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Nocturnal Monitoring of Growth Hormone, Insulin, C-Peptide, and Glucose in Patients With Acromegaly
Nocturnal Monitoring of Growth Hormone, Insulin, C-Peptide, and Glucose in Patients With Acromegaly JIR S. TSAI, MD, LILIAN L. ZORRILLA, BA, KIRSTEN K. JACOB, BA, SAUL ROSENBERG, BA, DAVID L. MARCUS, PHD
ABSTRACT: Circulating growth hormone, insulin, C-peptide, and glucose levels were compared during the sleep state in adults with acromegaly and healthy control subjects. Growth hormone secretion was episodic in both groups, with the sleep-related growth hormone peak noticeably absent in the acromegalic subjects. The mean nocturnal plasma insulin concentration was greater in the acromegalies. There was no significant difference in the C-peptide between the two groups. Insulin and glucose levels did not show an early morning rise in either acromegalies or healthy subjects. The authors conclude that there is a marked difference in the circulating levels of growth hormone and insulin between the acromegalic and the healthy groups during the sleep state, and there is no sleep-related nocturnal growth hormone peak in the acromegalic subjects. The hyperinsulinism of patients with acromegaly cannot be attributed to excess secretion of insulin. KEY INDEXING TERMS: Growth hormone; Insulin; C-Peptide; Acromegaly. [Am J Med Sci 1996;311(6):281285.]
I
t was shown that growth hormone plays an important role in the regulation of glucose metabolism. The intricate relation among the pituitary and pancreatic hormones in the regulation of glucose use was investigated. 1•2 It was postulated that early morning surges of growth hormone result in insulin resistance From the Department of Medicine, New York University Medical Center, New York, New York. Supported in part by the Pope Foundation, the Rose and Harry Rothman Geriatric Research Fund, and the Weinstein Family Fund. Submitted October 19, 1995; accepted in revised form February 21, 1996. Correspondence: David L. Marcus, PhD, New York University Medical Center, 550 First Ave, New York, NY 10016. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
several hours later as a possible mechanism of the "dawn phenomenon" among healthy and diabetic patients. To define whether pituitary or pancreatic hormones play more dominant role in control of glucose metabolism, we have studied basal growth hormone and insulin secretion in nondiabetic acromegalic and .healthy subjects during sleep. Materials and Methods Human Subjects. Written informed consent was ob-
tained from five nondiabetic acromegalic and eight healthy volunteers. The diagnostic criteria for acromegaly were: 1) suggestive clinical features; 2) elevated basal growth hormone and somatomedin-C levels; 3) nonsuppressible growth hormone secretion by oral glucose tolerance test; and 4) radiographically demonstrable pituitary adenoma. Study Protocol. The study was conducted at the Clinical Research Center at New York University Medical Center. On admission (day 1), the subjects underwent oral glucose tolerance testing and sleep adaptation in a special room designed for sleep monitoring. The patients with acromegaly who had a normal glucose response to the conventional glucose tolerance test were included in the study. All the participants in this study were maintained on a caffeine-free diet throughout the study. On day 2, the subjects were instructed to avoid food ingestion after supper (6 PM), and an intravenous catheter was inserted at that time. Sleep monitoring via polysomnography was started at 11 PM; when the lights were turned off, until 7 AM the following morning, when the lights were turned on again. Five-milliliter blood samples were drawn via the indwelling venous catheter at 30-minute intervals from 9 PM to 11 PM and then at 20-minute intervals during sleep monitoring. The blood specimens were contained in coded tubes that were immediately centrifuged and placed in a freezer at -20° C. The plasma samples were later analyzed for glucose concentration by the hexokinase method (Sigma Diagnostics, St. Louis, MO). Growth hormone levels were determined by the immunora281
Monitoring in Selected Acromegaly
450
Table 1. Characteristics of Study Population Control Subjects (n =
Age (yrs) Gender (man/woman) Body mass index (kg/m 2 ) Glucose tolerance
8)
400
Acromegalies
35.8
7/1
4/1
24.2 Normal
27.6 Normal
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300
01
250 . 200
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150 100
diommetric method (Allegro TM HGHimmunoassay, Nichols Institute Diagnostic, San Juan Capistrano, CA). The inter- and intra-assay variability was 6.0%. The insulin levels were assayed by radioimmunoassay (RSL 125 I InsulinKit, ICN Biochemicals, Carson, CA) and the C-peptide levels were measured by Immunex TM· RIA system for human C-peptide of proinsulin (Immunex, Carson City, NV) . The variability of the insulin and C-peptide assays were 6.0% and 6.0-6.5%, respectively. The sleep patterns were analyzed and scored visually based on the electroencephalograph records. The blood samples were decoded after hormonal analysis and then correlated with the sleep pattern. The data presented in the text, figures, and tables are the means with the corresponding standard errors. The mean integrated nocturnal growth hormone and insulin for each group were determined by calculating the mean of the area beneath the appropriate curves. Statistical significance was determined by the twotailed Student's t-test. Results The patients with acromegaly and the healthy control subjects had a similar body mass index and comparable blood sugar response to the dral glucose tolerance test (Table 1). However, the subjects with acromegaly had nonsuppressible growth hormone secretion by glucose loading, as expected. The patients with acromegaly appeared to have a slight increase in the total duration of stage 3 and stage 4 sleep (data not shown). Otherwise, the sleep characteristics for the healthy and acromegalic groups were comparable, in our analysis. Our study also indicated that the sleep efficiency (the percentage of total polygraphic recording time actually spent in sleep) was similar in both groups. Growth hormone secretion is episodic in nature in healthy subjects. 3 Our observation also revealed that the growth hormone secretion remains episodic during the sleep cycle. 3 Similar observations were reported by other investigators. 3 A secretory pulse of growth hormone secretion usually occurred shortly after the onset of sleep and in association with the first phase of slowwave sleep. This appeared in association with the first phase of slow-wave sleep and was observed in 7 of 8 healthy subjects. However, the sleep-related growth hormone peak was not observed in all of the patients
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TIME Figure 1. Growth hormone levels (mean ± standard error of the mean) ~uring sleep in acromegalies (0) and control subjects (.6.) , shown m 24-hour clock time.
