MOLECULAR MECHANISMS OF PANCREATIC BETA-CELL DESTRUCTION IN AUTOIMMUNE DIABETES - POTENTIAL TARGETS FOR PREVENTIVE THERAPY

Mononuclear cell infiltration into the islets of the pancreas (insulit is) is characteristic of autoimmune diabetes. T lymphocytes are the pr edominant subpopulation seen in insulitis, and are involved in the aut oimmune process. Insulin-producing beta cells are thought to be destro yed by cytotoxic T cells, cytokines or nitric oxide, and beta-cell dea th occurs, at least partly, via apoptosis. Beta-cell death induced by cytokines is inhibited by Bcl-2, suggesting its potential as a tool fo r gene therapy. The Fas/Fas-ligand system plays a critical role in ind ucing insulitis and overt diabetes in nonobese diabetic (NOD) mice, a model of autoimmune diabetes. T-cell receptor gene usage in infiltrati ng T cells is not restricted in NOD mice, but there are some observati ons indicating relative restriction in human IDDM patients. Preventive strategies might be developed by focusing on these molecules involved in beta-cell destruction. The establishment of screening techniques f or detecting prediabetic patients is also necessary to allow successfu l intervention.