Prevention of type 1 diabetes: from the view point of β cell damage

Abstract 

The hallmark of immune-mediated type 1 diabetes is T cell-mediated destruction of the insulin-producing β cells in the islets, which results from an imbalance between disease promoting factors and protective elements. The precise mechanisms of β cell destruction leading to diabetes remain unclear. There are many molecules, including Fas ligand (FasL) and cytokines, such as IL-1, TNF-α and IFN-γ that cause release of other cytokine-mediators that have potential to damage the β cells. The β cell-death appears to ultimately be caused by receptor (Fas/FasL)-mediated mechanisms and/or by secretion of cytotoxic molecules (e.g., granzymes, perforin). FasL-mediated β cell damage might play a role in promoting insulitis and β cell destruction in autoimmune diabetes in addition to toxic molecules, such as reactive oxygen species (superoxide, hydroxy radical, nitric oxide) or perforin. Furthermore, DNA damage in β cells leads to poly (ADP-ribose) polymerase-activation which will increase NAD consumption and rapid depletion of NAD compromise ATP production in the cells. Nicotinamide inhibits poly (ADP-ribose) polymerase and reduces nitric oxide accumulation in the NOD pancreas and protect β cells against radical-induced necrosis. Transgenic mice with β cell specific overexpression of copper, zinc superoxide dismutase, or thioredoxin are resistant to autoimmune and STZ-induced diabetes. It is apparent that a number of different mechanisms of β cell destruction are operative in type 1 diabetes. Blockage of multiple pathways, rather than a single pathway, of β cell-death may, therefore be necessary to fully protect β cells from destruction and thereby prevent type 1 diabetes.

Abbreviations:  NO, nitric oxide , APC, antigen presenting cell , SOD, superoxide dismutase , HSP70, heat shock protein 70 , FADD, Fas-associated death domain-containing protein , FLICE, FADD-like IL-1β-converting enzyme , FLIP, FLICE-inhibitory protein , iNOS, inducible nitric oxide synthase

Keywords:  Type 1 diabetes , Prevention , Apoptosis , Free radical , Cytokine