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Steroid effects on intracellular degradation of insulin and crinophagy in isolated pancreatic islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2007 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 277, no 1-2, 35-41 p.Article in journal (Refereed) Published
Abstract [en]

Under physiological conditions substantial amounts of hormone may be degraded within endocrine cells by a crinophagic process comprising fusions of secretory granules with lysosomes. Glucocorticoids may stabilise and progesterone destabilise lysosomal membranes. The effects of corticosterone and progesterone on intracellular degradation of insulin and crinophagy were determined in pancreatic β-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 β-cells. Corticosterone decreased and progesterone increased islet production of prostaglandin E2. 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 β-cells.

Place, publisher, year, edition, pages
2007. Vol. 277, no 1-2, 35-41 p.
Keyword [en]
Pancreatic islets, Corticosterone, Progesterone, Lysosomes, Intracellular insulin degradation, Prostaglandin E2
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-95490DOI: 10.1016/j.mce.2007.07.007ISI: 000250894000005PubMedID: 17869410OAI: oai:DiVA.org:uu-95490DiVA: diva2:169726
Available from: 2007-03-02 Created: 2007-03-02 Last updated: 2011-01-18Bibliographically approved
In thesis
1. Intracellular Degradation of Insulin in Pancreatic Islets
Open this publication in new window or tab >>Intracellular Degradation of Insulin in Pancreatic Islets
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a substantial intracellular degradation of insulin in pancreatic islets. This may be a physiological process, which, in correspondence with biosynthesis and secretion of insulin, would optimize the secretory granule content of the pancreatic β-cell. Insulin degradation may be effected by crinophagy, a process where secretory granules fuse with lysosomes. The general aim of this thesis was to investigate possible control mechanisms for intracellular degradation of insulin and crinophagy in isolated pancreatic islets. In islets incubated at low glucose concentrations there was an insulin degradation and this correlated well with the ultrastructural findings, where a lot of secondary lysosomes containing secretory granules were found. In islets incubated at a high glucose concentration there was no insulin degradation and the ultrastructure revealed only a few insulin granules and mostly primary lysosomes, indicating that there was no crinophagic activity. With interleukin-1β the islet insulin degradation, nitric oxide production and prostaglandin E2 production were increased. The effects were abolished either by inhibition of inducible nitric oxide synthetase by aminoguanidine, or by the specific cyclooxygenase-2 inhibitor rofecoxib. These findings indicate that there is a connection between the intracellular degradation of insulin, production of nitric oxide and cyclooxygenase-2 activation. The nitric oxide donor DETA/NO enhanced the intracellular degradation of insulin and cyclooxygenase-2 activation with subsequent production of prostaglandin E2, suggesting that the link between nitric oxide and insulin degradation may be a cyclooxygenase-2 activation and subsequent prostaglandin E2 production. With corticosterone added to islet incubations the insulin degradation decreased, which paralleled with a diminished crinophagy and formation of prostaglandin E2. With progesterone there was instead an increase in insulin degradation and crinophagy and an increased formation of prostaglandin E2. These effects were abolished by mifepristone, an inhibitor of intracellular corticosterone and progesterone receptors. This suggests that the effects from these steroids are exerted via a change in islet gene expression and cyclooxygenase-2 activation. It was also concluded that phospholipase A2 is involved in insulin degradation and that the isoform secretory phospholipase A2 may be involved in triggering this process. This suggests that cyclooxygenase-2 activation with a subsequent production of prostaglandin E2 may provide a control mechanism for intracellular degradation of insulin and crinophagy in pancreatic islets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 49 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 230
Cell biology, Cellbiologi
urn:nbn:se:uu:diva-7586 (URN)978-91-554-6807-1 (ISBN)
Public defence
2007-03-23, B7:101a, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2007-03-02 Created: 2007-03-02Bibliographically approved

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