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

Abstract

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 microg, 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 microg/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 microg/day, sc, bid), recombinant human insulin-like growth factor (rhIGF)-1 (750 microg/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 ofG7039 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.

Co-Localization of Growth Hormone Secretagogue Receptor and NPY mRNA in the Arcuate Nucleus of the Rat

“…A variety of peptidic and non-peptidic GHS compounds such as GHRP-2, GHRP-6 [27, 33], G7039 [34]and MK-677 [35]have a marked effect on the release of adrenocorticotropin and cortisol via a hypothalamic mechanism probably involving release of corticotropin-releasing hormone from the paraventricular nucleus (PVN) [28]. In some cases this release was comparable to that obtained with corticotropin-releasing hormone.…”

Ghrelin Modulates the Downstream Molecules of Insulin Signaling in Hepatoma Cells

“…We propose that ghrelin can affect gluconeogenesis, at least in the H4-II-E cells, by attenuating the effect of insulin on the expression of PEPCK. Considering the effect of ghrelin on glucose homeostasis, it is of note that GHSs are diabetogenic in rats (33). Physiological significance of ghrelin in vivo animals is to be clarified.…”

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

“…Treatment with hexarelin increased plasma glucose concentrations in obese rats but not in lean rats. One possibility of these findings may be related to the ability of hexarelin to stimulate the hypothalamic-pituitary-adrenal (HPA) axis [112,113]. However, the mechanism by which GHS stimulate the HPA axis is unknown.…”