with acromegaly in our study. As predicted, the growth hormone secretion among the acromegalies is persistently higher than that observed in the healthy group. The mean growth hormone concentration for the healthy subjects was 2.70 ± 0.75 ng/mL, whereas the mean plasma growth hormone level for the patients with acromegaly was 117.00 ± 71.60 ng/mL (Figure 1). However, the glucose concentrations are comparable (93.00 ± 4.89 mg/dL versus 88.90 ± 8.11 mg/dL) and remained relatively stable (in the range of 90-100 mg%) throughout the night in both groups (Figure 2). In addition, there is no significant rise of glucose in the early morning period. The plasma insulin concentration is noticeably higher among the patients with acromegaly throughout the sleep period as compared with that seen in the healthy subjects despite relatively similar plasma glu-
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TIME Figure 2. Glucose levels (mean± standard error of the mean) during sleep in acromegalies (0) and control subjects (.a.), shown in 24-hour clock time. June 1996 Volume 311 Number6
Tsai et al
cose concentration in the two study groups. The mean average insulin concentration of the patients with acromegaly (48.90 ± 19.0 ~U/mL) is approximately twofold higher than that seen in the healthy volunteers (18.10 ± 2.83 ~U/mL) (Figure 3). The insulin levels decline during the early sleep phase among the patients with acromegaly but the levels remain more or less steady among the healthy group throughout the entire sleep duration (Figure 3). Interestingly, the difference in the C-peptide levels between the two groups (3.08 ± 0.52 ng/mL versus 3.43 ± 0.91 ng/mL) was less striking despite significant difference in insulin levels between the groups (Figure 4) . Discussion Prolonged fasting affects the pattern of growth hormone secretion. 4 It is also shown that somatostatin, a powerful growth hormone inhibitor, is usually elevated within 30 minutes after a high-fat diet. 5 In addition, an increase in glucose after a high-carbohydrate meal may also inhibit growth hormone release. 6 Conversely, food intake appears to have impact on sleep. 7 Therefore, a careful dietary management was given to the participants of the study to minimize the effect of dietary intake on the sleep-related growth hormone secretion. Growth hormone secretion has distinct bursts that usually coincide with the initial period of slow wave sleep. 8 It was reported that growth hormone administration to either animals or human subjects cause an increased amount of time spent in rapid eye movement sleep.9 •10 Although the sleep efficiency of the healthy subjects and patients with acromegaly are very similar (data not shown), our study suggested that the stage III and IV sleep among the patients with acromegaly are slightly prolonged. A significantly increased growth hormone level in the patients with acromegaly may be the cause of this finding. It was reported that a decrease
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TIME Figure 3. Insulin levels (mean± standard error of the mean) during sleep in acromegalies (0) and control subjects (A), shown in 24-hour clock time. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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in rapid eye movement sleep time occurs in the acromegalic as compared with healthy subjects.U However, the recent report by Kern et al suggested that growth hormone does not affect human sleepY The present study demonstrates the pulsatile secretion patterns and levels of growth hormone, insulin, and C-peptide of nondiabetic acromegalies and healthy subjects. The pulsatile secretion characteristic of growth hormone secretion in the patients with acromegaly was reported previously. 3 It also was suggested that the pulse frequency of growth hormone secretion increases in the patients with acromegaly. 3 Our observation also confirms the episodic nature of the growth hormone secretion in acromegalies during the sleep period. However, the study does not suggest an increase in pulse frequency in the acromegalies compared with that seen in healthy subjects. Absence of the sleeprelated growth hormone peak among the patients with acromegaly, as previously described, 13·14 was also noted in our study. Both growth hormone and insulin play an important role in the maintenance of glucose homeostasis. It was shown that hyperinsulinemia exists among acromegalics.15 Growth hormone plays a tonic role in the control of insulin and glucagon release in the isolated rat pancreas. 16 It is known that growth hormone affects the insulin action. 17·18 It may affect the insulin action at the receptor level by changes in binding affinity. 18 It is also possible that growth hormone may stimulate insulin secretion directly or indirectly via an altered glucose concentration. The similarity of the plasma glucose levels between the healthy subjects and those observed among the acromegalies suggested that the balance of growth hormone and insulin action are essential in the regulation of metabolic equilibrium. The nocturnal pattern of circulating insulin levels demonstrates a phase of rapid decline before sleep onset followed by a continued gradual decline, eventually
