T-Cell-Mediated Autoimmunity May Be Involved in Fulminant Type 1 Diabetes

According to the new classification of diabetes by the American Diabetes Association (1,2), type 1B diabetes is considered to be “idiopathic,” i.e., of unknown origin. However, the existence of type 1B diabetes itself has not yet been defined. Recently, a subtype of type 1B diabetes, so-called “fulminant” type 1 diabetes, has been proposed (3). This type of type 1 diabetes is characterized by the following criteria: 1) no detectable “islet-associated” autoantibody; 2) regardless of diabetic ketoacidosis, near-normal HbA_1c levels, suggesting extremely acute onset; and 3) high levels of pancreatic exocrine enzymes. On pancreatic biopsy in this type of type 1 diabetes, no insulitis is found, although infiltration of T-cells in exocrine tissue is observed. On the other hand, Tanaka et al. (4) reported that, at autopsy, clear CD8-dominant insulitis was found in a patient who died of diabetic ketoacidosis with no islet-associated autoantibody and a low HbA_1c level. Therefore, it has not yet been concluded whether T-cell-mediated autoimmunity is involved in this type of diabetes. Because the majority of type 1 diabetes is considered to be caused by cellular immunity, assessment of antigen-specific T-cell reactivity is obviously necessary. However, probably because of the very low frequency of pancreatic β-cell antigen-specific lymphocytes in the periphery, a system to assess islet-associated antigen-specific T-cell reactivity has not yet been established. Recently, we reported that the level of serum interferon (IFN)-inducible protein-10 (IP-10), an important chemokine inducing migration of activated T-cells to local lesions, was significantly elevated in type 1 diabetes and that the serum IP-10 level positively correlated with the number of GAD-reactive IFN-γ-producing CD4⁺ cells in autoimmune-related type 1 diabetes (5). Therefore, the measurement of these markers, serum IP-10 level, and GAD-reactive IFN-γ-producing CD4⁺ cells was considered to be useful to assess whether T-cell-mediated autoimmunity is involved in fulminant type 1 diabetes. We recently encountered a 33-year-old man who was considered to have so-called “fulminant” type 1 diabetes, characterized by diabetic ketosis (plasma glucose 23.9 mmol/l, urine ketone bodies 4⁺), low HbA_1c (5.8%, normal range <5.4%), negative GAD antibody (detection limit <0.4 u/ml, 100% sensitivity and specificity of the assay in the GAD antibody proficiency test) (Immunology of Diabetes Workshop, Lab Identification no. 305), negative IA-2 (insulinoma-associated protein-2) antibody (detection limit <0.75 u/ml) (M. Powell, S. Chen, H. Tanaka, M. Masuda, C. Beer, B. Rees Smith, J. Farmaniak; unpublished observations), and elevated pancreatic exocrine enzymes (elastase-1 567 ng/ml, trypsin 739 ng/ml). Probably because the patient visited our hospital in a very early phase, he had not yet developed an acidosis; his bicarbonate level was 22.9 mEq/l. Although thyroid-associated autoantibodies, such as thyroid peroxidase antibody and thyroglobulin antibody, were negative, a high level of serum IP-10 (296 pg/ml, mean 38.2 in healthy subjects) was observed, and GAD-reactive IFN-γ-producing CD4⁺ cells were detected in peripheral blood in this case (55 of 50,000 CD4⁺ cells; mean 8 of 50,000 CD4⁺ cells in healthy subjects). Glucagon-stimulated C-peptide level was low (0.7 ng/ml), and HLA A24, which is considered to be related to total β-cell destruction (6), was detected. Other HLA types include A33, B7, B62, Cw7, Cw3, DQ1, DQ3, DR1, and DR6. Therefore, intensive insulin treatment was started immediately after admission (total 31 units/day at discharge). Previously, it has been reported that CD4⁺ cells are rarely observed in the islet lesion of fulminant type 1 diabetes at autopsy (4); therefore, the finding of GAD-reactive IFN-γ-producing CD4⁺ cells in peripheral blood in this type of diabetes is of importance. This case suggests the involvement of T-cell-mediated autoimmunity in fulminant type 1 diabetes, and this type of diabetes should not be diagnosed as type 1B diabetes based on the negativity of islet-associated autoantibody. We propose that more discussion and accumulation of cases are essential to conclude whether autoimmunity is involved in this type of diabetes.