Aging Correlates With Decreased β-Cell Proliferative Capacity and Enhanced Sensitivity to Apoptosis

A Potential Role for Fas and Pancreatic Duodenal Homeobox-1

  1. Kathrin Maedler1,
  2. Desiree M. Schumann2,
  3. Fabienne Schulthess1,
  4. José Oberholzer3,
  5. Domenico Bosco4,
  6. Thierry Berney4 and
  7. Marc Y. Donath2
  1. 1Larry L. Hillblom Islet Research Center, University of California, Los Angeles, California
  2. 2Division of Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland
  3. 3Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois
  4. 4Department of Surgery, University Medical Center, Geneva, Switzerland
  1. 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

Abstract

Type 2 diabetes is characterized by a deficit in β-cell mass, and its incidence increases with age. Here, we analyzed β-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 β-cell apoptosis, which was augmented when glucose was further increased to 33.3 mmol/l. In parallel, β-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 β-cell death and a decrease in proliferation. Additionally, in cultivated human islets, age correlated positively with the sensitivity to glucose-induced β-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 β-cell apoptosis.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 16, 2006.
    • Received December 7, 2005.
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