Clinical Endocrinology (1 990), 32, 539-543
EFFECT OF ORAL GLUCOSE ON THE LATE GROWTH HORMONE RISE AND GROWTH HORMONE RESPONSES TO GHRH IN NORMAL SUBJECTS R. VALCAVI, M. ZINI, C . DIEGUEZ, I. PORTIOLI M. F. SCANLON
AND
Neuroendocrine Unit, Department of Medicine, University of Wales College of Medicine, Cardif, UK, Departamento de Fisiologia, Facultad de Medicina, Santiago de Compostela, Spain, and 2a Divisione di Medicina Generale, Sezione Endocrino Metabolica, Arcispedale S. Maria Nuova, Reggio Emilia, Italy (Received 4 August 1989; returned for revision 8 September 1989;finally revised 26 September 1989; accepted 10 October 1989)
SUMMARY
A late rise in serum GH occurs 3-5 h following oral glucose in man. In order to investigate the mechanisms through which this occurs we have studied the late GH rise after oral glucose during administration of a supramaximal dose of GHRH. In eight normal subjects, oral glucose (100 g) greatly enhanced the G H responses to a supramaximal dose of GHRH (50 pg bolus, followed immediately by 100 pg/h infusion for 3 h) given 3.5 h after the glucose. G H peak (mean SEM) elicited by GHRH (bolus +infusion) rose from 55.2 f20-4 to 133.4f29.6 mU/1 (P c 0.02) after glucose pretreatment. In conclusion, it is likely that the late rise in G H secretion induced by oral glucose occurs via a nonGHRH-dependent mechanism. These data are consistent with the hypothesis that the delayed GH response to glucose is a consequence of reduced release of somatostatin from the hypothalamus.
Glucose administration has a biphasic effect on GH secretion in man. Following oral glucose, plasma G H levels are suppressed for 2-3 h initially (Roth et al., 1963; Yalow et al., 1969) followed by a marked rise in G H levels in the postabsorbtive phase 3.5-5 h after glucose administration (Roth et al., 1963; Hunter et al., 1967; Yalow et al., 1969). It has been proposed that the acute inhibitory effect of glucose on plasma G H levels is due to an alteration in hypothalamic activity, since both oral glucose (Davies et al., 1984; Masuda et a[., 1985) and intravenous glucose (Sharp et al., 1984) inhibit basal and GHRHstimulated G H release. In contrast, the mechanisms involved in the delayed G H rise after Correspondence: Dr R. Valcavi, 2a Divisione di Medicina Generale, Sezione Endocrino Metabolica, Arcispedale S. Maria Nuova, v. le Umberto I, 50.42100 Reggio Emilia, Italy.
539
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R. Vakavi et al.
glucose are unknown. We have investigated this latter phenomenon by comparing G H responses to supramaximal doses of GHRH administered at appropriate time intervals after oral glucose or placebo. MATERIALS A N D METHODS Eight normal subjects of both sexes (five female and three male) were recruited for this study. They ranged between 18 and 30 years of age (mean fSEM, 23.0 f 1.4) and weighed from 82 to 101% of ideal body weight. None had a family history of diabetes and they were all free of medications. Local health authority ethical approval was granted and informed coiisent was given by all subjects. Studies were run double-blind in random order at 0800 h after an overnight fast from midnight on three separate occasions at least a week apart. All subjects remained recumbent throughout the studies. Thirty minutes before the studies began, indwelling venous catheters were placed into antecubital veins of both arms for blood sampling and GHRH or saline infusion. Either 100 g glucose dissolved in 200 ml water or the same volume of plain water was then administered orally and blood sampling commenced. Three and a half hours (210 min) after glucose administration, 50 pg of dissolved GHRH (1-44) (Peninsula Laboratories Inc., Belmont, California, USA) were injected as an i.v. bolus, followed immediately by the infusion of GHRH (1-44) dissolved in 250 mlO.9% NaCl containing 0.2% human albumin, delivered by a volumetric pump at the constant rate of 100 pg/h for 3 h (from 210 to 390 min). A saline infusion was given in the control study instead of GHRH. The study design consisted of three tests, randomly carried out: test 1, placebo (0 min) + GHRH (bolus+ infusion from 2 10 to 390 rnin); test 2, glucose (0 min) saline infusion; test 3, glucose (0 min) + GHRH (as above). Samples for serum G H and plasma glucose were collected at 30-min intervals from 0 to 210 min, then at 15-min intervals throughout the GHRH or saline infusions (from 210 to 390 min). Blood glucose was measured by the glucose oxidase method. Serum G H was measured by liquid-phase, double-antibody radioimmunoassay (Sorin, Saluggia, Varese, Italy). The lower limit of detection was 0.4 mU/1 with inter and intra-assay coefficients of variation of 11.1 and 7.6% respectively, at a concentration of 10.4 mU/1. All results are expressed as the mean+SEM. Statistical analysis was performed by analysis of variance (ANOVA) and paired Student’s t-test.
