This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weinhaus, A. J. Articles by Sorenson, R. L. Search for Related Content PubMed PubMed Citation Articles by Weinhaus, A. J. Articles by Sorenson, R. L.

Dexamethasone Counteracts the Effect of Prolactin on Islet Function: Implications for Islet Regulation in Late Pregnancy¹

Department of Cell Biology and Neuroanatomy, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Address all correspondence and requests for reprints to: Robert L. Sorenson, Ph.D., Department of Cell Biology and Neuroanatomy, University of Minnesota Medical School, 4–144 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455-0303. E-mail: soren{at}lenti.med

Islets undergo a number of up-regulatory changes to meet the increased demand for insulin during pregnancy, including increased insulin secretion and ß-cell proliferation. It has been shown that elevated lactogenic hormone is directly responsible for these changes, which occur in a phasic pattern, peaking on day 15 of pregnancy and returning to control levels by day 20 (term). As placental lactogen levels remain elevated through late gestation, it was of interest to determine whether glucocorticoids (which increase during late gestation) could counteract the effects of lactogens on insulin secretion, ß-cell proliferation, and apoptosis.

We found that insulin secretion measured over 24 h in culture and acute secretion measured over 1 h in response to high glucose were increased at least 2-fold by PRL treatment after 6 days in culture. Dexamethasone (DEX) treatment had a significant inhibitory effect on secretion in a dose-dependent manner at concentrations greater than 1 nM. At 100 nM, a concentration equivalent to the plasma corticosteroid level during late pregnancy, DEX inhibited secretion to below control levels. The addition of DEX (>1 nM) inhibited secretion from PRL-treated islets to levels similar to those produced by DEX treatment alone.

Bromodeoxyuridine (10 µM) staining for the final 24 h of a 6-day culture showed that PRL treatment increased cell proliferation 6-fold over the control level. DEX treatment alone (1–1000 nM) did not reduce cell division below the control level, but significantly inhibited the rate of division in PRL-treated islets.

YoYo-1, an ultrasensitive fluorescent nucleic acid stain, was added (1 µM; 8 h) to the medium after 1–3 days of culture to examine cell death. Islets examined under confocal microscopy showed that DEX treatment (100 nM) increased the number of cells with apoptotic nuclear morphologies. This was quantified by counting the number of YoYo-labeled nuclei per islet under conventional epifluorescence microscopy. The numbers of YoYo-1-positive nuclei per islet in control and PRL-treated islets were not different after 3 days of culture. However, DEX treatment increased YoYo-1 labeling 7-fold over that in controls. DEX also increased YoYo-1 labeling in PRL-treated islets 3-fold over the control level.

These data show that the increased plasma glucocorticoid levels found during the late stages of pregnancy could effectively reverse PRL-induced up-regulation of islet function by inhibiting insulin secretion and cell proliferation while increasing apoptosis.

This article has been cited by other articles:

				R. Arumugam, E. Horowitz, D. Lu, J. J. Collier, S. Ronnebaum, D. Fleenor, and M. Freemark The Interplay of Prolactin and the Glucocorticoids in the Regulation of {beta}-Cell Gene Expression, Fatty Acid Oxidation, and Glucose-Stimulated Insulin Secretion: Implications for Carbohydrate Metabolism in Pregnancy Endocrinology, November 1, 2008; 149(11): 5401 - 5414. [Abstract] [Full Text] [PDF]

				T C. Brelje, N. V Bhagroo, L. E Stout, and R. L Sorenson Beneficial effects of lipids and prolactin on insulin secretion and {beta}-cell proliferation: a role for lipids in the adaptation of islets to pregnancy J. Endocrinol., May 1, 2008; 197(2): 265 - 276. [Abstract] [Full Text] [PDF]

				S. K. Karnik, H. Chen, G. W. McLean, J. J. Heit, X. Gu, A. Y. Zhang, M. Fontaine, M. H. Yen, and S. K. Kim Menin Controls Growth of Pancreatic {beta}-Cells in Pregnant Mice and Promotes Gestational Diabetes Mellitus Science, November 2, 2007; 318(5851): 806 - 809. [Abstract] [Full Text] [PDF]

				G. F Anhe, T. C A Nogueira, J. E Nicoletti-Carvalho, C. Lellis-Santos, H. C Barbosa, J. Cipolla-Neto, J. R Bosqueiro, A. C Boschero, and S. Bordin Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period J. Endocrinol., October 1, 2007; 195(1): 17 - 27. [Abstract] [Full Text] [PDF]

				H. Ghanaat-Pour, Z. Huang, M. Lehtihet, and A. Sjoholm Global expression profiling of glucose-regulated genes in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats J. Mol. Endocrinol., August 1, 2007; 39(2): 135 - 150. [Abstract] [Full Text] [PDF]

				J. C. Voltarelli, C. E. B. Couri, A. B. P. L. Stracieri, M. C. Oliveira, D. A. Moraes, F. Pieroni, M. Coutinho, K. C. R. Malmegrim, M. C. Foss-Freitas, B. P. Simoes, et al. Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus JAMA, April 11, 2007; 297(14): 1568 - 1576. [Abstract] [Full Text] [PDF]

				M. J. Holness, G. K. Greenwood, N. D. Smith, and M. C. Sugden Peroxisome Proliferator-Activated Receptor-{alpha} and Glucocorticoids Interactively Regulate Insulin Secretion During Pregnancy Diabetes, December 1, 2006; 55(12): 3501 - 3508. [Abstract] [Full Text] [PDF]

				F. Ranta, D. Avram, S. Berchtold, M. Dufer, G. Drews, F. Lang, and S. Ullrich Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes, May 1, 2006; 55(5): 1380 - 1390. [Abstract] [Full Text] [PDF]

				Y. Fujinaka, D. Sipula, A. Garcia-Ocana, and R. C. Vasavada Characterization of Mice Doubly Transgenic for Parathyroid Hormone-Related Protein and Murine Placental Lactogen: A Novel Role for Placental Lactogen in Pancreatic {beta}-Cell Survival Diabetes, December 1, 2004; 53(12): 3120 - 3130. [Abstract] [Full Text] [PDF]

				E. Gesina, F. Tronche, P. Herrera, B. Duchene, W. Tales, P. Czernichow, and B. Breant Dissecting the Role of Glucocorticoids on Pancreas Development Diabetes, September 1, 2004; 53(9): 2322 - 2329. [Abstract] [Full Text] [PDF]

				J. Shao, L. Qiao, and J. E. Friedman Prolactin, progesterone, and dexamethasone coordinately and adversely regulate glucokinase and cAMP/PDE cascades in MIN6 {beta}-cells Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E304 - E310. [Abstract] [Full Text] [PDF]

				M. J. Holness and M. C. Sugden Dexamethasone during Late Gestation Exacerbates Peripheral Insulin Resistance and Selectively Targets Glucose-Sensitive Functions in {beta} Cell and Liver Endocrinology, September 1, 2001; 142(9): 3742 - 3748. [Abstract] [Full Text] [PDF]

				B. Blondeau, J. Lesage, P. Czernichow, J. P. Dupouy, and B. Breant Glucocorticoids impair fetal {beta}-cell development in rats Am J Physiol Endocrinol Metab, September 1, 2001; 281(3): E592 - E599. [Abstract] [Full Text] [PDF]