Seroconversion of GAD Antibody in “Unclassified” Diabetes With Long Duration of Disease

Latent autoimmune diabetes in adults (LADA) (1), or slowly progressive insulin-dependent diabetes mellitus (SPIDDM) (2), is a subtype of type 1 diabetes with a slowly progressive course. LADA, or SPIDDM, is diagnosed by the detection of islet-associated autoantibodies such as islet cell antibody (ICA) or GAD antibody (GADA) in the serum; moreover, patients with LADA are usually originally diagnosed as having type 2 diabetes. If islet-associated autoantibodies are not detected in the serum, these patients who are originally diagnosed as having type 2 diabetes cannot be diagnosed as having LADA and are followed as “unclassified” diabetes at present.

In clinical situations, if islet-associated autoantibodies are not initially detected in the serum, these cases are usually followed as type 2 diabetes or “unclassified diabetes” without reevaluation of autoantibodies because it is unknown whether islet-associated autoantibodies will appear later in the disease course. It has been reported that islet-associated autoantibodies are detected within 1 year after onset in ∼15% of cases of “classical” type 1 diabetes without islet-associated autoantibodies at the onset of disease (3).

The following case patient, who was confirmed as not having GADAs at 31 years after the onset of diabetes and was followed as having “unclassified diabetes,” is a rare case in whom GADA was detected at 36 years.

The patient was diagnosed as having type 2 diabetes at age 47 years, had an HbA_1c level of ∼7%, and was being treated with a sulfonylurea (glibenclamide). However, glycemic control subsequently worsened despite being treated with 8.75 mg/day of glibenclamide, 150 mg/day of buformin, and 0.9 mg/day of voglibose, and she was admitted to the hospital at age 78. On admission, her height was 155 cm and her body weight was 38.8 kg (BMI 16.1 kg/m²), with no history of obesity. According to laboratory findings, her fasting plasma glucose level was 338 mg/dl and her HbA_1c level was 10.1%. Her insulin secretion was also low (serum C-peptide level 0.3 ng/ml on fasting, 0.9 ng/ml at 2 h after breakfast, and 24-h urine C-peptide level 10.5 μg/day), thus requiring insulin therapy (total 16 units/day at discharge). Based on these findings, it was possible that she had SPIDDM; however, GADA was negative (detection limit <0.4 units/ml; 100% sensitivity and 100% specificity of the assay in the GADA proficiency test [Immunology of Diabetes Workshop], lab ID no. 305), resulting in the diagnosis of “unclassified diabetes.”

At age 83, she was again admitted to the hospital because of acute myocardial infarction. On the second admission, her body weight was 39.4 kg (BMI 16.4 kg/m²). Laboratory results indicated that her fasting plasma glucose level was 198 mg/dl, her HbA_1c level 7.2%, and her 24-h urine C-peptide level 12.5 μg/day. Surprisingly, GADA, which was negative at the time of her first admission, was now positive (144 units/ml), although insulinoma-associated protein 2 antibody was negative. Furthermore, HLA typing detected DR4, which is considered to be a susceptible HLA type for type 1 diabetes (other HLA types: A24, A26, B35, B55, DR8). Based on these observations, she was diagnosed as having SPIDDM.

The frequency of seroconversion of GADA in diabetic patients who were originally diagnosed as having type 2 diabetes is not known, and a more extensive large- scale study is needed to clarify the frequency of seroconversion in this type of diabetes. Based on this case, however, we would like to emphasize that it is essential to measure islet-associated autoantibodies such as GADA periodically for the precise diagnosis of diabetes, especially in patients given the diagnosis of “unclassified diabetes,” even if the patient has suffered from diabetes for a long period of time.