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Abteilung Klinische Endokrinologie, Medizinische Hochschule Hannover, 30623 Hannover, Germany
Address all correspondence and requests for reprints to: Dr. Christof Schöfl, M.D., Abteilung Klinische Endokrinologie, Medizinische Hochschule Hannover, 30623 Hannover, Germany. E-mail: schoefl.christof{at}MH-Hannover.de
Abstract
In humans, the role of hypothalamic centers for activation of counterregulatory release of catecholamines and glucagon during hypoglycemia is unclear. To address this question, we investigated the counterregulatory response to acute insulin-induced hypoglycemia of glucagon, epinephrine, and norepinephrine in eight patients who had undergone transcranial surgery for a craniopharyngioma extending to the hypothalamic region. We compared the patients’ responses with those of four patients suffering from hypopituitarism and of six healthy subjects. After the iv injection of 0.1 U of human insulin per kg of body weight in the patients or 0.15 U in healthy subjects, the plasma glucose concentrations decreased to similar minimum levels within 30 min in all three groups. All subjects recovered spontaneously from hypoglycemia within 2 h. In five of eight craniopharyngioma patients, only a small counterregulatory rise in plasma epinephrine (
2-fold) and norepinephrine could be observed (P < 0.05 for epinephrine and P = 0.22 for norepinephrine vs. healthy controls). During hypoglycemia, virtually no adrenergic symptoms (tremor, heart pounding, and anxiety) were reported by these five patients, and changes in the heart rate were diminished. In three craniopharyngioma patients, the counterregulatory increase in catecholamines was unimpaired, adrenergic symptoms were reported and a rise in heart rate was observed during hypoglycemia. In all craniopharyngioma patients, the counterregulatory glucagon response to hypoglycemia was preserved and orthostasis increased both catecholamines and the heart rate similar to in the patients with hypopituitarism as well as in the healthy controls. Our results demonstrate selective impairment of counterregulatory sympathoadrenal activation in patients who had undergone surgery for a craniopharyngioma extending to the hypothalamic region. This strongly suggests the involvement of hypothalamic centers in hypoglycemia-induced activation of the sympathoadrenal axis in humans. It remains unclear as to whether hypoglycemia-induced glucagon secretion is also controlled by the hypothalamus. However, a common hypothalamic center controlling both counterregulatory catecholamine and glucagon release is unlikely, and sympathoadrenal activation is not required for hypoglycemia-induced glucagon secretion in humans.
A DECREASE IN blood glucose stimulates the secretion of several counterregulatory hormones such as glucagon, catecholamines, cortisol, and GH (1, 2). These hormones act in concert to prevent or correct hypoglycemia. The role and contribution of the individual counterregulatory hormones in the correction of hypoglycemia is relatively well understood (1, 2). The mechanisms, however, and the loci responsible for activation of counterregulatory hormone release are less well defined. In various animal models, conflicting results were reported concerning the tissues that sense hypoglycemia and those which coordinate the counterregulatory endocrine responses (3, 4, 5, 6, 7, 8, 9, 10, 11, 12). More recent studies in rats suggested that nuclei in the ventromedial hypothalamus are involved in the activation of counterregulatory glucagon and catecholamine secretion (13, 14). In humans, however, the role of hypothalamic centers for activation of counterregulatory release of catecholamines and glucagon during hypoglycemia is poorly understood. Evidence that the hypothalamus is involved stems from a patient who suffered from neurosarcoidosis and infiltration of the hypothalamus, and who had a complete loss of the counterregulatory response to hypoglycemia (15). To further explore this question, we investigated the counterregulatory response of glucagon, epinephrine, and norepinephrine in patients who had undergone transcranial surgery for a craniopharyngioma extending to the hypothalamic region. We compared them to a group of patients suffering from hypopituitarism and to a group of normal subjects.
Subjects and Methods
Subjects
Eight patients who received transcranial surgery for a craniopharyngioma extending to the hypothalamic region (group A), four patients with hypopituitarism (group B), and six healthy volunteers (group C) were studied.
Group A: Patients with craniopharyngioma (six males and two females) who were aged 18–46 yr (mean ± SEM 34 ± 3.5 yr) and had a body mass index (BMI) of 19–38 kg/m2 (mean ± SEM 28.3 ± 1.8 kg/m2). Transcranial surgery was performed 1–16 yr (mean ± SEM 4 ± 2 yr) before this study. Postoperatively, the patients required standard replacement therapy for hypopituitarism (hydrocortisone, levothyroxine, and sexual hormones), and diabetes insipidus (desmopressin). According to their adrenergic counterregulatory response, the patients were divided into groups A1 and A2 (see Results). The BMI of patients in group A1 was 26.6 ± 2 kg/m2 (mean ± SEM, n = 5), and in the patients of group A2 it was 31.1 ± 3.6 kg/m2 (n = 3). Five craniopharyngioma patients suffered from postoperative weight gain (four in group A1 and one in group A2).