283
Monitoring In Selected Acromegaly
achieving a plateau in the early morning hours. The rapid decline phase appears more pronounced in the patients with acromegaly. This nocturnal insulin decline was described previously .18- 20 A concomitant change in the C-peptide hormone levels also was reported.18 It is speculated that these observed phenomena reflect a decrease in beta cell secretion rather than an increase in hepatic insulin extraction or clearance rate. The decline in insulin before the onset of sleep may represent a physiologic circadian phenomenon.18 Alternatively, it was speculated that the fall in growth hormone during the night results in an increase in peripheral insulin sensitivity2 and a consequent decrease in insulin secretion to maintain normoglycemia. In contrast with those observed by the other investigators, the patients with acromegaly in our study demonstrate a marked insulin decline despite the absence of a fall in growth hormone levels. A similar observation of a pronounced decline in insulin levels during sleep in the patients with acromegaly was described.20 Therefore, it appears that the insulin decline is independent of growth hormone changes. However, those patients with isolated growth hormone deficiency demonstrated only slight and insignificant insulin change during the initial phase of sleep. 20 Therefore, growth hormone may still play some role in the regulation of serum insulin level during the resting sleep stage. 20 Despite a significant difference in insulin levels between the acromegalic and healthy subjects, the concomitant C-peptide levels appear to be quite similar between the two groups (Figure 4) . The calculated insulin/C-peptide ratio is, therefore, higher among the acromegalies. The C-peptide reflects pancreatic insulin secretion. Therefore, the persistent higher plasma insulin and insulin/C-peptide ratio of the nondiabetic acromegalic subjects are not due to larger amounts of insulin secretion. Although the precise mechanism by which this discrepancy between insulin and C-peptide levels occurs is unknown, it is possible that acromegalic patients may have different insulin clearance. An examination of insulin turnover may reveal our presumed increase in insulin clearance. However, this is beyond the scope of the present study and is the subject of another investigation. Growth hormone induces insulin-like growth factor (IGF). It was reported that infusion of recombinant human IGF-1 causes hypoglycemia. 21 However, a high IGF-1 level does not always mimic the insulin effect. The high IGF-1 level in acromegalies who are insulin resistant is usually associated with high insulin and Cpeptide levels.22 This may be due to high growth hormone concentration-induced IGFBP-3, which provides high IGF binding capacity and causes increased insulin levels. 23 Under these circumstance, most of the IGF-1 is bound to specific IGFSP, which prevents IGF-1 from causing hypoglycemia. 24
284
Active acromegalies are associated with elevated growth hormone and insulin level. 15 Frequently, impaired glucose tolerance or frank diabetes is seen. The reasons to explain the normal glucose tolerance despite elevations of these hormones known to affect glucose metabolism among the acromegalies in our study is not clear. Of note in our observation of nocturnal insulin and glucose levels was the absence of an early morning decline in insulin level or rise in glucose level. It was speculated that the growth hormone surge during sleep results in insulin resistance, which may cause a rise in· glucose levels during the early morning. 1 In fact, the dawn phenomenon was abolished by the administration of somatostatin and replicated by the addition of hourly growth hormone injection to somatostatin infusion. 25 Therefore, a sustained elevation of growth hormone as seen in acromegaly is not etiologically implicated in the occurrence of the dawn phenomenon. The slow decrease in insulin levels after the onset of sleep for the patients with acromegaly was not associated with a concomitant decline in growth hormone levels, suggesting that other factors may contribute to hyperinsulinemia and acromegaly. Whether the dawn phenomenon is seen in the nondiabetic 18·19·26·27 or it is other factors in the diabetic state coupled with elevated growth hormone that results in expression of the dawn phenomenon remains unclear. Our study suggests that the nondiabetic acromegalic and healthy subjects do not have the early morning rise of glucose described as the "dawn phenomenon." References 1. Press M, Tamborlane WV, Sherwin RS. Importance of raised growth hormone levels in mediating the metabolic derangements of diabetes. N Eng! J Med. 1984;310:810-5. 2. Rizza RA, Mandarinao LJ, Gerich JE. Effects of growth hormone on insulin action in man: Mechanisms of insulin resistance, impaired suppression of glucose production, and imp a ired stimulation of glucose utilization. Diabetes. 1982;31:6639.
