Islet antibody–negative or type 1B (idiopathic) diabetes constitutes 5–10% of Caucasian diabetic subjects with recent-onset type 1 diabetes (1). A study from Italy (2) failed to show clinical differences between these patients and those with antibodies. In contrast, a fulminant form of type 1B diabetes with associated exocrine pancreatic involvement, possibly secondary to viral infection, has been described in Japanese (3). There is little information on type 1B diabetes in other racial groups. Therefore, we studied the frequency and characteristics of type 1B diabetes in children of north Indian origin.
We studied all 55 children (32 male and 23 female) with recent-onset type 1 diabetes who presented at our diabetes clinic over a 10-year period. Subjects had an age at onset <20 years (9.7 ± 5.0 years [mean ± SD]), duration of diabetes <3 months (33 ± 20 days), severe hyperglycemia (plasma glucose 20.7 ± 8.6 mmol/l), and required insulin continuously after diagnosis. Chronic pancreatitis was ruled out by abdominal ultrasonography. GAD and insulinoma-associated protein 2 (IA-2) antibodies (GADAs and IA-2As) were determined by immunoprecipitation of recombinant 35S-labeled human antigen, as described previously (4). The antibody assays were included in all workshops and Immunology of Diabetes Society serum exchanges, and they have proven sensitivity and specificity. HLA typing for 12 DR antigens was performed using sequence-specific oligonucleotide probes.
GADAs were present in 23 subjects (42%), and IA-2As were only found in 18 subjects (33%). Both antibodies were absent in 25 children (45%). When compared with control subjects, the only HLA genotype associated with type 1 diabetes was DRB1*03/03 (8/41 [19.5%] vs. 1/105 [1%], odds ratio [OR] 26.4, Pc < 0.001). When children with GADAs or IA2As (type 1A diabetes) were compared with those in whom neither was present (type 1B diabetes), there were no differences in their clinical features (age at onset, duration of symptoms before diagnosis, frequency of ketosis, or BMI) or metabolic profile (plasma glucose, HbA1c, or fasting plasma C-peptide). The frequency of the HLA-DRB1* 03/03 genotype, when compared with control subjects, was increased in the type 1A (7/24 [29%] vs. 1/105 [1%], OR 44.8, P < 0.001) but not in the type 1B (1/17 [6%]) diabetic subgroup. No patient with fulminant type 1B diabetes (duration of symptoms <1 week and elevated serum trypsin) was detected. In fact, patients with type 1B diabetes had lower serum trypsin levels compared with the levels in those with type 1A diabetes (19.4 ± 11.9 vs. 29.1 ± 16.6 μg/l, P = 0.03; normal range 10–57 μg/l).
We found a far higher frequency of type 1B diabetes (45%) among children and adolescents with recent-onset type 1 diabetes than previously reported in other Caucasian populations (1). This may be related in part to the low frequency of IA-2A in the current study. This finding has also been reported earlier (4,5) and may be due to the low prevalence of HLA-DR4 in type 1 diabetic subjects in this racial group (5). Alternatively, an increase in diabetes from “nonautoimmune” causes such as viral infections, toxins, mutations in transcription factors, or subclinical pancreatitis is possible. The association of the high-risk genotype DRB1*03/03 with only type 1A diabetes suggests that different pathogenetic mechanisms may exist for type 1A and 1B diabetes in this study population. In view of the absence of the type of fulminant type 1B diabetes found in Japanese subjects in both the current study and earlier reports in other Caucasian groups (2), it is likely that type 1B diabetes will be heterogeneous in its etiology.