Group B: Patients with hypopituitarism (three males and one female) were aged 34–48 yr (mean ± SEM 41 ± 3.2 yr) and had a BMI of 24–28 kg/m2 (mean ± SEM 25.6 ± 1 kg/m2). Causes of the hypopituitarism in these patients were due to transsphenoidal surgery of a chromophobe pituitary adenoma (1 patient), autoimmune hypophysitis (one patient), and empty sella syndrome (two patients). All patients received standard replacement therapy for hypopituitarism (hydrocortisone, levothyroxine, and sexual hormones).
Group C: Healthy volunteers (6 males) aged between 23 and 27 yr (mean ± SEM 24 ± 1.4 yr) had a BMI of 19–26 kg/m2 (mean ± SEM 22.3 ± 2.3 kg/m2). Screening of the volunteers included a medical history, a physical examination, and routine laboratory testing. None of the healthy volunteers had a history or showed signs of complete or partial hypopituitarism. Written informed consent was obtained from each subject, and the study was approved by the local ethical committee.
Study design
All subjects reported to the hospital at 0800 h after an overnight fast of 10–12 h, and the patients were advised to take their regular hormone replacement therapy (hydrocortisone and levothyroxine) between 0600 and 0700 h. An indwelling central venous catheter and an iv cannula in the opposite arm was put in place. Thereafter, the patients rested in a 45-degree position for at least 1 h before the commencement of blood sampling and until the end of the insulin hypoglycemia test.
Insulin hypoglycemia test. Baseline sampling was started at 1000 h and human insulin (0.1 IU/kg body weight in patients and 0.15 IU/kg body weight in healthy volunteers) was administered iv after 10 min. Samples for plasma glucose, plasma catecholamines, and glucagon were taken for 2 h thereafter. Blood samples were drawn every 2 min for determining plasma catecholamines and plasma glucose, and every 4 min for determining plasma glucagon. The samples were collected into prechilled EDTA-containing tubes. The protease inhibitor aprotinin (Bayer Corp., Leverkusen, Germany) at a concentration of 1000 IU/ml blood was added to the blood samples assigned for measuring plasma glucagon. Plasma was separated immediately by use of a refrigerated centrifuge, and stored in aliquots at -70 C (catecholamines) or -20 C (glucagon) until time for analysis. The total volume of blood taken during the test was approximately 150 ml. The venous catheter was kept open by a slow infusion of saline (total volume 250 ml). For subjects safety glucose levels were monitored in parallel by a glucose sensor (Glucometer Elite, Bayer Corp., Leverkusen, Germany) at 2-min intervals. In accordance with Towler et al. 1993 (16) neurogenic (sweating, hunger, tingling, tremor, heart pounding, and anxiety) and neuroglycopenic symptoms (weakness, difficulty in thinking, fatigue, dizziness, and blurred vision) were assessed at baseline (-10 and 0 min), during hypoglycemia (30 and 45 min), and at the end of the test (90 and 120 min). Each symptom was given a score from 0 (none) to 5 (severe). The mean of the two scores for each time segment was taken for further analysis. The neurogenic and neuroglycopenic symptom scores were obtained by adding the scores of the respective symptoms. To calculate the hypoglycemia-induced differences in the adrenergic or cholinergic symptom score, the incremental changes in the respective parameters from baseline to hypoglycemia were added. The heart rate was determined at baseline, during hypoglycemia and at the end of the test.
Orthostasis test. After the insulin-hypoglycemia test, the subjects were allowed to stand-up, and after 10 min blood samples for the measurement of plasma catecholamines were taken. The heart rate was measured before orthostasis and once again after a 10-min time lapse.
Assays
Blood glucose was measured by the glucosedehydrogenase method (Hoffman-LaRoche Inc., Grenzach, Germany). Plasma epinephrine and norepinephrine were determined in duplicate by a single isotope COMT radioenzymatic assay combined with separation of the labeled metabolites by reverse-phase HPLC before scintillation counting (17, 18). The lower detection limit of this method was 5.5 pg/ml (epinephrine) and 7.8 pg/ml (norepinephrine). The intra and interassay coefficients of variation at the relevant plasma concentrations were 5.2% and 8.8% for epinephrine, and 4.6% and 7.2% for norepinephrine, respectively. Plasma glucagon was measured by a commercial RIA (DPC Biermann GmbH, Bad Nauheim, Germany). The intra and interassay coefficients of variation were 4.4% and 5.7% in the relevant range. All samples were assayed in duplicate and the samples of one subject were analyzed in the same run to avoid interassay variation.
