. Thus, the inappropriately low serum GH responses cannot be due to a difference in the level of hypoglycemia achieved between the two groups.
The ITT is performed after an overnight fast. During the fast insulin secretion is inhibited, allowing an increase in the counterregulatory hormones. These hormones will increase NEFA and ketone body concentrations. Fasting studies in adults have shown that serum cortisol increases during the fast, whereas serum GH levels are not significantly elevated (15). By giving a bolus of insulin during the ITT, this prevailing metabolic milieu is rapidly changed, with insulin causing suppression of NEFA release and ketone body formation. It is possible that this sudden change in the metabolic milieu caused by the administration of insulin may also be a trigger for the glucosensors in the hypothalamus.
Studies in adults have shown that increases in plasma NEFA levels inhibit GH responses to a variety of pharmacological and physiological stimuli (16). As GH plays an important role in intermediary metabolism, a feedback relationship has been postulated between plasma NEFA concentrations and GH (17). Pharmacological reductions in circulating NEFA cause GH release, and NEFA elevations reduce or block GH secretion stimulated by a variety of physiological or pharmacological conditions (18, 19). It is thought that NEFA block GH secretion by acting directly at the level of the pituitary gland and block GHRH-stimulated GH secretion (16). In the present study plasma NEFA concentrations ranged from 0.05–3.5 mmol/liter. The lowest plasma NEFA concentration occurred in the group with HI due to the dominant anabolic effects of insulin inhibiting the lipolytic response to hypoglycemia. The highest plasma NEFA concentration was found in children with the fatty acid oxidation disorder and those with ketotic hypoglycemia. Children with HI have the lowest documented plasma NEFA concentrations, and they would be expected to generate the highest serum GH responses. In our study we found no significant difference in the serum GH responses between children with low or high plasma NEFA, in contrast with the studies by Casanueva et al. (16). One reason for this difference could be related to the high pharmacological concentrations of NEFA used in the studies by Casanueva et al. to assess the GH response to GHRH. The highest plasma NEFA concentration in our group of children was 3.5 nmol/liter. This is the normal physiological concentration of NEFA for this group.
The other major difference between hypoglycemia induced spontaneously and that induced by the ITT is related to the administration of iv insulin. This raises the question of whether iv insulin administration itself has a role in modulating GH release from anterior pituitary somatotrophs. It is now well established that insulin rapidly crosses the blood-brain barrier by a receptor-mediated transport mechanism that involves insulin receptors expressed by brain microvessels (20). Insulin receptor substrate-1 and insulin receptors are also coexpressed in discrete populations of neurons, suggesting probable transduction mechanisms by which insulin may influence metabolism in the brain (21). It is suggested that specific insulin receptors are located on the arcuate and paraventricular nuclei of the hypothalamus and, when stimulated with insulin, send inhibitory impulses to the vagus and excitatory impulses to the sympathetic nuclei (22). This is then thought to trigger the release of CRF, which stimulates cortisol release, but suppresses GH secretion (23). This central action of insulin might explain why low serum GH levels were observed in our group of older children with hyperinsulinism, as they all had elevated serum insulin levels at the time of hypoglycemia. However, this mechanism does not explain the inappropriately low serum GH responses observed in the ketotic group as well as in the other nonhyperinsulinemic hypoglycemic groups in which serum insulin levels were undetectable at the time of hypoglycemia.
The precise mechanism by which the ITT induces GH response is not clear, nor is it known what concentrations of insulin are achieved in the plasma or cerebrospinal fluid when an iv bolus of insulin is given during the ITT. West et al. (24) reported that it was the hypoglycemic stimulus per se, rather than insulin, that was the triggering factor for GH release. Shibasaki et al. (25) suggested that the ITT stimulates GH release through a mechanism that is largely independent of GHRH. Page et al. (26) showed that hypoglycemia induced by the ITT releases GH through inhibition of SS secretion, and data from animal work have demonstrated that glucose can alter hypothalamic SS release through a direct action (27).
In summary, this study has highlighted the different serum GH and cortisol responses to hypoglycemia induced by the ITT and induced spontaneously. The different serum GH responses to ITT and spontaneous hypoglycemia may be related to the rate of change in the blood glucose concentration as well as the rate of change in the metabolic milieu when insulin is administered, but the mechanism is unclear. Further work is needed to understand the precise mechanism by which the ITT induces serum GH secretion.
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Footnotes
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Some of this work was undertaken by Great Ormond Street Hospital for Children National Health Service Trust, which 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: CoA, Coenzyme A; HI, hyperinsulinism of infancy; ITT, insulin tolerance test; NEFA, nonesterified fatty acid; SS, somatostatin.
Received January 28, 2003.
Accepted April 29, 2003.
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References
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Abstract
Introduction
, GH to ITT-induced hypoglycemia; 
, GH to spontaneous hypoglycemia.
