Effect of Insulin Antibodies and Their Kinetic Characteristics on Plasma Free Insulin Dynamics in Patients With Diabetes Mellitus zyxwvutsrqponmlkjihgfedcbaZ Timon W. Van Haeften, Geremia B. Bolli, George D. Dimitriadis, Irving S. Gottesman, David L. Horwitz, and John E. Gerich To determine the influence of insulin antibodies (and their equilibrium kinetic properties) on the pharmacokinetics of insulin, we examined the relationship between insulin antibody binding and the initial rate of increase, time to peek, and return to baseline of therapeutic doses of insulin injected subcutaneously (0.15 U/kg) and the half-life, distribution space, and metabolic clearance rate of intravenously infused insulin (2 mU/kg/min) in insulin-treated patients with diabetes mellitus. Compared to age-weight-matched nondiabetic subjects, the diabetic subjects had reduced initial rates of increase (0.33 + 0.2 Y 0.44 + 0.03 ~U/mL/min, P < 0.05). delayed time to peak (130 + 12 Y 88 * 8 min. p < 0.02). and prolonged return to baseline (486 + 37 Y 313 + 13 min. P < 0.01 I of plasma free insulin levels after subcutaneous injection of insulin, and a prolonged half-life (18.8 f 5.8 ~4.3 + 0.3 min. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA P < 0.02). increased distribution space (804 + 284 v 108 + 10 mL/kg, P < 0.001). and augmented metabolic clearance rate (28.5 + 1.8 Y 17.3 + 0.7 mL/kg/min, P < 0.001) after intravenously infused insulin. All of these abnormal parameters were significantly correlated with binding of insulin to insulin antibodies at tracer insulin concentrations (Bo) and with the high affinity of insulin antibody binding sites as determined by Scatchard analysis. However, patients with ‘zsl insulin antibody binding (Bo) less than 10 percent had normal or near normal plasma free insulin pharmacokinetics. We conclude that in patients with insulin antibody binding (Bo) in excess of 10%. insulin antibodies may alter plasma free insulin kinetics so as to make it difficult to achieve near normoglycemia with intensive insulin therapy. o zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 1986 by Grune & Stratton, Inc. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA T REATMENT of patients with diabetes mellitus with insulin for more than three months usually leads to production of antibodies against insulin.‘-’ Occasionally, high titers of these antibodies develop and cause severe insulin resistance.U However, the clinical significance of the low insulin antibody titers that are generally found in insulin-treated patients is still controversial.‘-3o It has been proposed that insulin antibodies may be advantageous in preventing large glycemic excursions by providing a reservoir for insulin and by acting as a buffer against drastic fluctuations in plasma free insulin levels.7*8 Nevertheless, some investigators have found insulin antibod- ies to be associated with metabolic lability,9*‘0and it has been postulated that the release, at inopportune times, of insulin bound to antibodies may cause hypoglycemia.‘.‘0“4 Addi- tional evidence for an adverse effect of insulin antibodies on glycemic control has come from the finding of a positive correlation between insulin antibody binding and either insulin requirements or glycosylated hemoglobin values in some studies.3*‘5-20 However, at least an equal number of studies have not found such correlations.2S’072’-29 Recently, the results of intensified insulin regimens designed to achieve near normoglycemia have reinforced the importance of appropriate increases in plasma insulin con- centrations at the time of meal ingestion31-33; earlier increases in plasma insulin diminish postprandial hypergly- cemia3”6 and lessen the risk of late hypoglycemia.35*36If insulin entering the circulation were rapidly bound by insulin antibodies and subsequently released, as studies suggest,4*30*37 the pharmacokinetics of insulin could be altered in patients with antibodies of sufficient titer so as to impair attempts to achieve normoglycemia. In the present studies, therefore, we examined the influence of insulin antibodies (and their equilibrium kinetic properties) on the pharmacokinetics of therapeutic doses of subcutanaously injected insulin as well as intravenously infused insulin in insulin-treated patients with diabetes mellitus. Metabolism, Vol 35, No 7 (July), 1986; pp 649-656 MATERIALS AND METHODS zyxwvutsrqponmlkjihg Subjects Informed written consent was obtained from 28 otherwise healthy, nonobese (101 f 1% ideal body weight), insulin-treated diabetic subjects (13 women, 15 men), whose ages ranged from 19 to 56 years (mean 32 A 2 years) and from 14 age- and weight-matched nondiabetic volunteers (7 men, 7 women, 36 f 3 years, 103 + 2% body weight (Table 1). On the basis of their C-peptide response to the glucagon stimulation test, 38 20 patients were classified as having insulin-dependent diabetes mellitus (IDDM), and the remaining eight were classified as having noninsulin-dependent diabetes melli- tus (NIDDM). The known duration of diabetes and the glycosylated hemoglobin level? were 11.5 f 1.2 years and 10.2 + 0.4% in the IDDM patients and 4.1 f 1.2 years and 9.0 L 0.3% in the NIDDM patients. The diabetic subjects were selected for study only on the basis of not having clinically evident autonomic neuropathy as tested by respiratory beat-to-beat variation in heart rate and change in blood pressure on standing as described by Ewing et aI4 and Hilsted and Jensen”’ to exclude possible variation in absorption of subcuta- neously administered insulin due to alterations in subcutaneous blood Row.~* None was considered to be insulin resistant or “brittle,” and all had been under treatment with highly purified insulins. Protocols Preparation of subjects. Prior to the study, the diabetic subjects were withdrawn from their long-acting insulin 48 hours (NPH, From the Diabetes Research Laboratory. Endocrine Research Unit, Departments of Medicine and Physiology, Mayo Medical School. Rochester, Mnn and the Department of Medicine, Univer- sity of Illinois Health Science Center, Chicago. Supported in part by US Public Health Service Grants AM 20411 and RR 00585. Address reprint requests to John E. Gerich. Diabetes Research Laboratory, Endocrine Research Unit. Departments of Medicine and Physiology, Mayo Medical School, Rochester, MN 55905. o 1986 by Grune & Stratton, Inc. 0026-0495/86/3507-0014$03.00/0 649