Growth Hormone Secretagogues Stimulate the Hypothalamic-Pituitary-Adrenal Axis and Are Diabetogenic in the Zucker Diabetic Fatty Rat1

• Published in: Endocrinology (Philadelphia) Vol. 138; no. 10; pp. 4316 - 4323
• Main Authors: Clark, R. G, Thomas, G. B, Mortensen, D. L, Won, W. B, Ma, Y. H, Tomlinson, E. E, Fairhall, K. M, Robinson, I. C. A. F
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01-10-1997
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.138.10.5424

Besides stimulating GH release, some GH secretagogues also release ACTH
and adrenal steroids. Several novel classes of potent GH secretagogues
have recently been described, and we have now tested their ability to
release corticosterone in conscious normal rats. All analogs that
released GH also stimulated corticosterone release to some degree,
though the relative effects on GH and corticosterone varied somewhat.
The corticosterone responses for some analogs were in the range of
those obtained with CRF (2 μg, iv), whereas closely related analogs
inactive for GH release failed to release corticosterone.
Activation of the hypothalamic-pituitary-adrenal axis with GH release
by GHRPs could be a highly diabetogenic combination in susceptible
individuals. Therefore, a potent GHRP pentapeptide analog (G7039, 100μ
g/day, sc, bid) was given to young obese male Zucker diabetic fatty
rats (ZDF, n = 8/group) for 24 days. Other groups received hGH
(500 μg/day, sc, bid), recombinant human insulin-like growth factor
(rhIGF)-1 (750 μg/day, sc, infusion) or excipient, alone or in
combination. Both G7039 and hGH increased weight gain, markedly raised
serum glucose (G7039, 542 ± 37; hGH, 725 ± 30; excipient,
330 ± 57 mg/dl) and doubled insulin levels but had opposite
effects on serum triglycerides (G7039, 1412 ± 44; hGH 501 ±
46; excipient 1058 ± 73 mg/dl) and fat depot weights. In
contrast, treatment with IGF-1, alone or in combination with hGH or
G7039, improved the diabetic state and stimulated growth. Thus, both
G7039 and hGH treatment stimulated growth in ZDF rats, but greatly
worsened diabetes, unless IGF-1 was coadministered. Some of the effects
of G7039 could be explained by GH release, but the effects on blood
lipids and body fat were not seen with hGH and may reflect the
additional activation of the hypothalamic-pituitary-adrenal axis by the
secretagogue. The magnitude of these adverse effects in the ZDF animals
suggest that chronic administration of GHRP analogs with
cortisol-releasing activity to obese or diabetes-prone individuals
warrants careful evaluation.