Fulminant Autoantibody-Negative and Type 1A Diabetes Phenotypes in a Korean HLA Identical Dizygotic Twin

Type 1 diabetes is a complex, heterogenous autoimmune disease. Many genetic and environmental factors are thought to be involved in type 1 diabetes pathogenesis as shown in other autoimmune disorders. Although some immune-related genes such as HLA, AIRE, and CTLA-4 have been elucidated about their association in pathogenesis, the detailed genetic factors causing type 1 diabetes are unclear. In a study of twins with type 1 diabetes, significant subsets of monozygotic and dizygotic twins did not progress to clinical diabetes (1), suggesting that genetic heterogeneity and other random factors are crucial for type 1 diabetic pathogenesis, even in twins. Typically, type 1 diabetes is initiated by an autoimmune response against β-cells and followed by progressive defect of insulin secretion from β-cells. These results cause hyperglycemia and transient, usually partial remission, and finally lead to complete insulinopenia. Since Imagawa et al. (2) reported 11 cases of fulminant autoantibody (Ab)-negative type 1B diabetes as a novel subtype, ∼200 additional cases have been described. Most of the cases were characterized as abrupt and severe onset, negative Abs, elevated exocrine pancreatic enzymes, and involvement of some specific HLA subtypes such as DRB1*0405 or DRB*0901, and DQA1*0303-DQB1*0401 or DQA1*0302-DQB1*0303. There is a lot of emerging evidence supporting the involvement of autoimmune mechanisms in the destruction of islet cells (3–5). In addition, HLA haplotypes associated with fulminant Ab-negative type 1 diabetes are also closely correlated with those in type 1A diabetes (6,7).

Here, we report a dizygotic twin with different type 1 diabetic phenotypes; one brother has a fulminant Ab-negative, and the other shows type 1A.

A 35-year-old man (index case) was admitted to our hospital with diabetic ketoacidosis. He was relatively healthy and had suffered from flu-like symptoms for 7 days before admission. He complained of thirst and polydipsia for 2 days. His body weight was 66.2 kg (BMI 21.4 kg/m²). He did not take any medications. We found that serum glucose (39.6 mmol/l), BUN/Cr (28/1.5 mg/dl), amylase/lipase (187/254 units/l), and fructosamine (356 μmol/l) levels in the patient were highly elevated, but HbA1c (A1C) (5.4%) was decreased. Both serum and urinary ketones were positive. According to arterial blood gas determination, the patient had mild metabolic acidosis. Both fasting serum and 24-h urine C-peptide levels were below the detection limit. After treatment with intravenous insulin and a large volume of fluid administration, his symptoms were rapidly improved, and laboratory parameters were close to near normal values. Any diabetes-related Abs, anti-insulin, GAD, islet cell, and thyroid Abs were not detected. The patient had HLA-DRB1*0405/*0701, DQA1*0303/*0201, and DQB1*0401/*0202 haplotypes. These haplotypes have also been previously reported about their association with fulminant Abs-negative and type 1A diabetes (2,6,8).

The proband’s dizygotic twin mate also had type 1 diabetes, which has been well managed by regularly injecting NPH (0.13 units · kg⁻¹ · day⁻¹) before breakfast with near normal A1C levels. He had a high plasma glucose level (19.3 mmol/l) when he visited a local clinic and complained of polyuria and weight loss in February of 2002. At that time, he had 0.2 ng/ml serum C-peptide, 9.5% A1C, and positive anti-GAD antibodies (6.5, RR <1.0 unit/ml). All siblings, including a sister who has a normal glucose tolerance, revealed the same HLA II subtype. In consideration of all clinical and laboratory findings, we concluded that this dizygotic twin with the same HLA haplotype has different phenotypes of type 1 diabetes. One brother reveals fulminant Ab-negative, the other has type 1A phenotype.

Many previous reports suggest that autoimmunity might be directly or indirectly involved in the development of fulminant type 1 diabetes. This dizygotic twin report also suggests that the immunogenetic mechanism is required for islet destruction in proband. The clinical courses among type 1 diabetes patients are different with respect to their onset age and ethnicity, suggesting that the presence of attacking or preventing genetic and environmental factors might determine the pathogenesis. Why are there different clinical courses between twin brothers who have the same HLA subtype? We need to further identify genetic and environmental factors determining these clinical variabilities in type 1 diabetes.