+
RESULTS Oral glucose loading was not followed by any significant reactive hypoglycaemia, with the exception of one subject who had a blood glucose value of 0.8 mmol/l at 210 min during test 2. Mean plasma glucose and glucose Area Under Curve (AUC) were not significantly different in the second phase (from 210 to 390 min) of any test (Fig. Ib), as assessed by paired t-test and ANOVA. Serum GH was suppressed by glucose in all subjects with a mean nadir of 2.8 f 1.2 mU/1 at 150 min. At the time of commencement of GHRH (or saline) infusion (210 min) this suppressive effect had disappeared and mean serum GH levels were the same in the three tests (Fig. la). The late GH rise ( 2 2 0 mU/1) occurred in all subjects, achieving a mean
Glucose-induced GH rise and GHRH 5Opg
Glucose 100 g p.0. or placebo
+ lWpg/h
541
GHRH (1-44) or N/S
I40 120
-
100
-
80
-
60
-
40
-
20
-
0-
I
I
I
I
I
I
8r ( b )
I
T
7-
6 -
5 -
4-
I 0
p I I L -I I I I I I I I I I I I I I I ~ 30 60 90 120 150 180 210 240 270 300 330 360 390 Time ( m i n )
Fig. la, Serum GH and b, plasma glucose levels during a period of 6+ h after the administration of oral glucose (100 g at 0 min) or placebo, followed by saline infusion or GHRH (1-44) 50 pg i.v. bolus+ 100 pg/h infusion (over 210-390 rnin). -0-, glucose+saline infusion; -0-, placebo+GHRH infusion; -0-, glucose+GHRH infusion. Both a and b represent meanf SEM values in eight normal subjects of both sexes.
peak of 32.6 9.0 mU/1 at 31 5 min. The delayed release of GH following oral glucose was considerable, since the AUC for this period (from 21 0 to 390 min) was 43 12 f 1 1 10 mU/1/ 3 h when oral glucose alone was administered. Statistically there was no difference in the GH AUC for the same period during GHRH infusion in the unprimed study (6960 f 1974, NS).
542
R. Valcavi et al.
GHRH bolus + infusion produced the expected G H release with a maximum of 55.2 f20.4 mU/l at 240 min and a plateau at this level up to 270 min. Afterwards, serum GH progressively declined to 14.4 & 3.4 mU/1 despite the GHRH infusion maintained up to 390 min. When the same GHRH bolus + infusion was repeated following oral glucose pretreatment, serum G H release was greatly enhanced to a peak of 133.4f29.6 mU/1 at 255 min (P< 0.02). ANOVA revealed the presence of statistically significant differences between the two infusion studies from 240 to 3 15 min. However, the pattern of GH release during GHRH infusion was not modified by oral glucose pretreatment, showing the same attenuation of GH release (Fig. la). Analysis of AUCs confirmed that glucose pretreatment greatly enhanced the GH response to GHRH. Following glucose priming, G H AUC during GHRH infusion (from 210 to 390 min) increased from 6960 f 1974 to 15400& 1752 mU/1/3 h ( P < 0.01).
