Clinical Endocrinology (1992) 36,487-490

Differential effects of arginine on growth hormone releasing hormone and insulin induced growth hormone secretion H. P. F. Koppeschaar, C. D. ten Horn, J. H. H. Thljssen, M. D. Page', C. Dieguezt and M. F. Scanion* Department of Endocrinology, University Hospital Utrecht, The Netherlands, 'Department of Medicine, University of Wales College of Medicine, Cardiff, UK and ?Department of Physiology, University of Santiago de Compostela, Spain (Received 25 September 1991; returned for revision 19 November 1991; finally revised 29 November 1991; accepted 17 December 1991)

Summary

assessed using several neuropharmacological and metabolic tests, of which insulin-induced hypoglycaemia (IST), arginine and GHRH are most employed. Although there is no doubt that GHRH-induced G H release is exerted directly at the level of the somatotrophs, lack of a suitable animal model has prevented obtaining clear knowledge of the mechanisms by which IST and arginine induce G H release in humans. Nevertheless, recent data suggest that both IST and arginineinduced GH release are mediated by similar mechanisms, namely by a decrease of hypothalamic somatostatinergic tone. In order to gain further insight into the mechanisms by which GH secretion is stimulated, we studied the interaction of arginine, GHRH and IST on G H secretion in normal adult subjects.

OBJECTIVE We wished to investigate the interaction of

arglnine, GHRH and insulin stress on OH secretion. DESIGN Six healthy, non-obese volunteers underwent seven separate studes in random order. They received (1) insulin alone at 0 minutes; (2) GHRH alone at 15 minutes; (3) arglnlne alone at 0-30 minutes; (4) arglnlne at 0-30 minutes and GHRH at 15 minutes; (5) Insulin at 0 minutes and arglnine at 0-30 minutes; (6) Insulin at 0 minutes, GHRH at 15 minutes and arglnine at 0-30 minutes; (7) insulin at 0 minutes and GHRH at 15 mlnutes. MEASUREMENTSGH and PRL were measured from -30 to 150 minutes at intervals of 15 minutes. RESULTS Arginlne increased GH responses to GHRH and decreased GH responses to hypoglycaemla, but this inhibitory effect of arglnine was reversed by GHRH. CONCLUSIONS The findings suggest that arginlneInduced GH release is mainly mediated by a decrease In somatostatinergic tone, while GH responses to Insulin stress are probably mediated by both an Increase In hypothaiamlcGHRHreleaseand lnhlbltlonof somatostatin.

GH secretion from the anterior pituitary gland is under the dual control of the hypothalamic GH-releasing hormone (GHRH) and the release inhibiting hormone somatostatin. These hypothalamic peptides are released from the median eminence into the portal system and modulate GH release by acting directly on the pituitary. Pituitary GH reserve can be

Subjects and methods

Tests were carried out in six healthy, non-obese volunteers (age range 22-26 years) following local ethical committee approval. After an overnight fast, separate indwelling venous cannuIae were inserted for blood sampling and administration of test substances. The subjects remained recumbent throughout the tests. At 0830 h (at least 30 minutes after insertion of the cannula) each subject received a combination of insulin (Actrapid, Novo Laboratories, 0.15 U/kg i.v.), GHRHL&(1 pg/kg i.v.) and arginine (30 g i.v. over 30 minutes) according to the following regimes which were carried out in random order: (1) insulin alone at 0 minutes, (2) GHRH alone at 15 minutes, (3) arginine alone at 0-30 minutes, (4) arginine at 0-30 minutes in combination with GHRH at 15 minutes, (5) insulin at 0 minutes with arginine at 0-30 minutes, (6) insulin at 0 minutes, followed by GHRH at 15 minutes and arginine at 0-30 minutes and (7) insulin at 0 minutes followed by GHRH at 15 minutes. Samples were taken at 15 minute intervals and assayed for G H and PRL by double polyclonal antibody radioimmunoassay. The intra and inter-assay coefficients of variation were 7.2-9.3% and 9-1 1.5% for G H and 7.3-12.1% and 78.5% for PRL respectively. Glucose was assayed by the GluCIMET reagent method. Statistical analysis

Correspondence: H. P. F. Koppeschaar, Afdeling Endocrinologie, Huispostnr. G 02.228, Academisch Ziekenhuis Utrecht, Postbus 85500, 3508 GA Utrecht, The Netherlands.

The results were analysed by Friedman analysis. An area under the curve (AUC) variable was calculated for the GH 487

0

0.87 f0.24 1.03f0.4 1 64.13 f 19.82 0.30+ 0.03 0.23 0.02 0.46 k0.06

2.07f 1.08 149f0.17 0.38f0-04 0.27f0.01 4.6 & 0.3 4.2& 0.2

1.25f0.2 1 1.02f0.24 0.36 f 0.04 4.0k0.1 3.7f0.2

ARG/GHRH GH PRL

IST/ARG/GHRH GH PRL GLU

IST/GHRH GH PRL GLU

Values are the mean f SEM.

