title: Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1.
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.
authors.affiliation: Larry L. Hillblom Islet Research Center, University of California, Los Angeles, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Maedler
authors.forename: Desiree M
authors.initials: DM
authors.lastname: Schumann
authors.forename: Fabienne
authors.initials: F
authors.lastname: Schulthess
authors.forename: José
authors.initials: J
authors.lastname: Oberholzer
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D015534:Trans-Activators; D048069:Tumor Necrosis Factors; D019014:fas Receptor; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose