Effect of Insulin Antibodies on Insulin Pharmacokinetics and Glucose Utilization in Insulin-dependent Diabetic Patients

To determine the impact of insulin-binding antibodies on total (TIRI) and free insulin (FIRI) as well as on insulin sensitivity, 10 insulin-dependent diabetic patients (IDDM) with poststimulatory C-peptide <100 pmol/L and an insulin binding capacity (IBC) between <1 and 294 μg/L serum were studied during and after a 1-h nonprimed, constant-rate insulin infusion (study 1: 0.057 U/kg body wt, study 2: 0.286 U/kg body wt). Euglycemia was maintained by variable glucose infusion. Control studies were performed in 5 healthy subjects. Basal TIRI (mU/L) was lowest in healthy subjects (16 ± 1 [SE]) and elevated in diabetic patients (IBC 25 μg/L: 1772 ± 842), whereas serum concentrations of FIRI were considerably smaller but still two- to threefold greater ( P < 0.01) in the patients than in healthy subjects (13 ± 1). After intravenous (i.v.) insulin administration, almost identical increments in serum TIRI were seen in healthy subjects and in diabetic patients with low IBC (<25 μg/L), whereas those with high IBC (<25 μg/L) had a heterogeneous response. The increments of free serum insulin induced by the infusion of 0.057 and 0.286 U of insulin/kg body wt were almost identical for healthy subjects and diabetic patients, whereas overall glucose utilization, as estimated by the glucose infusion rate necessary to maintain euglycemia, was mostly lower in the diabetic patients (low IBC: study 1: 3.2 ± 0.4 mg/kg min, study 2: 4.0 ± 0.3; high IBC: study 1: 1.2 ± 0.1, study 2: 3.8 ± 0.3) than in healthy subjects (study 1: 3.9 ± 0.6, study 2: 6.1 ± 0.5). Insulin clearance remained constantly within the normal range, but tended to be elevated in diabetic patients with high IBC, who also displayed a 50–100% rise in apparent insulin half-life. We conclude that elevated insulin-binding capacity: (1) increases serum total insulin, but affects serum free insulin only to a minor extent, and (2) is associated with a rise in apparent free insulin half-life in diabetic patients with high IBC only. (3) Insulin sensitivity is significantly impaired in IDDM and is not improved by short-term normal glycemia; and (4) the relative contribution of insulin antibodies and nonimmunologic factors to impaired insulin action in IDDM cannot be separated by the euglycemic clamp technique.