Hypoglycemia due to Serum-Complexed Insulin in a Patient with Diabetes Mellitus

A 28-year-old woman with insulin-dependent diabetes mellitus presented with a “hyperlabile” state of hyperglycemia and ketoacidosis alternating with hypoglycemia. Measurements of total and free insulin levels suggested that the clinical syndrome may have been due to antibody binding of insulin. Equilibrium analysis of insulin binding to the patient's serum demonstrated two classes of anti-insulin activities. The first class was of high affinity (dissociation constant ≈10⁻⁹ M) and low capacity (150 μU/ml). At low total serum insulin concentrations, most of the circulating insulin was bound to the high-affinity binding activity, and the patient presented with hyperglycemia or ketosis. The second class of insulin binding activity had a lower affinity (dissociation constant ≈5 × 10⁻⁷ M). The insulin that was bound to this low-affinity serum substance still maintained biologic activity in vivo. Isophane insulin (NPH) had a markedly prolonged serum half-life, which resulted in delayed hypoglycemia. Serum insulin complexes—that is, bound insulin—may not be “inactive” but may contribute to total insulin action. A determination of insulin activity, not only free insulin levels, may help explain hypoglycemia in selected patients with diabetes mellitus.