DISCUSSION In agreement with early reports (Roth et al., 1963; Hunter et al., 1967;Yalow et al., 1969) we have confirmed that a late GH rise follows an oral glucose load. Although we gave a large dose of oral glucose (100 g), the mean blood glucose did not fall to the hypoglycaemic range in the postabsorbtive phase. Therefore it seems unlikely that the late GH rise was due to hypoglycaemia and this view is further supported by the presence of a delayed GH rise during the euglycaemic glucose clamp (Sharp et al., 1987; Kraegen & Lazarus, 1988). This latter excludes the possibility that the late G H rise is dependent on neural or enteric factors associated with oral administration. Our data demonstrate that oral glucose greatly enhances GH responsiveness to GHRH when administered 3.5 h prior to the GHRH. We designed this study assuming that little, if any, GH release could be induced by endogenous GHRH while subjects were on a highdose GHRH infusion, since there is a limited quantity of GH which can be released by GHRH (Vance et al., 1985).Thus, our data showing a clear enhancement of GH secretion when GHRH infusion was preceded by an oral glucose load make it unlikely that the delayed GH-releasing activity of oral glucose is mediated via GHRH. However, our data do not allow us to reach firm conclusions at present on the mechanisms through which these changes occur. A direct pituitary effect seems unlikely, since we have previously shown that neither glucose nor insulin influences basal G H secretion or GH responses to GHRH in uitro (Page et al., 1987). A more likely possibility would be a suppressive late effect of glucose on somatostatin secretion. Supporting this hypothesis are the clear findings obtained by several groups showing that glucose suppresses somatostatin release from incubated rat hypothalami (Berelowitz et al., 1982; Lengyel et al., 1984). However, because of the well established interspecies differences in relation to the neuroregulation of GH secretion in rodents and primates (Dieguez et al., 1988), further data are needed. Finally, it has been shown that the late G H rise following glucose is associated with a rise in plasma adrenaline (Kleinbaum & Shamoon, 1982). Alpha-adrenergic pathways have a potent stimulatory effect on GH release (Blackard & Hubbel, 1970), and might therefore mediate the late GH rise following oral glucose. In summary, our data show that oral glucose markedly increases G H responses to GHRH when administered 3.5 h prior to GHRH. In contrast, glucose administered 1 h prior to GHRH causes suppression of the GH response to GHRH (Davies et al., 1984;
Glucose-induced GH rise and GHRH
543
Masuda et al., 1985). Whether this delayed interaction of glucose and GHRH could explain the lack of suppression of GH responses to GHRH in patients who have poorly controlled diabetes mellitus (Dieguez et al., 1988) remains to be established. REFERENCES
BERELOWITZ, M., DUDLAK, D. & FROHMAN, L.A. (1982) Release of somatostatin-like immunoreactivity from incubated rat hypothalamus and cerebral cortex. Journal of Clinical Investigation, 69, 1293-1301. BLACKARD, W.G. & HUBBEL,G.J. (1970) Stimulating effect of exogenous catecholamines on plasma growth hormone concentrations in presence of j?-adrenergic blockade. Metabolism, 19,547-552. DAVIES, R.R., TURNER, S. &JOHNSTON, D.G. (1984)Oral glucose inhibits growth hormone secretion induced by human pancreatic growth hormone releasing factor 1-44 in normal man. Clinical Endocrinology, 21,477481. DIEGUEZ, C., PAGE,M.D. & SCANLON, M.F. (1988) Growth hormone neuroregulation and its alterations in disease states. Clinical Endocrinology, 28, 109-143. HUNTER, W.M., WOLFSDORF, J., FARQUHAR, J.W. & RIGAL,W.M. (1967) Screening tests for growth-hormone deficiency in dwarfism. Lancet, ii, 1271-1273. KLEINBAUM, J. & SHAMCQN, H. (1982) Selective CounterreguIatory hormone response after oral ghcose in man. Journal of Clinical Endocrinology and Metabolism, 55, 787-790. KRAEGEN, E.W. & LAZARUS,L. (1988) A late plasma growth hormone rise after insulin administration with maintenance of euglycaemia: similarities to reported responses after oral glucose. Diabetes, Nutrition & Metabolism, 1,221-226. LENGYEL, A.