High doses of dexamethasone induce increased beta-cell proliferation in pancreatic rat islets.
Activation of insulin signaling and cell cycle intermediates is required for adult beta-cell proliferation. Here, we report a model to study beta-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 beta-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in beta-cell proliferation and an increase (17%) in beta-cell size, with significant increase in beta-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in beta-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 beta-cell alterations. Augmented beta-cell mass involves beta-cell hyperplasia and, to a lower extent, beta-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for beta-cell proliferation in the dexamethasone-induced insulin resistance.
Rafacho
Alex
A
Department of Physiology and Biophysics, Institute of Biology, University of Campinas, Rua Monteiro Lobato, s/n. Cidade Universitária, Campinas, São Paulo, Brazil, 13083-970. rafacho@unicamp.br
Cestari
Tânia M
TM
Taboga
Sebastião R
SR
Boschero
Antonio C
AC
Bosqueiro
José R
JR
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000473:pathology; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar
D003907:Dexamethasone