Statistics
Data are presented as the mean ± SEM. Statistical analysis was performed by ANOVA, followed by Fisher’s protected least significant difference test to analyze differences between the groups. The two-tailed paired t test was used to analyze the effects of hypoglycemia and orthostasis on heart rate, epinephrine and norepinephrine within groups as indicated in the text. Fisher’s r to z transformation was applied to determine statistical significance of correlation coefficients. All calculations were performed using StatView software for the Macintosh (Abacus, Berkeley, CA). The level of significance was taken as P < 0.05.
Results
Insulin-induced hypoglycemia
Plasma glucose.
In the craniopharyngioma patients (group A) and in the patients with hypopituitarism (group B), baseline plasma glucose concentrations were 4.2 ± 0.3 mmol/liter (n = 8) and 4.1 ± 0.1 mmol/liter (n = 4) respectively, which was lower than in group C (4.8 ± 0.2 mmol/liter, n = 6, P = 0.0003 vs. group A and B). In all three groups including the subgroups A1 and A2 (see below), the plasma glucose concentrations declined to similar minimum levels within 30 min after the iv insulin bolus (Fig. 1
). All subjects recovered spontaneously from hypoglycemia within a period of 2 h. For patients of group A and group B, the time course of recovery was slower and the plasma glucose concentrations reached at the end of the test were lower than in group C (Fig. 1). In healthy subjects, plasma glucose amounted to 4.9 ± 0.3 mmol/liter on termination of the test, whereas plasma glucose was 3.7 ± 0.3 mmol/liter in craniopharyngioma patients (P = 0.001 vs. healthy controls) and 3.3 ± 0.4 mmol/liter in patients with hypopituitarism (P = 0.0006 vs. healthy controls). These values tended to be lower than at baseline in both groups (P = 0.016 for group A, P = 0.16 for group B).
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). In the eight craniopharyngioma patients, plasma epinephrine rose 4.7 ± 2.2-fold (range 1.4–19.7), which tended to be lower than in the controls (P = 0.11). In five of the eight patients, however, only a small rise in plasma epinephrine could be observed ( 2-fold), and which was clearly below the normal range (Fig. 2A). In these 5 patients (group A1) plasma epinephrine increased from 122 ± 17 pg/ml at baseline to 221 ± 36 pg/ml (1.7 ± 0.2-fold, range 1.4–2.0), which was significantly lower than in the healthy controls (P = 0.01). In the other 3 patients (group A2) plasma epinephrine concentrations rose 9.3 ± 2.6-fold (range 4.1–19.7, P = 0.84 vs. healthy controls) as depicted in Fig. 2A. In patients with hypopituitarism in group B, hypoglycemia induced a 7 ± 1.2-fold rise in epinephrine (range 4.5–13, n = 4, P = 0.51 vs. healthy controls, Fig. 2A). Plasma norepinephrine concentrations at baseline were 255 ± 47 pg/ml (group A), 214 ± 67 pg/ml (group B), and 243 ± 30 pg/ml (group C). In group C, hypoglycemia caused a 2.3 ± 0.3-fold (range 1.3–3.4, n = 6) increase in plasma norepinephrine (Fig. 2B). In the eight craniopharyngioma patients, plasma norepinephrine rose 2.0 ± 0.5-fold (range 1.3–5.4, P = 0.66 vs. healthy controls). In the five patients of group A1, however, plasma norepinephrine levels rose only 1.4 ± 0.1-fold (range 1.3–1.9), which was lower than in healthy subjects (P = 0.22), whereas, however, norepinephrine increased 2.9 ± 1.2-fold (range 1.6–5.4) in the three patients of group A2. Patients with hypopituitarism had a 2.6 ± 0.5-fold (range 1.5–3.9, n = 4) increase in plasma norepinephrine, which was similar to that of the healthy controls as shown in Fig. 2B. Taking the groups on the whole (group A, B, and C), a high correlation was observed between the hypoglycemia-induced increases in plasma epinephrine and norepinephrine (r = 0.80, P = 0.0001, n = 18).
