Insulin receptor antibodies inhibit insulin uptake by the liver: In vivo I-123-insulin scintigraphic scanning and in vitro characterization in autoimmune hypoglycemia

Background: Insulin receptor antibodies can induce severe hypoglycemia or i nsulin resistance in rare autoimmune syndromes. In vitro properties of thes e antibodies occasionally explain the clinical features of the syndrome, bu t direct evidence of their in vivo activity is poor. We studied a 58-year-o ld male with rheumatoid arthritis who presented with hypoglycemic coma. Methods and Results: Antibodies were detected by inhibition of I-125-insuli n binding to human insulin receptor-3T3 cells by the patient's serum. By im munofluorescence, they were immunoglobulin G of all four subclasses, immuno precipitated insulin receptors from biotin-labeled cells, and triggered pho sphorylation of the beta submit of the insulin receptor. Insulin binding on the patient's red blood cells was markedly reduced. A biodistribution stud y after intravenous I-123-Tyr A14 insulin showed a marked inhibition of tra cer uptake by the liver, reaching 10% of the injected dose (controls, mean/-SD, 21.1+/-1.7%; n=10), Time activity curves generated on the liver and o n the heart were parallel, with a T-1/2 of 11.5 minutes for both, suggestin g that no specific uptake occurred in the liver, where tracer activity repr esented only the blood pool. Clearance of insulin from the blood was indeed slower than in controls and mainly occurred through the kidneys, Analysis of plasma I-123-insulin immunoreactivity and trichloroacetic acid precipita te showed that insulin degradation did not occur as in normal controls. Conclusions: In this patient with hypoglycemic syndrome, insulin receptor a ntibodies with in vitro insulin-like activity are capable of blocking in vi vo the access of insulin to the liver receptor compartment, as directly dem onstrated by the markedly altered biodistribution of intravenously injected 123I-insulin.