-M.J., NIEUWENHUYZEN KRUSEMAN, A.C., GROSSMAN, A., REES,L.H. & BESSER,G.M. (1984) Glucose-induced changes in somatostatin-I4 and somatostatin-28 released from rat hypothalamic fragments in vitro. Life Sciences, 35,713-719. MASUDA,A,, SHIBASAKI, T., NAKAHARA, M., IMAKI,T., KIYISAWA, T., JIBIKI,K., DEMURA, H., SHIZUME, K. & LING,N. (1985)The effect of glucose on growth hormone (GH)-releasing hormone-mediated GH secretion in man. Journal of Clinical Endocrinology and Metabolism, 60,523-526. PAGE,M.D., KOPPESCHAAR, H.P.F., EDWARDS,C.A., DIEGUEZ, C., SCANLON, M.F. (1987) Additive effects of growth hormone releasing factor and insulin hypoglycaemia on growth hormone release in man. Clinical Endocrinology, 26, 589-595. ROTH,J., CLICK, S.M., YALOW,R. & BERSON, S.A. (1963) Secretion ofhuman growth hormone: physiologic and experimental modification. Metabolism, 12, 577-579. SHARP,P.S., FOLEY,K., CHAHAL, P. & KOHNER,E.M. (1984) The effect of plasma glucose on the growth hormone response to human pancreatic growth hormone releasing factor in normal subjects. Clinical Endocrinology, 20,497-501. SHARP,P.S., MOHAN,V., MANESCHI, F., VITELLI, F., CLOKE,H.R., BURRIN,J.M. & KOHNER,E.M. (1987) Changes in plasma growth hormone in diabetic and nondiabetic subjects during the glucose clamp. Metabolism, 36,71-75. VANCE,M.L., KAISER, D.L., EVANS,W.S., THORNER, M.O., FURLANETTO, R., RIVIER, J., VALE,W., PERISUTTI, G. & FROHMAN, L.A. (1985) Evidence for a limited growth hormone (GH)-releasing hormone (GHRH)releasable quantity of GH: effects of 6-hour infusion of GHRH on G H secretion in normal man. Journal of Clinical Endocrinology and Metabolism, 60, 370-375. YAMw, R.S., GOLDSMITH, S.J. & BERSON, S.A. (1969) Influence of physiologic fluctuations in plasma growth hormone on glucose tolerance. Diabetes, 18,402-408.
EFFECT OF ORAL GLUCOSE ON THE LATE GROWTH HORMONE RISE AND GROWTH HORMONE RESPONSES TO GHRH IN NORMAL SUBJECTS R. VALCAVI, M. ZINI, C . DIEGUEZ, I. PORTIOLI M. F. SCANLON
AND
Neuroendocrine Unit, Department of Medicine, University of Wales College of Medicine, Cardif, UK, Departamento de Fisiologia, Facultad de Medicina, Santiago de Compostela, Spain, and 2a Divisione di Medicina Generale, Sezione Endocrino Metabolica, Arcispedale S. Maria Nuova, Reggio Emilia, Italy (Received 4 August 1989; returned for revision 8 September 1989;finally revised 26 September 1989; accepted 10 October 1989)
SUMMARY
A late rise in serum GH occurs 3-5 h following oral glucose in man. In order to investigate the mechanisms through which this occurs we have studied the late GH rise after oral glucose during administration of a supramaximal dose of GHRH. In eight normal subjects, oral glucose (100 g) greatly enhanced the G H responses to a supramaximal dose of GHRH (50 pg bolus, followed immediately by 100 pg/h infusion for 3 h) given 3.5 h after the glucose. G H peak (mean SEM) elicited by GHRH (bolus +infusion) rose from 55.2 f20-4 to 133.4f29.6 mU/1 (P c 0.02) after glucose pretreatment. In conclusion, it is likely that the late rise in G H secretion induced by oral glucose occurs via a nonGHRH-dependent mechanism. These data are consistent with the hypothesis that the delayed GH response to glucose is a consequence of reduced release of somatostatin from the hypothalamus.