3. Hartman M , Faria A, Thorner M. Pulse frequency and basal growth hormone concentrations are increased in acromegaly. Proc 70th Meeting of Endocrine Soc. 1988;48. 4. Quabbs HJ, Schilling E, Helgi H. Patterns of growth hormone secretion during a twenty-four hours fast in normal adults. J Clin Endocrinol Metab. 1966;26:1173-7. 5. Penman E, Wass JAH, Medbak S, Morgan L, Lewis JM, Besser GH, Rees LH. Response of circulating immunoreactive somatostat in to nutritional stimuli in normal subjects. Gastro· enterology. 1981;81:692-9. 6. Galbo H. Endocrinology a nd metabolism in exercise. lnt J Sports Med. 1981;2:203-11. 7. Parkes JD. Sleep and Its Disorder. New York: Saunders; 1985;48- 9. 8. Takahashi Y, Kipnis DM, Daughday WH. Growth hormone secretion during sleep. J Clin Invest. 1986;47:2079-90. 9. Stern WC, Jalowiec JE, Shabshelowitz H, Morgane PJ. E ffects of growth hormone on sleep-waking patterns in cats. H orm Behav. 1975;6:189- 96. 10. Mendelson WB, Caine ED, Goyer P, Ebert M, Gillin C. Sleep in Gilles de Ia Tourette syndrome. Bioi Psychiatry. 1980;15: 339- 43. June 1996 Volume 311 Number 6
Tsal et al
11. Astron C, Christensen L, Gjerris F, Trojaborg W. Sleep in acromegaly before and after treatment with adenomectomy. Neuroendocrinology. 1991;53:328-31. 12. Kern W, Halder R, Al-Reda S, Spath-Schwalbe E, Fehm HL, Born J. Systemic growth hormone does not affect human sleep. J Clin Endocrinol Metab. 1993;76:1428-32. 13. Cryer P, Daughaday W, Regulation of growth hormone secretion in acromegaly. J Clin Endocrinol Metab. 1969;29:38693. 14. Carlson H, Gillin J, Gorden P, Snyder F. Absence of sleeprelated growth hormone peaks in aged normal subjects and in acromegaly. J Clin Endocrinol Metab. 1972;34:1102- 5. 15. Holly J, Cotterill A, Jemmott R, Shears D, al-Othoman S, Chard T, Wass J. Interrelations between growth hormone, insulin, insulin-like growth factor- I (IGF-1), IGF-bindingprotein1 (IGFBP-1) and sex hormone-binding globulin in acromegaly. Clin Endocrinol. 1991;34:275- 80. 16. Tai T, Pek S. Direct stimulation by glucagon and insulin release from isolated pancreas. Endocrinology. 1976;99:669-77. 17. Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R. Insulin resistance in acromegaly: Defects in both hepatic and extrahepatic insulin action. Am J Physiol. 1986;250: 269- 73. 18. Levy I, Recasens A, Casamitjana R, Figuerola D. Nocturnal insulin and C-peptide rhythms in normal subjects. Diabetes Care. 1987;10:148- 51. 19. Schmidt M, Lin Q, Gwynne J, Jacobs S. Fasting early morning rise in peripheral insulin: Evidence of the dawn phenomenon in nondiabetes. Diabetes Care. 1984;7:32- 5.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
20. Mauras N, Rogol A, Clarke W. Failure to detect the "dawn phenomenon" in nondiabetic subjects with markedly different patterns of nocturnal growth hormone secretion. J Clin Endocrinol Metab. 1986;62:975-9. 21. Guler H, Zapf J, Froesch E. Short-term metabolic effects of recombinant human insulin-like growth factor 1 in healthy adults. N Eng! J Med. 1987;317:137- 40. 22. Sonksen P, Grennwood F, Ellis J, Lowy C, Rutherford A, N abano J. Changes of carbohydrate tolerance in acromegaly with progress of disease and in response to treatment. J Clin Endocrinol Metab. 1967;27:1418- 30. 23. WhiteR, Nissley S, Mosed A, Rechler M, Johnsonbaugh R. The growth hormone dependence of a somatomedin-binding protein in human serum. J Clin Endocrinol Metab. 1981;53:4957. 24. Zapf J, Haui C, Waldvogel M, Froesch E. Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophysectomized rats. J Clin Invest. 1986;77:1768-75. 25. Campbell PJ, Bolli GB, Cryer PE, Gerich JE. Pathogenesis of dawn phenomenon in patients with insulin -dependent diabetes mellitus. N Eng! J Med. 1985;312:1473- 9. 26. Bolli GB, DeFeo P, DeCosmo S. Demonstration of a dawn phenomenon in normal human volunteers. Diabetes. 1984;33: 1150- 3. 27. Simon C, Brandenberger G, Follenius M. Absence of the dawn phenomenon in normal subjects. J Clin Endocrinol Metab. 1988;67:203-5.
