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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/E681    most recent 90931.2008v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rafacho, A. Articles by Bosqueiro, J. R. Search for Related Content PubMed PubMed Citation Articles by Rafacho, A. Articles by Bosqueiro, J. R.

High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

¹Department of Physiology and Biophysics, Institute of Biology, State University of Campinas; ²Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo; ³Department of Biology, Institute of Biosciences, Humanities, and Exact Sciences and ⁴School of Sciences, Department of Physical Education, São Paulo State University, São Paulo, Brazil

Submitted 19 November 2008 ; accepted in final form 16 January 2009

Activation of insulin signaling and cell cycle intermediates is required for adult β-cell proliferation. Here, we report a model to study β-cell proliferation in living rats by administering three different doses of dexamethasone (0.1, 0.5, and 1.0 mg/kg ip, DEX 0.1, DEX 0.5, and DEX 1.0, respectively) for 5 days. Insulin sensitivity, insulin secretion, and histomorphometric data were investigated. Western blotting was used to analyze the levels of proteins related to the control of β-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in β-cell proliferation and an increase (17%) in β-cell size, with significant increase in β-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in β-cell proliferation. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only islet function. Activation of the insulin receptor substrate 2/phosphatidylinositol 3-kinase/serine-threonine kinase/ribosomal protein S6 kinase pathway, as well as protein retinoblastoma in islets from DEX 1.0 and DEX 0.5, but not in DEX 0.1, rats was also observed. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory β-cell alterations. Augmented β-cell mass involves β-cell hyperplasia and, to a lower extent, β-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for β-cell proliferation in the dexamethasone-induced insulin resistance.

β-cell growth; glucocorticoid; hyperglycemia; hyperinsulinemia; insulin resistance

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