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DOI: 10.2337/db05-1586
© 2006 by the American Diabetes Association
Aging Correlates With Decreased ß-Cell Proliferative Capacity and Enhanced Sensitivity to Apoptosis
A Potential Role for Fas and Pancreatic Duodenal Homeobox-1
1 Larry L. Hillblom Islet Research Center, University of California, Los Angeles, California
2 Division of Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland
3 Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois
4 Department of Surgery, University Medical Center, Geneva, Switzerland
Address correspondence and reprint requests to Marc Y. Donath, MD, Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: marc.donath{at}usz.ch
Abbreviations:
KRB, Krebs-Ringer bicarbonate buffer; PDX, pancreatic duodenal homeobox; TUNEL, transferase-mediated dUTP nick-end labeling
Type 2 diabetes is characterized by a deficit in ß-cell mass, and its incidence increases with age. Here, we analyzed ß-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 ß-cell apoptosis, which was augmented when glucose was further increased to 33.3 mmol/l. In parallel, ß-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 ß-cell death and a decrease in proliferation. Additionally, in cultivated human islets, age correlated positively with the sensitivity to glucose-induced ß-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 ß-cell apoptosis.
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