285
ABSTRACT: Circulating growth hormone, insulin, C-peptide, and glucose levels were compared during the sleep state in adults with acromegaly and healthy control subjects. Growth hormone secretion was episodic in both groups, with the sleep-related growth hormone peak noticeably absent in the acromegalic subjects. The mean nocturnal plasma insulin concentration was greater in the acromegalies. There was no significant difference in the C-peptide between the two groups. Insulin and glucose levels did not show an early morning rise in either acromegalies or healthy subjects. The authors conclude that there is a marked difference in the circulating levels of growth hormone and insulin between the acromegalic and the healthy groups during the sleep state, and there is no sleep-related nocturnal growth hormone peak in the acromegalic subjects. The hyperinsulinism of patients with acromegaly cannot be attributed to excess secretion of insulin. KEY INDEXING TERMS: Growth hormone; Insulin; C-Peptide; Acromegaly. [Am J Med Sci 1996;311(6):281285.]
I
t was shown that growth hormone plays an important role in the regulation of glucose metabolism. The intricate relation among the pituitary and pancreatic hormones in the regulation of glucose use was investigated. 1•2 It was postulated that early morning surges of growth hormone result in insulin resistance From the Department of Medicine, New York University Medical Center, New York, New York. Supported in part by the Pope Foundation, the Rose and Harry Rothman Geriatric Research Fund, and the Weinstein Family Fund. Submitted October 19, 1995; accepted in revised form February 21, 1996. Correspondence: David L. Marcus, PhD, New York University Medical Center, 550 First Ave, New York, NY 10016. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
several hours later as a possible mechanism of the "dawn phenomenon" among healthy and diabetic patients. To define whether pituitary or pancreatic hormones play more dominant role in control of glucose metabolism, we have studied basal growth hormone and insulin secretion in nondiabetic acromegalic and .healthy subjects during sleep. Materials and Methods Human Subjects. Written informed consent was ob-
tained from five nondiabetic acromegalic and eight healthy volunteers. The diagnostic criteria for acromegaly were: 1) suggestive clinical features; 2) elevated basal growth hormone and somatomedin-C levels; 3) nonsuppressible growth hormone secretion by oral glucose tolerance test; and 4) radiographically demonstrable pituitary adenoma. Study Protocol. The study was conducted at the Clinical Research Center at New York University Medical Center. On admission (day 1), the subjects underwent oral glucose tolerance testing and sleep adaptation in a special room designed for sleep monitoring. The patients with acromegaly who had a normal glucose response to the conventional glucose tolerance test were included in the study. All the participants in this study were maintained on a caffeine-free diet throughout the study. On day 2, the subjects were instructed to avoid food ingestion after supper (6 PM), and an intravenous catheter was inserted at that time. Sleep monitoring via polysomnography was started at 11 PM; when the lights were turned off, until 7 AM the following morning, when the lights were turned on again. Five-milliliter blood samples were drawn via the indwelling venous catheter at 30-minute intervals from 9 PM to 11 PM and then at 20-minute intervals during sleep monitoring. The blood specimens were contained in coded tubes that were immediately centrifuged and placed in a freezer at -20° C. The plasma samples were later analyzed for glucose concentration by the hexokinase method (Sigma Diagnostics, St. Louis, MO). Growth hormone levels were determined by the immunora281
Monitoring in Selected Acromegaly
450
Table 1. Characteristics of Study Population Control Subjects (n =
Age (yrs) Gender (man/woman) Body mass index (kg/m 2 ) Glucose tolerance
8)
400
Acromegalies
35.8
7/1
4/1
24.2 Normal
27.6 Normal
E
300
01
250 . 200
'
c
I
(.!)
150 100
diommetric method (Allegro TM HGHimmunoassay, Nichols Institute Diagnostic, San Juan Capistrano, CA). The inter- and intra-assay variability was 6.0%. The insulin levels were assayed by radioimmunoassay (RSL 125 I InsulinKit, ICN Biochemicals, Carson, CA) and the C-peptide levels were measured by Immunex TM· RIA system for human C-peptide of proinsulin (Immunex, Carson City, NV) . The variability of the insulin and C-peptide assays were 6.0% and 6.0-6.5%, respectively. The sleep patterns were analyzed and scored visually based on the electroencephalograph records. The blood samples were decoded after hormonal analysis and then correlated with the sleep pattern. The data presented in the text, figures, and tables are the means with the corresponding standard errors. The mean integrated nocturnal growth hormone and insulin for each group were determined by calculating the mean of the area beneath the appropriate curves. Statistical significance was determined by the twotailed Student's t-test. Results The patients with acromegaly and the healthy control subjects had a similar body mass index and comparable blood sugar response to the dral glucose tolerance test (Table 1). However, the subjects with acromegaly had nonsuppressible growth hormone secretion by glucose loading, as expected. The patients with acromegaly appeared to have a slight increase in the total duration of stage 3 and stage 4 sleep (data not shown). Otherwise, the sleep characteristics for the healthy and acromegalic groups were comparable, in our analysis. Our study also indicated that the sleep efficiency (the percentage of total polygraphic recording time actually spent in sleep) was similar in both groups. Growth hormone secretion is episodic in nature in healthy subjects. 3 Our observation also revealed that the growth hormone secretion remains episodic during the sleep cycle. 3 Similar observations were reported by other investigators. 3 A secretory pulse of growth hormone secretion usually occurred shortly after the onset of sleep and in association with the first phase of slowwave sleep. This appeared in association with the first phase of slow-wave sleep and was observed in 7 of 8 healthy subjects. However, the sleep-related growth hormone peak was not observed in all of the patients
282
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TIME Figure 1. Growth hormone levels (mean ± standard error of the mean) ~uring sleep in acromegalies (0) and control subjects (.6.) , shown m 24-hour clock time.
with acromegaly in our study. As predicted, the growth hormone secretion among the acromegalies is persistently higher than that observed in the healthy group. The mean growth hormone concentration for the healthy subjects was 2.70 ± 0.75 ng/mL, whereas the mean plasma growth hormone level for the patients with acromegaly was 117.00 ± 71.60 ng/mL (Figure 1). However, the glucose concentrations are comparable (93.00 ± 4.89 mg/dL versus 88.90 ± 8.11 mg/dL) and remained relatively stable (in the range of 90-100 mg%) throughout the night in both groups (Figure 2). In addition, there is no significant rise of glucose in the early morning period. The plasma insulin concentration is noticeably higher among the patients with acromegaly throughout the sleep period as compared with that seen in the healthy subjects despite relatively similar plasma glu-
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TIME Figure 2. Glucose levels (mean± standard error of the mean) during sleep in acromegalies (0) and control subjects (.a.), shown in 24-hour clock time. June 1996 Volume 311 Number6
Tsai et al
cose concentration in the two study groups. The mean average insulin concentration of the patients with acromegaly (48.90 ± 19.0 ~U/mL) is approximately twofold higher than that seen in the healthy volunteers (18.10 ± 2.83 ~U/mL) (Figure 3). The insulin levels decline during the early sleep phase among the patients with acromegaly but the levels remain more or less steady among the healthy group throughout the entire sleep duration (Figure 3). Interestingly, the difference in the C-peptide levels between the two groups (3.08 ± 0.52 ng/mL versus 3.43 ± 0.91 ng/mL) was less striking despite significant difference in insulin levels between the groups (Figure 4) . Discussion Prolonged fasting affects the pattern of growth hormone secretion. 4 It is also shown that somatostatin, a powerful growth hormone inhibitor, is usually elevated within 30 minutes after a high-fat diet. 5 In addition, an increase in glucose after a high-carbohydrate meal may also inhibit growth hormone release. 6 Conversely, food intake appears to have impact on sleep. 7 Therefore, a careful dietary management was given to the participants of the study to minimize the effect of dietary intake on the sleep-related growth hormone secretion. Growth hormone secretion has distinct bursts that usually coincide with the initial period of slow wave sleep. 8 It was reported that growth hormone administration to either animals or human subjects cause an increased amount of time spent in rapid eye movement sleep.9 •10 Although the sleep efficiency of the healthy subjects and patients with acromegaly are very similar (data not shown), our study suggested that the stage III and IV sleep among the patients with acromegaly are slightly prolonged. A significantly increased growth hormone level in the patients with acromegaly may be the cause of this finding. It was reported that a decrease
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TIME Figure 3. Insulin levels (mean± standard error of the mean) during sleep in acromegalies (0) and control subjects (A), shown in 24-hour clock time. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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07:00
TIME Figure 4. C-peptide levels (mean ± standard error of the mean) during sleep in acromegalies (0) and control subjects (A), shown in 24-hour clock time.
in rapid eye movement sleep time occurs in the acromegalic as compared with healthy subjects.U However, the recent report by Kern et al suggested that growth hormone does not affect human sleepY The present study demonstrates the pulsatile secretion patterns and levels of growth hormone, insulin, and C-peptide of nondiabetic acromegalies and healthy subjects. The pulsatile secretion characteristic of growth hormone secretion in the patients with acromegaly was reported previously. 3 It also was suggested that the pulse frequency of growth hormone secretion increases in the patients with acromegaly. 3 Our observation also confirms the episodic nature of the growth hormone secretion in acromegalies during the sleep period. However, the study does not suggest an increase in pulse frequency in the acromegalies compared with that seen in healthy subjects. Absence of the sleeprelated growth hormone peak among the patients with acromegaly, as previously described, 13·14 was also noted in our study. Both growth hormone and insulin play an important role in the maintenance of glucose homeostasis. It was shown that hyperinsulinemia exists among acromegalics.15 Growth hormone plays a tonic role in the control of insulin and glucagon release in the isolated rat pancreas. 16 It is known that growth hormone affects the insulin action. 17·18 It may affect the insulin action at the receptor level by changes in binding affinity. 18 It is also possible that growth hormone may stimulate insulin secretion directly or indirectly via an altered glucose concentration. The similarity of the plasma glucose levels between the healthy subjects and those observed among the acromegalies suggested that the balance of growth hormone and insulin action are essential in the regulation of metabolic equilibrium. The nocturnal pattern of circulating insulin levels demonstrates a phase of rapid decline before sleep onset followed by a continued gradual decline, eventually
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Monitoring In Selected Acromegaly
achieving a plateau in the early morning hours. The rapid decline phase appears more pronounced in the patients with acromegaly. This nocturnal insulin decline was described previously .18- 20 A concomitant change in the C-peptide hormone levels also was reported.18 It is speculated that these observed phenomena reflect a decrease in beta cell secretion rather than an increase in hepatic insulin extraction or clearance rate. The decline in insulin before the onset of sleep may represent a physiologic circadian phenomenon.18 Alternatively, it was speculated that the fall in growth hormone during the night results in an increase in peripheral insulin sensitivity2 and a consequent decrease in insulin secretion to maintain normoglycemia. In contrast with those observed by the other investigators, the patients with acromegaly in our study demonstrate a marked insulin decline despite the absence of a fall in growth hormone levels. A similar observation of a pronounced decline in insulin levels during sleep in the patients with acromegaly was described.20 Therefore, it appears that the insulin decline is independent of growth hormone changes. However, those patients with isolated growth hormone deficiency demonstrated only slight and insignificant insulin change during the initial phase of sleep. 20 Therefore, growth hormone may still play some role in the regulation of serum insulin level during the resting sleep stage. 20 Despite a significant difference in insulin levels between the acromegalic and healthy subjects, the concomitant C-peptide levels appear to be quite similar between the two groups (Figure 4) . The calculated insulin/C-peptide ratio is, therefore, higher among the acromegalies. The C-peptide reflects pancreatic insulin secretion. Therefore, the persistent higher plasma insulin and insulin/C-peptide ratio of the nondiabetic acromegalic subjects are not due to larger amounts of insulin secretion. Although the precise mechanism by which this discrepancy between insulin and C-peptide levels occurs is unknown, it is possible that acromegalic patients may have different insulin clearance. An examination of insulin turnover may reveal our presumed increase in insulin clearance. However, this is beyond the scope of the present study and is the subject of another investigation. Growth hormone induces insulin-like growth factor (IGF). It was reported that infusion of recombinant human IGF-1 causes hypoglycemia. 21 However, a high IGF-1 level does not always mimic the insulin effect. The high IGF-1 level in acromegalies who are insulin resistant is usually associated with high insulin and Cpeptide levels.22 This may be due to high growth hormone concentration-induced IGFBP-3, which provides high IGF binding capacity and causes increased insulin levels. 23 Under these circumstance, most of the IGF-1 is bound to specific IGFSP, which prevents IGF-1 from causing hypoglycemia. 24
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Active acromegalies are associated with elevated growth hormone and insulin level. 15 Frequently, impaired glucose tolerance or frank diabetes is seen. The reasons to explain the normal glucose tolerance despite elevations of these hormones known to affect glucose metabolism among the acromegalies in our study is not clear. Of note in our observation of nocturnal insulin and glucose levels was the absence of an early morning decline in insulin level or rise in glucose level. It was speculated that the growth hormone surge during sleep results in insulin resistance, which may cause a rise in· glucose levels during the early morning. 1 In fact, the dawn phenomenon was abolished by the administration of somatostatin and replicated by the addition of hourly growth hormone injection to somatostatin infusion. 25 Therefore, a sustained elevation of growth hormone as seen in acromegaly is not etiologically implicated in the occurrence of the dawn phenomenon. The slow decrease in insulin levels after the onset of sleep for the patients with acromegaly was not associated with a concomitant decline in growth hormone levels, suggesting that other factors may contribute to hyperinsulinemia and acromegaly. Whether the dawn phenomenon is seen in the nondiabetic 18·19·26·27 or it is other factors in the diabetic state coupled with elevated growth hormone that results in expression of the dawn phenomenon remains unclear. Our study suggests that the nondiabetic acromegalic and healthy subjects do not have the early morning rise of glucose described as the "dawn phenomenon." References 1. Press M, Tamborlane WV, Sherwin RS. Importance of raised growth hormone levels in mediating the metabolic derangements of diabetes. N Eng! J Med. 1984;310:810-5. 2. Rizza RA, Mandarinao LJ, Gerich JE. Effects of growth hormone on insulin action in man: Mechanisms of insulin resistance, impaired suppression of glucose production, and imp a ired stimulation of glucose utilization. Diabetes. 1982;31:6639.