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). In group C, hypoglycemia caused a 2.2 ± 0.1-fold (range 2.0–2.4) rise in plasma glucagon. In the eight craniopharyngioma patients, glucagon increased 2.2 ± 0.2-fold (range 1.5–3.5), and in the patients of group B, a 2.4 ± 0.4-fold (range 1.5–7.3, n = 4) increase in the plasma glucagon concentration could be observed, as shown in Fig. 2C. In patients of group A1, who had an impaired catecholaminergic response to hypoglycemia, glucagon increased 1.9 ± 0.1-fold (range 1.5–2.5), which did not differ from the healthy controls (P = 0.76). No significant correlations could be found between the hypoglycemiainduced changes in glucagon and epinephrine or norepinephrine (r = 0.30 and 0.35, respectively).
Heart rate.
The heart rate response in the craniopharyngioma patients with an impaired catecholaminergic counterregulatory response (group A1) was reduced (Table 1) and was lower than that of the craniopharyngioma patients of group A2 (P = 0.19) or of the healthy subjects (P = 0.009).
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. The neurogenic symptom scores reached during hypoglycemia were similar in all groups. According to Towler et al. (16), neurogenic symptoms can be grouped into adrenergic (tremor, heart pounding, and anxiety) and cholinergic symptoms (sweating, hunger, and tingling). In the craniopharyngioma patients of group A1, with impaired catecholaminergic counterregulatory response, virtually no change was reported in the adrenergic symptoms during hypoglycemia (Fig. 3B). Taking the groups on the whole (group A, B, and C), the correlations between the hypoglycemia-induced changes in the adrenergic symptoms and the plasma catecholamines were r = 0.88 for epinephrine (P < 0.0001) and r = 0.69 for norepinephrine (P < 0.01). On contrast, the cholinergic symptoms increased during hypoglycemia to a degree similar in all groups (Fig. 3C), and there was no significant correlation with the plasma catecholamines (r = 0.30, respectively). The total score for neuroglycopenic symptoms (weakness, difficulty in thinking, fatigue, dizziness, and blurred vision) transiently increased during hypoglycemia and decreased with recovery of the plasma glucose concentrations in all groups as shown in Fig. 3D. Statistically, there were no significant differences in the symptom scores reached during hypoglycemia between the groups, and correlations with plasma catecholamines were not significant (r = 0.03 for epinephrine and r = -0.17 for norepinephrine).
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Plasma catecholamines and heart rate.
Orthostasis caused a significant rise in both plasma catecholamines and heart rate in all groups (Table 2). There were no marked differences between the normal controls, the craniopharyngioma patients, and the patients with hypopituitarism. In the five craniopharyngioma patients of group A1, the orthostasis-induced increase in plasma catecholamines and heart rate was unimpaired (Table 2).
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A decrease in plasma glucose causes prompt release of several counterregulatory hormones including glucagon, catecholamines, cortisol, and GH, which act in concert to prevent or correct hypoglycemia. Several lines of evidence strongly suggest a critical role of the central nervous system in the detection and counterregulation of hypoglycemia (7, 11, 12, 13, 14). Studies in rats implicated the involvement of specific hypothalamic regions for the stimulation of glucagon and catecholamine secretion (13, 14), which play an important role for rapid glucose counterregulation, and for early autonomic warning signs. In humans, however, the role of the hypothalamus in the counterregulatory release of catecholamines and of glucagon in response to hypoglycemia is largely undefined. To address this question, we investigated the counterregulatory response to acute insulin-induced hypoglycemia of glucagon, epinephrine and norepinephrine in eight patients who had undergone transcranial surgery for a craniopharyngioma extending to the hypothalamic region. In five of eight patients, we found a largely reduced adrenergic and noradrenergic plasma response to hypoglycemia. Deficiency of pituitary hormones as the underlying cause can be excluded, because three of the eight craniopharyngioma patients, and four patients with panhypopituitarism, as previously reported (15, 19), had a normal response. Structural and/or functional damage of hypothalamic centers are, therefore, the most likely explanation for the observed impairment of sympathoadrenal counterregulation in the craniopharyngioma patients. The fact that not all the craniopharyngioma patients were affected can be explained by a variable extent of the hypothalamic damage caused by the tumor or the operation, which may have led to an alteration of different hypothalamic centers in the patients. Accordingly, some, but not all the craniopharyngioma patients suffered from postoperative weight gain, presumably caused by damage to hypothalamic centers controlling food intake and energy consumption. However, there was no indication showing a link between defective sympathoadrenal counterregulation and postoperative weight gain or BMI, which would suggest a common center for both phenomena. In the five patients with an impaired counterregulatory rise in plasma catecholamines, the increase in heart rate and the development of neurogenic symptoms such as tremor, heart