Hyperinsulinemic hypoglycemia due to polyclonal gammopathy with insulin autoantibodies

Insulin-producing islet cell tumors, nesidioblastosis and glycogenosis type 1 have to be considered in cases of endogenous hypoglycemia. In addition, insulin-specific autoantibodies have been described as a cause of hypoglycemia.

Here, we report on a female patient (78yrs.) with type 2 diabetes mellitus and repeated nocturnal episodes of hypoglycemia. Diabetes mellitus was diagnosed at the age of 65 years. Insulin administration was started at the age of 72 years. Five years later nocturnal hypoglycemia occurred. Athough bedtime insulin was stopped, hypoglycemias did not disappear. After 37 hours of a supervised fast, blood glucose level decreased to less than 40mg/dL (2.2 mmol/L), while insulin levels were inadequately elevated to 51.6 mIU/L (normal for euglycemia: 6.0–27.0). In contrast, C-peptide values (4.1µg/L) and proinsulin levels (10 pmol/L) were normal. Measurements for sulfonylurea in urine were negative. Imaging studies including endosonography, magnetic resonance and octreotid scanning showed no pathology. Serum electrophoresis and immunofixation revealed an increased polyclonal gamma peak (7.42g/dL; normal: 0.7–1.7). Quantification of serum globulins showed elevated IgG (5920mg/dL, normal: 700–1600), whereas IgA was normal (148mg/dL; normal: 70–400mg/dL) and IgM even low (<19mg/dL; normal: 40–230). Insulin autoantibody measurements revealed a rate of insulin binding of 96 percent. On affinity chromatography insulin-specific autoantibodies were proven to constitute a small portion of the gamma fraction. Bone marrow biopsy revealed an immunocytoma-like lymphatic infiltration (45%), while plasmocytoma could be excluded. Nocturnal hypoglycemia has been described in patients with insulin autoantibodies and this was explained by temporary binding of insulin to antibodies followed by dissociation. Antibody-binding may extend the half-life of insulin without interfering with its biological activity. To our knowledge, this is the first report of antibody-associated hypoglycemia caused by antibodies of polyclonal origin.