The effects of anti-insulin receptor antibodies (AIRA) on receptor binding and insulin metabolism were studied in two patients with the type B, severe insulin resistance syndrome. Insulin binding was determined using rat hepatocytes in primary culture and the patient's own red blood cells. Plasma and urinary insulin concentrations and metabolic clearance rates (MCR) were determined in the two patients and in four normal controls in response to infusions of insulin for 60-120 min at rates ranging from 1 to 925 mU/kg/min. In patient 1, basal insulin concentration was 1400 microU/ml. After infusion of 1, 10, and 925 mU/kg/min of insulin it rose to 3800, 5500, and 225,000 microU/ml, respectively. Respective MCRs were 19, 110, and 186 ml/min. In patient 2, basal insulin concentration was 440 microU/ml. After infusion of 1, 10, and 100 mU/kg/min of insulin it rose to 720, 2500, and 18,800 microU/ml, respectively. Respective MCRs were 193, 262, and 294 ml/min. In controls, basal insulin concentration was 4 +/- 0.3 microU/ml. After infusion of 1 and 10 mU/kg/min of insulin, it rose to 82 +/- 17 and 1288 +/- 50 microU/ml. Respective MCRs were 950 and 630 ml/min. These data showed that, in patients with AIRA: (1) insulin metabolism took place at the same rate but at higher insulin concentrations than in normal controls, and (2) MCR increased with rising insulin concentration but remained subnormal even at the highest insulin concentrations. In contrast, MCR in normal controls decreased with increasing insulin concentrations. The data suggest that prevention of insulin binding prevents insulin metabolism at physiologic insulin concentrations and that supraphysiologically elevated insulin concentrations are needed to activate nonreceptor mechanisms.