pounding, and anxiety attributed to adrenergic activation (16) were diminished or absent during hypoglycemia. Cholinergic neurogenic symptoms, however, comprising of sweating, hunger, and tingling, and neuroglycopenic symptoms (16) were fully intact in these patients. Although there was a highly significant correlation between the rise in plasma epinephrine and the severity of adrenergic symptoms, it remains to be seen whether these symptoms are solely mediated by epinephrine or whether activation of sympathetic neurons are employed. The involvement of sympathetic nerves appears to be possible because the counterregulatory rise in plasma norepinephrine that originates from the spillover of sympathetic nerve endings and reflects sympathetic nervous system activity was also reduced. This is in sequence with a report from a patient with hypothalamic sarcoidosis and loss of counterregulation, who had decreased sympathetic nerve activity during hypoglycemia (15). Thus it appears that, in these five patients, hypoglycemic counterregulatory activation of the sympathetic nervous system comprising of adrenal secretion of epinephrine, cardiac stimulation with a rise in heart rate, and the development of hypoglycemic adrenergic symptoms was selectively impaired. The fact that activation of sympathetic reflexes by orthostasis, which involve the brain stem and which are independent from the hypothalamus triggered a normal rise in plasma catecholamines and in the heart rate demonstrate that the sympathetic nervous system was otherwise intact. This indicates a selective defect in the sympathetic nervous system defined to the hypothalamic region in these patients and supports the concept that hypothalamic centers are crucial for the coordination of the sympathetic counterregulatory response during hypoglycemia.
The glucagon response to hypoglycemia was preserved in all craniopharyngioma patients including the five patients who had an impaired sympathetic counterregulation. In humans, the role of the autonomic nervous system for the stimulation of glucagon secretion is controversial (16, 20, 21, 22). Our results clearly argue against an exclusive role played by the sympathetic nervous system including the adrenal medulla in hypoglycemia-induced glucagon release. Similar results were shown in sympathectomized patients caused by cervical cord transection and who had a normal glucagon counterregulation despite a loss of a hypoglycemic sympathoadrenal response (20). Apart from pancreatic sympathetic nerves and the adrenal medullary hormone epinephrine, pancreatic parasympathetic nerves are activated by hypoglycemia, which can stimulate glucagon secretion (23). In addition, or alternatively, other factors like direct islet effects of low glucose may contribute to glucagon secretion during hypoglycemia (24, 25). It still has to be proven whether distinct hypothalamic centers for the control of hypoglycemia-induced glucagon release exist in humans as suggested by Fery et al. (15). They reported a patient with complete loss of counterregulation presumably caused by hypothalamic sarcoidosis. Their patient, however, initially presented with multiple brain and lung lesions that resolved under glucocorticoid treatment with the exception of one in the hypothalamus. Because sarcoidosis is a systemic disease, it cannot be ruled out with certainty that lesions on other sites, including residual intracranial infiltrates undetected by magnetic resonance imaging and resistant to glucocorticoid treatment, may have contributed to the findings reported (15). Our findings clearly demonstrate that there is no common hypothalamic center that controls the counterregulatory release of both catecholamines and glucagon.
Craniopharyngiomas account for approximately 3% of all intracranial tumors and, therefore, defective counterregulation to hypoglycemia may occur more often than appreciated so far. No obvious alteration of glucose recovery from acute hypoglycemia could be observed in patients with impaired sympathetic counterregulation compared with patients who had normal sympathoadrenal counterregulation or panhypopituitarism. This is consistent with previous studies demonstrating normal glucose recovery in bilaterally adrenalectomized subjects and after pharmacological 
- and ß-adrenergic blockade (1, 21). Therefore, the risk of hypoglycemia in these patients does not appear to increase as long as glucagon counterregulation is preserved. Selective impairment of sympathetic counterregulation, however, may become relevant if glucagon counterregulation fails, such as in diabetes mellitus type 1 (26), because in this situation the lack of typical adrenergic hypoglycemic symptoms may obscure the diagnosis and awareness of hypoglycemia.
Acknowledgments
We thank Dr. H. Herrmann, Ph.D., Department of Biometrics, for statistical advice, and A. Coughlan for linguistic help.
Footnotes
Abbreviation: BMI, Body mass index.
Received March 7, 2001.
Accepted October 23, 2001.
References
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) in symptom scores were calculated as described under methods. Neurogenic symptoms assessed were sweating, hunger, tingling, tremor, heart pounding, and anxiety, with tremor, heart pounding, and anxiety being regarded as adrenergic symptoms, and sweating, hunger, tingling as cholinergic symptoms. The neuroglycopenic symptoms comprised weakness, difficulty in thinking, fatigue, dizziness, and blurred vision. B and C, The changes (