There are two types of autoimmune hypoglycemia, one due to autoantibodies acting against the insulin receptor and the other due to autoantibodies acting against insulin itself in individuals who have or have never received exogenous insulin, respectively (1). Both types are rare and can produce fasting and postprandial reactive hypoglycemia.

A 72-year-old woman with frequent severe hypoglycemia was admitted to the emergency room, presenting with loss of consciousness. Three weeks before her admission, she was diagnosed with diabetes and received insulin at a local hospital. In the emergency room, her blood glucose level was 40 mg/dl. She had been in good general health, except for hypertension for 30 years and postmenopausal osteoporosis 10 years before admission. She has no evidence of other diseases associated with altered immunity.

Three weeks ago, her biceps tendon ruptured when she slipped and fell, and during treatment, her blood glucose levels were >400 mg/dl. She was treated with insulin. However, she stopped insulin treatment because of frequent hypoglycemic events. Although she had had intravenous glucose injections, she had frequent hypoglycemic attacks, such as disorientation, loss of consciousness, palpitation, and diaphoresis. Her blood glucose levels had been <40 mg/dl on every hypoglycemic event, especially during fasting hypoglycemia.

Physical examination revealed normal vital signs except for a chronically ill appearance. Her HbA1c was 6.3% (range 3–6%), plasma glucose 40 mg/dl, insulin 103.7 μU/ml, C-peptide 4.1 ng/ml, GAD autoantibody levels 0.01 units/ml (normal range 0–1.45 units/ml; RSR, Cardiff, U.K. ), and insulinoma-associated protein 2 autoantibody 0.01 units/ml (normal range 0–1.1 units/ml; RSR). Her thyroid, liver, and adrenal function studies were normal. She was anemic, with a hemoglobin level of 9.2 g/dl. Her creatinine level was 0.8 mg/dl. Tests for anti-nuclear antibody, anti-DNA antibody, anti-smooth antibody, and anti-microsomal antibody were all negative. Insulin antibody levels were 58.5% (nonspecific binding, normal range <7%, measured by radioimmunoassay [Cobra 5010; Biosource Europe, Nivelles, Belgium]), and she was positive for insulin receptor antibodies (measured by radioreceptor assay [LKB 1261; BML, Tokyo, Japan]).

She was prescribed glucocorticoids and glucose tablets. Treatment with prednisone and glucose tablets was accompanied by the resolution of hypoglycemic episodes within 48 h. Six months later, her insulin antibody level was 67%, and she was negative for insulin receptor antibodies.

Most cases of insulin autoimmune hypoglycemia described in Asian races (2,3) have shown a strong correlation with certain HLA systems, suggesting the existence of a predisposing genetic component. This subject’s HLA typing result was HLA-DRB1*. Autoimmune hypoglycemia is associated with certain HLA systems, such as DR4 and DQw3, and especially DRB1*0406/DQA1*0302/DQB1*0302. There have been 190 cases of insulin autoimmune syndrome reported over the past 20 years. It is noteworthy that HLA-DRB1*0406 is quite prevalent in Japanese patients (2,3). Our patient’s HLA typing is predisposed to autoimmune hypoglycemia.

Several types of insulin antibodies have been reported and are most frequently seen in patients who receive insulin injections, but there have also been reports of them in nondiabetic patients with such autoimmune disease. Postprandial hypoglycemia is more common with this syndrome than fasting hypoglycemia (1), and the course of this condition is benign and self-limited, with remission usually occurring within 1 year.

The insulin receptor antibody is associated with the inhibition of insulin binding to insulin receptors, accelerated receptor degradation, receptor downregulation, and extreme insulin resistance and hyperglycemia (4). Insulin receptor antibodies act as agonists or antagonists to the insulin receptor. Insulin receptor antibodies may also inhibit insulin binding, thereby inhibiting insulin clearance and elevating levels of plasma insulin. The most important laboratory test in autoimmune hypoglycemia is a direct assay for the presence of antibodies directed against the insulin receptor or insulin.

Patients with this condition have low circulating insulin, C-peptide levels, and refractory hypoglycemia. Antibody titers generally decrease over time and remission eventually occurs in most patients. However, because of the severity of the hypoglycemia, aggressive treatment is indicated. High-dose glucocorticoids, plasmapheresis, and alkylating agents have been tried with varying success (5).

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