Glucose administration has a biphasic effect on GH secretion in man. Following oral glucose, plasma G H levels are suppressed for 2-3 h initially (Roth et al., 1963; Yalow et al., 1969) followed by a marked rise in G H levels in the postabsorbtive phase 3.5-5 h after glucose administration (Roth et al., 1963; Hunter et al., 1967; Yalow et al., 1969). It has been proposed that the acute inhibitory effect of glucose on plasma G H levels is due to an alteration in hypothalamic activity, since both oral glucose (Davies et al., 1984; Masuda et a[., 1985) and intravenous glucose (Sharp et al., 1984) inhibit basal and GHRHstimulated G H release. In contrast, the mechanisms involved in the delayed G H rise after Correspondence: Dr R. Valcavi, 2a Divisione di Medicina Generale, Sezione Endocrino Metabolica, Arcispedale S. Maria Nuova, v. le Umberto I, 50.42100 Reggio Emilia, Italy.
539
540
R. Vakavi et al.
glucose are unknown. We have investigated this latter phenomenon by comparing G H responses to supramaximal doses of GHRH administered at appropriate time intervals after oral glucose or placebo. MATERIALS A N D METHODS Eight normal subjects of both sexes (five female and three male) were recruited for this study. They ranged between 18 and 30 years of age (mean fSEM, 23.0 f 1.4) and weighed from 82 to 101% of ideal body weight. None had a family history of diabetes and they were all free of medications. Local health authority ethical approval was granted and informed coiisent was given by all subjects. Studies were run double-blind in random order at 0800 h after an overnight fast from midnight on three separate occasions at least a week apart. All subjects remained recumbent throughout the studies. Thirty minutes before the studies began, indwelling venous catheters were placed into antecubital veins of both arms for blood sampling and GHRH or saline infusion. Either 100 g glucose dissolved in 200 ml water or the same volume of plain water was then administered orally and blood sampling commenced. Three and a half hours (210 min) after glucose administration, 50 pg of dissolved GHRH (1-44) (Peninsula Laboratories Inc., Belmont, California, USA) were injected as an i.v. bolus, followed immediately by the infusion of GHRH (1-44) dissolved in 250 mlO.9% NaCl containing 0.2% human albumin, delivered by a volumetric pump at the constant rate of 100 pg/h for 3 h (from 210 to 390 min). A saline infusion was given in the control study instead of GHRH. The study design consisted of three tests, randomly carried out: test 1, placebo (0 min) + GHRH (bolus+ infusion from 2 10 to 390 rnin); test 2, glucose (0 min) saline infusion; test 3, glucose (0 min) + GHRH (as above). Samples for serum G H and plasma glucose were collected at 30-min intervals from 0 to 210 min, then at 15-min intervals throughout the GHRH or saline infusions (from 210 to 390 min). Blood glucose was measured by the glucose oxidase method. Serum G H was measured by liquid-phase, double-antibody radioimmunoassay (Sorin, Saluggia, Varese, Italy). The lower limit of detection was 0.4 mU/1 with inter and intra-assay coefficients of variation of 11.1 and 7.6% respectively, at a concentration of 10.4 mU/1. All results are expressed as the mean+SEM. Statistical analysis was performed by analysis of variance (ANOVA) and paired Student’s t-test.
+
RESULTS Oral glucose loading was not followed by any significant reactive hypoglycaemia, with the exception of one subject who had a blood glucose value of 0.8 mmol/l at 210 min during test 2. Mean plasma glucose and glucose Area Under Curve (AUC) were not significantly different in the second phase (from 210 to 390 min) of any test (Fig. Ib), as assessed by paired t-test and ANOVA. Serum GH was suppressed by glucose in all subjects with a mean nadir of 2.8 f 1.2 mU/1 at 150 min. At the time of commencement of GHRH (or saline) infusion (210 min) this suppressive effect had disappeared and mean serum GH levels were the same in the three tests (Fig. la). The late GH rise ( 2 2 0 mU/1) occurred in all subjects, achieving a mean
Glucose-induced GH rise and GHRH 5Opg
Glucose 100 g p.0. or placebo
+ lWpg/h
541
GHRH (1-44) or N/S
I40 120
-
100
-
80
-
60
-
40
-
20
-
0-
I
I
I
I
I
I
8r ( b )
I
T
7-
6 -
5 -
4-
I 0
p I I L -I I I I I I I I I I I I I I I ~ 30 60 90 120 150 180 210 240 270 300 330 360 390 Time ( m i n )
Fig. la, Serum GH and b, plasma glucose levels during a period of 6+ h after the administration of oral glucose (100 g at 0 min) or placebo, followed by saline infusion or GHRH (1-44) 50 pg i.v. bolus+ 100 pg/h infusion (over 210-390 rnin). -0-, glucose+saline infusion; -0-, placebo+GHRH infusion; -0-, glucose+GHRH infusion. Both a and b represent meanf SEM values in eight normal subjects of both sexes.
