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

Department of Endocrinology (R.G.C., D.L.M., W.B.W., Y.H.M, E.E.T.), Genentech Inc., South San Francisco, California 94080; and Department of Neurophysiology (G.B.T., K.M.F, I.C.A.F.R.), National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom

Address all correspondence and requests for reprints to: Dr. R. G. Clark, Genentech, Inc., Endocrine Research, 390 Point San Bruno Boulevard, Mail Stop #37, South San Francisco, California 94080. E-mail: rossc{at}gene.com

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, 100 µg/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.

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