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Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1

Maedler, Kathrin
Schumann, Desiree
Schulthess, Fabienne
Donath, Marc Y
Published in Diabetes. 2006, vol. 55, no. 9, p. 2455-62
Abstract Type 2 diabetes is characterized by a deficit in beta-cell mass, and its incidence increases with age. Here, we analyzed beta-cell turnover in islets from 2- to 3- compared with 7- to 8-month-old rats and in human islets from 53 organ donors with ages ranging from 17 to 74 years. In cultured islets from 2- to 3-month-old rats, the age at which rats are usually investigated, increasing glucose from 5.5 to 11.1 mmol/l decreased beta-cell apoptosis, which was augmented when glucose was further increased to 33.3 mmol/l. In parallel, beta-cell proliferation was increased by both 11.1 and 33.3 mmol/l glucose compared with 5.5 mmol/l. In contrast, in islets from 7- to 8-month-old rats and from adult humans, increasing glucose concentrations from 5.5 to 33.3 mmol/l induced a linear increase in beta-cell death and a decrease in proliferation. Additionally, in cultivated human islets, age correlated positively with the sensitivity to glucose-induced beta-cell apoptosis and negatively to baseline proliferation. In rat islets, constitutive expression of Fas ligand and glucose-induced Fas receptor expression were observed only in 7- to 8-month-old but not in 2- to 3-month-old islets, whereas no age-dependent changes in the Fas/Fas ligand system could be detected in human islets. However, pancreatic duodenal homeobox (PDX)-1 expression decreased with age in pancreatic tissue sections of rats and humans. Furthermore, older rat islets were more sensitive to the high-glucose-mediated decrease in PDX-1 expression than younger islets. Therefore, differences in glucose sensitivity between human and 2- to 3-month-old rat islets may be due to both differences in age and in the genetic background. These data provide a possible explanation for the increased incidence of type 2 diabetes at an older age and support the use of islets from older rats as a more appropriate model to study glucose-induced beta-cell apoptosis.
Keywords AdolescentAdultAgedAging/physiologyAnimalsAntigens, CD95/physiologyApoptosis/drug effects/physiologyCell ProliferationCells, CulturedFas Ligand ProteinGlucose/pharmacologyHomeodomain Proteins/physiologyHumansInsulin-Secreting Cells/cytologyMaleMembrane Glycoproteins/physiologyMiddle AgedRatsRats, Sprague-DawleyTrans-Activators/physiologyTumor Necrosis Factors/physiology
PMID: 16936193
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Research group La transplantation d'îlots de Langerhans (623)
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MAEDLER, Kathrin et al. Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1. In: Diabetes, 2006, vol. 55, n° 9, p. 2455-62. doi: 10.2337/db05-1586 https://archive-ouverte.unige.ch/unige:36975

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Deposited on : 2014-05-27

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