Tumor necrosis factor microsatellite polymorphism influences the development of insulin dependency in adult-onset diabetes patients with the DRB1*1502-DQB1*0601 allele and anti-glutamic acid decarboxylase antibodies

Abstract

Recently, several studies have demonstrated that tumor necrosis factor microsatellite polymorphism (TNFa) contributes to the susceptibility of type 1 diabetes. This study investigates the influence of TNFa on the predisposition to insulin dependency in adult-onset diabetic patients with type 1 diabetes-protective human leukocyte antigen haplotypes. The TNFa of three groups of DRB1*1502-DQB1*0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 yr was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 yr of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 yr. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1*1502-DQB1*0601 was strongly associated with the TNFa13 allele. DRB1*1502-DQB1*0601 was strongly associated with the TNFa12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFa12 and non-TNFa13 in group B reacted with GAD65 protein by Western blot. These results suggest that TNFa is associated with a predisposition to progression to insulin dependency in GADab/DRB1*1502-DQB1*0601-positive diabetic patients initially diagnosed with type 2 diabetes and that determination of these patients' TNFa genotype may allow for better prediction of their clinical course.