Defective function of the Fas apoptotic pathway in type 1 diabetes mellitus correlates with age at onset

The Fas death receptor triggers lymphocyte apoptosis through an extrinsic and an intrinsic pathway involving caspase-8 and -9 respectively. Inherited defects of Fas function are displayed by a proportion of patients with Type 1 diabetes mellitus (T1DM) especially those with a second autoimmunity (T1DM-p). This study assesses activation of both pathways in Fas-resistant (FasR) patients to localize the defect. 21/28 (75 percent) T1DM-p, 14/50 (38 percent) T1DM, and 7/150 (5 percent) controls were FasR. Analysis of the 35 FasR patients and 20 Fas-sensitive (FasS) controls showed that caspase-9 activity was lower in T1DM-p and T1DM than in controls, whereas caspase-8 activity was lower in T1DM-p than in T1DM and the controls. Single patient analysis showed that 16/35 patients displayed defective activity of one (FasR1), whereas 19 displayed normal activity of both caspases (FasR2). Ages at onset of diabetes mellitus in T1DM and the second autoimmune disease in T1DM-p were lower in FasR than in FasS patients. All FasR1 patients developed diabetes mellitus before the age of 9 years, whereas a later onset was displayed by 26% FasR2 and 53% FasS patients. These data show that defective Fas function may involve both the extrinsic and intrinsic pathway in T1DM and severity correlates with the precocity of the autoimmune attack and its tissue polyreactivity.     

Targeting type 1 diabetes before and at the clinical onset of disease

Autoimmune type 1 diabetes is strongly associated with a number of immune abnormalities that manifest themselves before and at the time of clinical diagnosis. The clinical onset is associated with a major loss of the pancreatic islet beta cells. Insulin treatment is the only treatment option since numerous trials with agents that suppress or modulate immune function have failed to preserve beta cell function long term. Recent studies suggest that it is possible to predict clinical onset of diabetes by combining genetic with autoantibody testing. In this review we will summarize current and future drug targets for subjects at risk for type 1 diabetes as well as for subjects with recent onset disease. We will also discuss the possible importance of initiating as well as contributing factors such as reactive oxygen species and modified autoantigens. It is speculated that drug targets of factors important to disease pathogenesis may provide safe and effective adductive treatment to preserve beta cell function in autoantibody positive subjects who are at maximum risk for disease.