0 5 7 f 0.08

1.12k0.26 0.31 kO.01 4.5k0.2

IST/ARG GH PRL GLU 102.57f24.76 0.51 kO.05

25.01 f6.97 0.74 f0.07 1.5k0.1

11.82k3.88 0.49_+ 0.06

44.71 f 10.20 0.20k 0.04

48.19 f7.86 1.22f 0.07 1.5f0.1

45

43.74f 8.96 0.43k0.04 0 6 f 0.2

69.72 f 13.37 1.15f 0.19 1.2f0.2

58.66+ 19-94 10550f 23.66 0.66 f0.05 040f0.06 1.1fO.1 1.6f0.2

0.95 f 0.12 10.45f 7 4 4 0.26+0*02 0.50 f 0.02 4.5k0.2 1.9f0.2

160_+0.38 8.43 k4.56 0.19f 0.03 0.39 k0.05

1.02f0.22 0.3 1& O W

ARG GH PR

1.1 1 20.14 36.77k 10.04 0.21 k0.03 0.22 f 0.04

8.05 f 3.38 0.33k0.06 0.9 k0.3

30

0.80f0.29 0-33fO.05

1.29f0.25 1.0150.24 0.30 f 0.04 0.23 k0.03 4.3fO.I 4.1 k0.3

-30

GHRH GH PRL

IST GH PRL GLU

Time (min)

82k68f 12.16 1.43f 0.17 1.4 f 0.2

121.87k20.00 0.57 f 0.04 1.1k0.2

100.55k29.29 0.41 kO.04

41.58 f 14.45 0.75 k0.13 1.3&04

12.24 k350 0.41 k0.04

47.89k9.30 0 17k0.03

78.61f 19.82 1.39 k0.08 1.6k0.2

60

98.80 k 19.62 1.26 k0.16 1.7 f 0.2

119.58f 10.05 0.71 fO.10 1.4f 0.2

+

96.42f23.31 0.33 0.04

51.94+ 12.81 0.77 k0.14 1.6f 0.1

11.41 *3.63 0.38 f 0.06

42.53 f 9.17 0.17 k0.03

101.70f 27.80 1.32f0.09 1.8f0.4

75

120

150

60.68 f 8.75 0.87k0.23 2.320.2

9.50 f4.71 0.25f044

25.50f6.23 0.13 k0.03

54.72 f 7.96 0.81 k0.24 2.7f0.3

6.42 f 3.94 020*094

19.23k4.43 0 15f 0.03

94.65k22.04 94,22f 19.03 77.35f 18.94 54.90 f 11.18 0.61 f0.08 0.73fO.11 1.12k0.15 0.94k0.13 3.2 f 0.3 2.8 f 0.2 2.1 f 0.2 2.3 f0.2

103.56k8.86 91.15+ 10.35 82.66f 14.12 50-82f 8.98 0.49 fO.15 0.75f0.19 0.68f0.21 0.79+0*19 3.4 f0.6 2.7 k0.4 2.2 k0.4 1.9k0.3

28.95 f 6.80 0.17 f0.03

37.35 f8.37 0.70k0.21 3.0f 0 4

3.70f2.20 0-17f O . 0 4

6.31 f2.1 I 0.14f0.02

9964k26.17 75.34f 11.15 44.88 f9.12 0.55+0.10 0.93+0-11 0.79k0.09 3.4 f 0.2 2.7f0.2 2.4f0.2

105

80.76f 15.11 65.01 k 10.37 44.99f6.62 0.21 k0.03 0928f003 0.222003

59.61 k9.82 040k0.22 2.020.3

0.31 kO.05

1 1.16k4.79

32.87f7.14 0.15 f0.03

9.5.92f2440 1.09+0.10 2.1f0.2

90

Table 1 GH (mU/1) and PRL (U/1) in response to insulin (IST), arginine (ARG) and GHRH alone and in the different combinations and blood glucose levels (nmol/l).

rn

Y

(c1

0

0

2. a

0

n

a

f

Clinical Endocrinology (1992) 36

Growth hormone secretion

489

release using the Wilcoxon rule. Results are shown as mean fSEM. Results

In the group of six subjects who received insulin alone at t =0 minutes GH levels rose significantly, peaking at 75 minutes after administration (mean k SEM 101.7Ok27.8 mU/l). Blood glucose levels were lowest at t = 30 (0.9f0.3 nmol/l). For GHRH (?= 15) and arginine ( t = 0-30) alone GH levels rose, peaking at t=60 (47.89_+9-3and 12.24k3.5 mU/l respectively). The area under the GH curves in response to IST us GHRH and IST us arginine was significantly higher (9135f2157 us 3920f749; P

Differential effects of arginine on growth hormone releasing hormone and insulin induced growth hormone secretion.

We wished to investigate the interaction of arginine, GHRH and insulin stress on GH secretion...
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