3. Hartman M , Faria A, Thorner M. Pulse frequency and basal growth hormone concentrations are increased in acromegaly. Proc 70th Meeting of Endocrine Soc. 1988;48. 4. Quabbs HJ, Schilling E, Helgi H. Patterns of growth hormone secretion during a twenty-four hours fast in normal adults. J Clin Endocrinol Metab. 1966;26:1173-7. 5. Penman E, Wass JAH, Medbak S, Morgan L, Lewis JM, Besser GH, Rees LH. Response of circulating immunoreactive somatostat in to nutritional stimuli in normal subjects. Gastro· enterology. 1981;81:692-9. 6. Galbo H. Endocrinology a nd metabolism in exercise. lnt J Sports Med. 1981;2:203-11. 7. Parkes JD. Sleep and Its Disorder. New York: Saunders; 1985;48- 9. 8. Takahashi Y, Kipnis DM, Daughday WH. Growth hormone secretion during sleep. J Clin Invest. 1986;47:2079-90. 9. Stern WC, Jalowiec JE, Shabshelowitz H, Morgane PJ. E ffects of growth hormone on sleep-waking patterns in cats. H orm Behav. 1975;6:189- 96. 10. Mendelson WB, Caine ED, Goyer P, Ebert M, Gillin C. Sleep in Gilles de Ia Tourette syndrome. Bioi Psychiatry. 1980;15: 339- 43. June 1996 Volume 311 Number 6
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11. Astron C, Christensen L, Gjerris F, Trojaborg W. Sleep in acromegaly before and after treatment with adenomectomy. Neuroendocrinology. 1991;53:328-31. 12. Kern W, Halder R, Al-Reda S, Spath-Schwalbe E, Fehm HL, Born J. Systemic growth hormone does not affect human sleep. J Clin Endocrinol Metab. 1993;76:1428-32. 13. Cryer P, Daughaday W, Regulation of growth hormone secretion in acromegaly. J Clin Endocrinol Metab. 1969;29:38693. 14. Carlson H, Gillin J, Gorden P, Snyder F. Absence of sleeprelated growth hormone peaks in aged normal subjects and in acromegaly. J Clin Endocrinol Metab. 1972;34:1102- 5. 15. Holly J, Cotterill A, Jemmott R, Shears D, al-Othoman S, Chard T, Wass J. Interrelations between growth hormone, insulin, insulin-like growth factor- I (IGF-1), IGF-bindingprotein1 (IGFBP-1) and sex hormone-binding globulin in acromegaly. Clin Endocrinol. 1991;34:275- 80. 16. Tai T, Pek S. Direct stimulation by glucagon and insulin release from isolated pancreas. Endocrinology. 1976;99:669-77. 17. Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R. Insulin resistance in acromegaly: Defects in both hepatic and extrahepatic insulin action. Am J Physiol. 1986;250: 269- 73. 18. Levy I, Recasens A, Casamitjana R, Figuerola D. Nocturnal insulin and C-peptide rhythms in normal subjects. Diabetes Care. 1987;10:148- 51. 19. Schmidt M, Lin Q, Gwynne J, Jacobs S. Fasting early morning rise in peripheral insulin: Evidence of the dawn phenomenon in nondiabetes. Diabetes Care. 1984;7:32- 5.
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20. Mauras N, Rogol A, Clarke W. Failure to detect the "dawn phenomenon" in nondiabetic subjects with markedly different patterns of nocturnal growth hormone secretion. J Clin Endocrinol Metab. 1986;62:975-9. 21. Guler H, Zapf J, Froesch E. Short-term metabolic effects of recombinant human insulin-like growth factor 1 in healthy adults. N Eng! J Med. 1987;317:137- 40. 22. Sonksen P, Grennwood F, Ellis J, Lowy C, Rutherford A, N abano J. Changes of carbohydrate tolerance in acromegaly with progress of disease and in response to treatment. J Clin Endocrinol Metab. 1967;27:1418- 30. 23. WhiteR, Nissley S, Mosed A, Rechler M, Johnsonbaugh R. The growth hormone dependence of a somatomedin-binding protein in human serum. J Clin Endocrinol Metab. 1981;53:4957. 24. Zapf J, Haui C, Waldvogel M, Froesch E. Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophysectomized rats. J Clin Invest. 1986;77:1768-75. 25. Campbell PJ, Bolli GB, Cryer PE, Gerich JE. Pathogenesis of dawn phenomenon in patients with insulin -dependent diabetes mellitus. N Eng! J Med. 1985;312:1473- 9. 26. Bolli GB, DeFeo P, DeCosmo S. Demonstration of a dawn phenomenon in normal human volunteers. Diabetes. 1984;33: 1150- 3. 27. Simon C, Brandenberger G, Follenius M. Absence of the dawn phenomenon in normal subjects. J Clin Endocrinol Metab. 1988;67:203-5.
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