Steroid effects on intracellular degradation of insulin and crinophagy in isolated pancreatic islets

Abstract

Please cite this article as: Sandberg, M., Borg, L.A.H., Steroid effects on intracellular degradation of insulin and crinophagy in isolated pancreatic islets, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The effects of corticosterone and progesterone on intracellular degradation of insulin and crinophagy were determined in pancreatic -cells, and possible pathways mediating these effects were evaluated. Pancreatic islets were isolated from mice, intracellular degradation of insulin was measured by a pulse-chase method, and crinophagy was studied by electron microscopy. The islets were exposed to 3.3, 5.5 or 28 mM glucose with or without corticosterone, progesterone or the receptor ligands A-224817.0 and WAY-161358.Mifepristone was used to block steroid receptors and indomethacin to inhibit prostaglandin synthesis. Corticosterone caused a concentration-dependent decrease of insulin degradation at the lower glucose concentrations. Progesterone effected a concentration-dependent stimulation of insulin degradation. These results were paralleled with changes of the crinophagic activity in the -cells. Corticosterone decreased and progesterone increased islet production of prostaglandin E 2 . Mifepristone abolished the steroid actions on insulin degradation and prostaglandin production. The effects of corticosterone were mimicked by the selective glucocorticoid receptor modulator A-224817.0, but in contrast to progesterone, the selective progesterone receptor agonist WAY-161358 had no effect on insulin degradation or prostaglandin production. Inhibition of cyclooxygenase blocked insulin degradation. The findings indicate that both corticosterone and progesterone could affect intracellular insulin degradation and crinophagy solely via the glucocorticoid receptor, and that prostaglandins may have a regulatory role in intracellular turnover of secretory material in pancreatic islet -cells.

Autophagy in the endocrine glands

“…As progesterone had an opposite effect on crinophagy in the pituitary compared with the pancreatic islets, there appears to be no universal relationship between progesterone and crinophagy. In the pancreatic islet B-cells, changes in crinophagy levels due to progesterone and corticosterone were blocked with mifepristone, a receptor antagonist for both corticosterone and progesterone receptors (Sandberg & Borg 2007). Furthermore, crinophagy levels positively correlated with increased production of prostaglandin E 2 via progesterone stimulation and its decreased production via corticosterone stimulation.…”

“…It has been established that crinophagy is upregulated in response to an inhibition of secretion or an overproduction of secretory material, but the mechanism of induction and regulation remains largely unknown. Modulation by steroids has been suggested in the pituitary, where oestrogen positively and progesterone negatively correlated with crinophagy of prolactin secretory granules (Poole et al 1981, Kuriakose et al 1989, and the pancreas, where progesterone upregulated and corticosterone downregulated crinophagy in B-cells (Sandberg & Borg 2007). As progesterone had an opposite effect on crinophagy in the pituitary compared with the pancreatic islets, there appears to be no universal relationship between progesterone and crinophagy.…”

“…Furthermore, crinophagy levels positively correlated with increased production of prostaglandin E 2 via progesterone stimulation and its decreased production via corticosterone stimulation. This suggests that in pancreatic B-cells, corticosterone and progesterone stimulation may directly modulate crinophagy through their regulation of prostaglandin E 2 (Sandberg & Borg 2007). In the pituitary, however, where oestrogen is known to induce the synthesis and secretion of prolactin, the correlation between oestrogen and crinophagy may be an indirect one; the increase in crinophagy triggered by the overproduction of prolactin rather than by oestrogen stimulation directly (Kuriakose et al 1989).…”

“…Along with the ability of glucose to modulate crinophagy levels, Sandberg & Borg (2007) showed that corticosterone and progesterone acting on glucocorticoid receptors affected intracellular degradation of insulin, potentially by affecting the production of prostaglandins within the B-cells. This finding represents the first mention of a possible downstream molecule that could be involved in the regulation of crinophagy.…”

Fructose Rich Diet-Induced High Plasminogen Activator Inhibitor-1 (PAI-1) Production in the Adult Female Rat: Protective Effect of Progesterone

“…It is openly accepted that AT-derived adipokines regulate gonadal function, and that sex steroids such as testosterone [5,11] modulate white adipocyte endocrine function; however, little is known about potential P4 activity on AT function. Although lipogenic P4 activity has been reported in isolated adipocytes [12,13], and in vivo in the normal female rat [14], P4 has also been identified as a stimulator of insulin degradation at the pancreatic level [15]. Contrary to the effect of androgens, P4 did not prevent pancreatic cell death [16].…”