peak of 32.6 9.0 mU/1 at 31 5 min. The delayed release of GH following oral glucose was considerable, since the AUC for this period (from 21 0 to 390 min) was 43 12 f 1 1 10 mU/1/ 3 h when oral glucose alone was administered. Statistically there was no difference in the GH AUC for the same period during GHRH infusion in the unprimed study (6960 f 1974, NS).
542
R. Valcavi et al.
GHRH bolus + infusion produced the expected G H release with a maximum of 55.2 f20.4 mU/l at 240 min and a plateau at this level up to 270 min. Afterwards, serum GH progressively declined to 14.4 & 3.4 mU/1 despite the GHRH infusion maintained up to 390 min. When the same GHRH bolus + infusion was repeated following oral glucose pretreatment, serum G H release was greatly enhanced to a peak of 133.4f29.6 mU/1 at 255 min (P< 0.02). ANOVA revealed the presence of statistically significant differences between the two infusion studies from 240 to 3 15 min. However, the pattern of GH release during GHRH infusion was not modified by oral glucose pretreatment, showing the same attenuation of GH release (Fig. la). Analysis of AUCs confirmed that glucose pretreatment greatly enhanced the GH response to GHRH. Following glucose priming, G H AUC during GHRH infusion (from 210 to 390 min) increased from 6960 f 1974 to 15400& 1752 mU/1/3 h ( P < 0.01).
DISCUSSION In agreement with early reports (Roth et al., 1963; Hunter et al., 1967;Yalow et al., 1969) we have confirmed that a late GH rise follows an oral glucose load. Although we gave a large dose of oral glucose (100 g), the mean blood glucose did not fall to the hypoglycaemic range in the postabsorbtive phase. Therefore it seems unlikely that the late GH rise was due to hypoglycaemia and this view is further supported by the presence of a delayed GH rise during the euglycaemic glucose clamp (Sharp et al., 1987; Kraegen & Lazarus, 1988). This latter excludes the possibility that the late G H rise is dependent on neural or enteric factors associated with oral administration. Our data demonstrate that oral glucose greatly enhances GH responsiveness to GHRH when administered 3.5 h prior to the GHRH. We designed this study assuming that little, if any, GH release could be induced by endogenous GHRH while subjects were on a highdose GHRH infusion, since there is a limited quantity of GH which can be released by GHRH (Vance et al., 1985).Thus, our data showing a clear enhancement of GH secretion when GHRH infusion was preceded by an oral glucose load make it unlikely that the delayed GH-releasing activity of oral glucose is mediated via GHRH. However, our data do not allow us to reach firm conclusions at present on the mechanisms through which these changes occur. A direct pituitary effect seems unlikely, since we have previously shown that neither glucose nor insulin influences basal G H secretion or GH responses to GHRH in uitro (Page et al., 1987). A more likely possibility would be a suppressive late effect of glucose on somatostatin secretion. Supporting this hypothesis are the clear findings obtained by several groups showing that glucose suppresses somatostatin release from incubated rat hypothalami (Berelowitz et al., 1982; Lengyel et al., 1984). However, because of the well established interspecies differences in relation to the neuroregulation of GH secretion in rodents and primates (Dieguez et al., 1988), further data are needed. Finally, it has been shown that the late G H rise following glucose is associated with a rise in plasma adrenaline (Kleinbaum & Shamoon, 1982). Alpha-adrenergic pathways have a potent stimulatory effect on GH release (Blackard & Hubbel, 1970), and might therefore mediate the late GH rise following oral glucose. In summary, our data show that oral glucose markedly increases G H responses to GHRH when administered 3.5 h prior to GHRH. In contrast, glucose administered 1 h prior to GHRH causes suppression of the GH response to GHRH (Davies et al., 1984;
