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Diabetes 50:1683-1690, 2001
© 2001 by the American Diabetes Association, Inc.

Glucose Induces ß-Cell Apoptosis Via Upregulation of the Fas Receptor in Human Islets

Kathrin Maedler1, Giatgen A. Spinas1, Roger Lehmann1, Pavel Sergeev1, Markus Weber2, Adriano Fontana3, Nurit Kaiser4, and Marc Y. Donath1

1 Division of Endocrinology and Diabetes, the
2 Department of Surgery, and the
3 Division of Clinical Immunology, University Hospital, Zurich, Switzerland
4 Department of Endocrinology and Metabolism, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

In autoimmune type 1 diabetes, Fas–to–Fas-ligand (FasL) interaction may represent one of the essential pro-apoptotic pathways leading to a loss of pancreatic ß-cells. In the advanced stages of type 2 diabetes, a decline in ß-cell mass is also observed, but its mechanism is not known. Human islets normally express FasL but not the Fas receptor. We observed upregulation of Fas in ß-cells of type 2 diabetic patients relative to nondiabetic control subjects. In vitro exposure of islets from nondiabetic organ donors to high glucose levels induced Fas expression, caspase-8 and -3 activation, and ß-cell apoptosis. The effect of glucose was blocked by an antagonistic anti-Fas antibody, indicating that glucose-induced apoptosis is due to interaction between the constitutively expressed FasL and the upregulated Fas. These results support a new role for glucose in regulating Fas expression in human ß-cells. Upregulation of the Fas receptor by elevated glucose levels may contribute to ß-cell destruction by the constitutively expressed FasL independent of an autoimmune reaction, thus providing a link between type 1 and type 2 diabetes.


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