Monokine Antagonism Is Reduced in Patients With IDDM

Interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 ± 40 vs. 530 ± 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 ± 0.22 vs. 4.72 ± 0.24 μg/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients. Although based on a limited number of patients, these preliminary findings suggest that μ-cells in IDDM patients may be more sensitive to the cytotoxic effects of TNF-α and IL-1 because of less production of TNFsRp55 and, in a subset of IDDM patients, of IL-IRa during the inflammatory challenge of insulitis.