Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets.
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 beta-cells. In the advanced stages of type 2 diabetes, a decline in beta-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 beta-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 beta-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 beta-cells. Upregulation of the Fas receptor by elevated glucose levels may contribute to beta-cell destruction by the constitutively expressed FasL independent of an autoimmune reaction, thus providing a link between type 1 and type 2 diabetes.
Maedler
K
K
Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland.
Spinas
G A
GA
Lehmann
R
R
Sergeev
P
P
Weber
M
M
Fontana
A
A
Kaiser
N
N
Donath
M Y
MY
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D018929:Cell Culture Techniques / Q000379:methods; D002455:Cell Division; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D019573:Epithelium, Corneal; D005109:Extracellular Matrix / Q000502:physiology; D053222:Fas Ligand Protein; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000502:physiology; D008875:Middle Aged; D012016:Reference Values; D019014:fas Receptor / Q000187:drug effects / Q000502:physiology*
D004792:Enzyme Precursors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D005947:Glucose