Glucose-induced GH rise and GHRH
543
Masuda et al., 1985). Whether this delayed interaction of glucose and GHRH could explain the lack of suppression of GH responses to GHRH in patients who have poorly controlled diabetes mellitus (Dieguez et al., 1988) remains to be established. REFERENCES
BERELOWITZ, M., DUDLAK, D. & FROHMAN, L.A. (1982) Release of somatostatin-like immunoreactivity from incubated rat hypothalamus and cerebral cortex. Journal of Clinical Investigation, 69, 1293-1301. BLACKARD, W.G. & HUBBEL,G.J. (1970) Stimulating effect of exogenous catecholamines on plasma growth hormone concentrations in presence of j?-adrenergic blockade. Metabolism, 19,547-552. DAVIES, R.R., TURNER, S. &JOHNSTON, D.G. (1984)Oral glucose inhibits growth hormone secretion induced by human pancreatic growth hormone releasing factor 1-44 in normal man. Clinical Endocrinology, 21,477481. DIEGUEZ, C., PAGE,M.D. & SCANLON, M.F. (1988) Growth hormone neuroregulation and its alterations in disease states. Clinical Endocrinology, 28, 109-143. HUNTER, W.M., WOLFSDORF, J., FARQUHAR, J.W. & RIGAL,W.M. (1967) Screening tests for growth-hormone deficiency in dwarfism. Lancet, ii, 1271-1273. KLEINBAUM, J. & SHAMCQN, H. (1982) Selective CounterreguIatory hormone response after oral ghcose in man. Journal of Clinical Endocrinology and Metabolism, 55, 787-790. KRAEGEN, E.W. & LAZARUS,L. (1988) A late plasma growth hormone rise after insulin administration with maintenance of euglycaemia: similarities to reported responses after oral glucose. Diabetes, Nutrition & Metabolism, 1,221-226. LENGYEL, A.-M.J., NIEUWENHUYZEN KRUSEMAN, A.C., GROSSMAN, A., REES,L.H. & BESSER,G.M. (1984) Glucose-induced changes in somatostatin-I4 and somatostatin-28 released from rat hypothalamic fragments in vitro. Life Sciences, 35,713-719. MASUDA,A,, SHIBASAKI, T., NAKAHARA, M., IMAKI,T., KIYISAWA, T., JIBIKI,K., DEMURA, H., SHIZUME, K. & LING,N. (1985)The effect of glucose on growth hormone (GH)-releasing hormone-mediated GH secretion in man. Journal of Clinical Endocrinology and Metabolism, 60,523-526. PAGE,M.D., KOPPESCHAAR, H.P.F., EDWARDS,C.A., DIEGUEZ, C., SCANLON, M.F. (1987) Additive effects of growth hormone releasing factor and insulin hypoglycaemia on growth hormone release in man. Clinical Endocrinology, 26, 589-595. ROTH,J., CLICK, S.M., YALOW,R. & BERSON, S.A. (1963) Secretion ofhuman growth hormone: physiologic and experimental modification. Metabolism, 12, 577-579. SHARP,P.S., FOLEY,K., CHAHAL, P. & KOHNER,E.M. (1984) The effect of plasma glucose on the growth hormone response to human pancreatic growth hormone releasing factor in normal subjects. Clinical Endocrinology, 20,497-501. SHARP,P.S., MOHAN,V., MANESCHI, F., VITELLI, F., CLOKE,H.R., BURRIN,J.M. & KOHNER,E.M. (1987) Changes in plasma growth hormone in diabetic and nondiabetic subjects during the glucose clamp. Metabolism, 36,71-75. VANCE,M.L., KAISER, D.L., EVANS,W.S., THORNER, M.O., FURLANETTO, R., RIVIER, J., VALE,W., PERISUTTI, G. & FROHMAN, L.A. (1985) Evidence for a limited growth hormone (GH)-releasing hormone (GHRH)releasable quantity of GH: effects of 6-hour infusion of GHRH on G H secretion in normal man. Journal of Clinical Endocrinology and Metabolism, 60, 370-375. YAMw, R.S., GOLDSMITH, S.J. & BERSON, S.A. (1969) Influence of physiologic fluctuations in plasma growth hormone on glucose tolerance. Diabetes, 18,402-408.
