GROWTH-HORMONE SECRETAGOGUES STIMULATE THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND ARE DIABETOGENIC IN THE ZUCKER DIABETIC FATTY RAT

Besides stimulating GH release, some GH secretagogues also release ACT H and adrenal steroids. Several novel classes of potent GH secretagogu es have recently been described, and we have now tested their ability to release corticosterone in conscious normal rats. All analogs that r eleased GH also stimulated corticosterone release to some degree, thou gh the relative effects on GH and corticosterone varied somewhat. The corticosterone responses for some analogs were in the range of those o btained with CRF (2 mu g, iv), whereas closely related analogs inactiv e for GH release failed to release corticosterone. Activation of the h ypothalamic-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 mu g/day, sc, bid) was given to young obese male Zucker diabetic fatty rats (ZDF, n = 8/grou p) for 24 days. Other groups received hGH (500 mu g/day, sc, bid), rec ombinant human insulin-like growth factor (rhIGF)-1 (750 mu g/day, sc, infusion) or excipient, alone or in combination. Both G7039 and hGH i ncreased weight gain, markedly raised serum glucose (G7039, 542 +/- 37 ; hGH, 725 +/- 30; excipient, 330 +/- 57 mg/dl) and doubled insulin le vels 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, bot h G7039 and hGH treatment stimulated growth in ZDF rats, but greatly w orsened diabetes, unless IGF-1 was coadministered. Some of the effects of G7039 could be explained by GH release, but the effects on blood l ipids and body fat were not seen with hGH and may reflect the addition al activation of the hypothalamic-pituitary-adrenal axis by the secret agogue. The magnitude of these adverse effects in the ZDF animals sugg est that chronic administration of GHRP analogs with cortisol-releasin g activity to obese or diabetes-prone individuals warrants careful eva luation.