Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes.
Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFkappa-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D.
Pirot
Pierre
P
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Cardozo
Alessandra K
AK
Eizirik
Décio L
DL
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D016207:Cytokines / Q000276:immunology* / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000502:physiology; D007107:Immune System / Q000276:immunology / Q000503:physiopathology; D007111:Immunity, Cellular / Q000276:immunology; D007328:Insulin / Q000276:immunology / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D011110:Polymorphism, Genetic
D001323:Autoantibodies; D016207:Cytokines; D007328:Insulin