TY - JOUR
T1 - Decrease in β-cell proliferation precedes apoptosis during diabetes development in bio-breeding/worcester rat
T2 - Beneficial role of exendin-4
AU - Pérez-Arana, Gonzalo
AU - Blandino-Rosano, Manuel
AU - Prada-Oliveira, Arturo
AU - Aguilar-Diosdado, Manuel
AU - Segundo, Carmen
PY - 2010/6
Y1 - 2010/6
N2 - In autoimmune type 1 diabetes mellitus, proinflammatory cytokine-mediated apoptosis of β-cells has been considered to be the first event directly responsible for β-cell mass reduction. In the Bio-Breeding (BB) rat, an in vivo model used in the study of autoimmune diabetes, β-cell apoptosis is observed from 9 wk of age and takes place after an insulitis period that begins at an earlier age. Previous studies by our group have shown an antiproliferative effect of proinflammatory cytokines on cultured β-cells in Wistar rats, an effect that was partially reversed by Exendin-4, an analogue of glucagon-like peptide-1. In the current study, the changes in β-cell apoptosis and proliferation during insulitis stage were also determined in pancreatic tissue sections in normal and thymectomized BB rats, as well as in Wistar rats of 5, 7, 9, and 11 wk of age. Although stable β-cell proliferation in Wistar and thymectomized BB rats was observed along the course of the study, a decrease in β-cell proliferation and β-cell mass from the age of 5 wk, and prior to the commencement of apoptosis, was noted in BB rats. Exendin-4, in combination with anti-interferon-γ antibody, induced a near-total recovery of β-cell proliferation during the initial stages of insulitis. This highlights the importance of early intervention and, as well, the possibilities of new therapeutic approaches in preventing autoimmune diabetes by acting, initially, in the insulitis stage and, subsequently, on β-cell regeneration and on β-cell apoptosis.
AB - In autoimmune type 1 diabetes mellitus, proinflammatory cytokine-mediated apoptosis of β-cells has been considered to be the first event directly responsible for β-cell mass reduction. In the Bio-Breeding (BB) rat, an in vivo model used in the study of autoimmune diabetes, β-cell apoptosis is observed from 9 wk of age and takes place after an insulitis period that begins at an earlier age. Previous studies by our group have shown an antiproliferative effect of proinflammatory cytokines on cultured β-cells in Wistar rats, an effect that was partially reversed by Exendin-4, an analogue of glucagon-like peptide-1. In the current study, the changes in β-cell apoptosis and proliferation during insulitis stage were also determined in pancreatic tissue sections in normal and thymectomized BB rats, as well as in Wistar rats of 5, 7, 9, and 11 wk of age. Although stable β-cell proliferation in Wistar and thymectomized BB rats was observed along the course of the study, a decrease in β-cell proliferation and β-cell mass from the age of 5 wk, and prior to the commencement of apoptosis, was noted in BB rats. Exendin-4, in combination with anti-interferon-γ antibody, induced a near-total recovery of β-cell proliferation during the initial stages of insulitis. This highlights the importance of early intervention and, as well, the possibilities of new therapeutic approaches in preventing autoimmune diabetes by acting, initially, in the insulitis stage and, subsequently, on β-cell regeneration and on β-cell apoptosis.
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U2 - 10.1210/en.2009-1113
DO - 10.1210/en.2009-1113
M3 - Article
C2 - 20410202
AN - SCOPUS:77954521533
VL - 151
SP - 2538
EP - 2546
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 6
ER -