Since 11 novel cases of fulminant autoantibody-negative type 1 diabetes were introduced by Imagawa and colleagues (1,2), about 150 additional cases have been reported. The development of typical fulminant autoantibody-negative type 1 diabetes is strictly confined to Japan. Although the pathogenetic mechanism still remains unclear, there is some evidence supporting the immunogenetic predisposition mechanism in the development of this subtype. A fulminant autoantibody-negative type 1 diabetic patient with insulitis and exocrine pancreatitis showed infiltration of a large number of CD8+ T-cell and peripheral GAD-reactive interferon-γ-producing CD4+ T-cell (3). According to previous reports, some HLA haplotypes, DRB1*0405-DQB1*0401, DQA1*0303-DQB1*0401, DQA1*0302-DQB1*0303, and DRB*0901 are closely associated with fulminant autoantibody-negative type 1 diabetes (1,4,5).
A 43-year-old man visited Gyeongsang National University Hospital complaining of nausea, vomiting, and epigastric pain, which began 1 day before admission. He was relatively healthy until several bouts of epigastric discomfort, polydipsia, and severe thirst developed 1 week before. He had lost weight: ∼7 kg over the last 4 days. Levels of serum glucose (51.9 mmol/l), ketone 3+, serum amylase and lipase (368 and 632 units/l, respectively), and fructosamine (385 μmol/l) were highly elevated, but HbA1c was normal at 5.4%. Arterial blood pH was 7.04. Anti-insulin, anti-GAD, and anti-islet cell antibodies were all negative. No abnormality has been observed on a simple abdominal X ray, computed tomography, and ultrasonography. We treated him with intravenous insulin injections and a large volume of intravenous normal saline administration for diabetic ketoacidosis. On the second day, nausea, vomiting, and epigastric pain had improved. Fasting serum C-peptide was below detection limit at 0.1 ng/ml, and 24-h urine C-peptide was 3.4 ng/day. Based on those clinical and laboratory observations, we concluded that this was a case of fulminant autoantibody-negative type 1 diabetes. HLA typing showed that he was a homozygous haplotype with HLA-DRB1*0901, DQA1*0302, and DQB1*0303.
Among 11 novel cases of fulminant autoantibody-negative type 1B diabetes introduced by Imagawa et al. (1), HLA-DRB1*0901, DQA1*0302, and DQB1*0303 genotypes were found in three patients, and two of them were homozygous. Most fulminant autoantibody-negative type 1 diabetes cases reported in Japan have at least one of two HLA haplotypes, DQA1*0302-DQB1*0303 and DQA1*0303-DQB1*0401 (1,5), also known as susceptible haplotypes for type 1 diabetes in Japan. In addition, they have a significantly high prevalence for heterozygous DQA1*0302, DQB1*0303 and HLA DQA1*0303, DQB1*0401 (RR13) HLA haplotypes rather than homozygous DQA1*0302, DQB1*0303 HLA haplotypes. The HLA DRB1*0901 allele is not only associated with fulminant autoantibody-negative diabetic patients but is also a highly frequent HLA DR subtype in type 1A diabetes in Korea and Japan (1,6). The homozygotes with HLA-DRB1*0901-DQB1*0303 were more frequent in type 1 diabetic than in control subjects, but there was no difference in haplotype frequency between the fulminant autoantibody-negative group and type 1A diabetes (4). In addition, the HLA-DRB1*09 has close linkage disequilibrium with the HLA DQA1*0302, DQB1*0303 haplotype in the Korean and Japanese population.
In conclusion, this case is very similar to those reported in Japan in terms of genetic and clinical characteristics. This finding suggests that the haplotype (DRB*0901-DQA1*0302-DQB1*0303) might be a considerable risk allele for fulminant autoantibody-negative type 1 diabetes as well as type 1 diabetes in Far East Asia, although the immunogenetic mechanism of this novel disease entity remains to be clarified further.
