Altered growth hormone (GH) secretion in vivo and in vitro in the diabetes-prone BB/Worcester rat

F. Nieves-Rivera, J. R. Kerrigan, R. J. Krieg, J. Egan, L. J. Hwang, E. Truumees, Johannes D Veldhuis, W. S. Evans, A. D. Rogol

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Abstract

Diminished concentrations of growth hormone (GH) have been observed in the male BB/Wor rat with diabetes mellitus (DM). The precise mechanism(s) responsible for the altered GH levels is not entirely understood. We have therefore employed independent techniques to investigate potential alterations in: 1) the peripheral metabolism of the hormone; 2) GH release by somatotropes; and 3) hypothalamic regulation of GH secretion. An extra group of insulin-untreated animals was included for the studies of acute DM. The results demonstrate diminished circulating mean concentrations of GH (35 ± 4 vs. 16 ± 4 μg/l; mean ± SEM; control vs. animal with DM, P = 0.006) due to impaired GH secretion. In particular, there was a decrease in the mass of GH secreted per burst (230 ± 22 vs. 136 ± 34 μg/l; P = 0.04) and in the GH secretory rate (24 ± 4 vs. 9 ± 3 μg/l/min; P < 0.01). No differences in the secretory burst frequency, (5.3 ± 0.3 vs. 5.2 ± 0.5 /8-h; P = 0.68), secretory half-duration (10 ± 2 vs. 17 ± 2 min; P = 0.09), or serum GH half-life (8 ± 1 vs. 6 ± 1 min; P = 0.13) were observed. In vitro studies of acutely dispersed somatotropes obtained from rats with DM demonstrated increased sensitivity to GHRH (1 nM), as detected by a greater mean hemolytic plaque area following exposure to an EC50 dose of the secretagogue (14.3 ± 3.3 vs. 17.4 ± 3.5 μm2 x 103; P = 0.049), and diminished sensitivity to SRIH (1 nM) inhibition of GH release following exposure to an EC50 dose of the secretagogue (10.0 ± 1.2 vs. 14.9 ± 2.3 μm2 x 103; P = 0.026). The number of the pituitary cells (18.0 ± 2.8 vs. 15.3 ± 1.0 x 105 cells; P = 0.38) as well as the number of somatotropes (7.3 ± 1.4 vs. 7.6 ± 0.9 x 105 cells; P = 0.87) were indistinguishable between experimental groups. Hypothalamic gene transcript levels for GH-releasing hormone (GHRH) and somatotropin release-inhibiting hormone (SRIH) were evaluated by in situ hybridization histochemistry to assess cellular synthetic activity. Insulin-treated and non-treated animals with acute DM (2 days duration) demonstrated a decrease in GHRH mRNA levels as assessed by densitometric analysis of (8.0 ± 0.5 vs. 6.1 ± 0.7 vs. 6.0 ± 0.5 μm2 x 104 control vs. insulin-treated vs. non-treated, P < 0.05) and grain counting measurements (110 ± 7 vs. 66 ± 5 vs. 70 ± 6 μm2, P < 0.05). The number of neurons expressing the GHRH gene was indistinguishable among the groups. No changes in GHRH gene transcript levels were observed in animals with chronic DM (> 2-21 days duration). No differences in preproSRIH mRNA levels were evident in rats with acute and/or chronic DM. We conclude that: 1) diminished GH concentrations in the BB/Wor rat with DM are due to diminished rate and mass of GH released per secretory episode without any alteration in the number or duration of secretory events, or in the estimated metabolic clearance rate of GH; 2) in vitro evidence of enhanced sensitivity of somatotropes from rats with DM to GHRH was found suggesting attenuated GHRH release in vivo. Conversely, somatotropes from animals with DM demonstrated decreased sensitivity to SRIH suggesting increased SRIH exposure in vivo, 3) GHRH gene transcript levels were diminished acutely in the BB/Wor rat following the onset of DM, but were invariant beyond 2 and up to 21 days after the development of DM. The altered GHRH mRNA levels may be, at least initially, causally related to the dampened pituitary GH secretion and the consequent lowered GH concentrations. Changes in hypothalamic SRIH gene transcript levels were not demonstrable in the diabetic animals.

Original languageEnglish (US)
Pages (from-to)235-244
Number of pages10
JournalGrowth Regulation
Volume3
Issue number4
StatePublished - 1993
Externally publishedYes

Keywords

  • Gene transcript
  • Growth hormone-releasing hormone
  • Somatostatin
  • Somatotrope

ASJC Scopus subject areas

  • Neuroscience(all)

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    Nieves-Rivera, F., Kerrigan, J. R., Krieg, R. J., Egan, J., Hwang, L. J., Truumees, E., Veldhuis, J. D., Evans, W. S., & Rogol, A. D. (1993). Altered growth hormone (GH) secretion in vivo and in vitro in the diabetes-prone BB/Worcester rat. Growth Regulation, 3(4), 235-244.