SummaryThe measurement of125I-insulin specific binding to erythrocytes obtained from seven infants and children with various hypoglycemic syndromes showed a significant increase in six patients with recurrent, documented, symptomatic hypoglycemia (percent specific125I-insulin binding 9 to 14versus6.1 ± 1.4%; mean ± 2 S.D. for 13 controls). The increase was due to an increased number of receptors sites per cell rather than to increased affinity for insulin. The patients incuded three children with nesidioblastosis, all after 90% pancreatectomy, two with leucine sensitivity, and two with glycogen storage disease type I. One of the patients with leucine sensitivity, who for 2 years before the study had no hypoglycemia, had normal insulin binding (4.8%). All seven patients had normal fasting basal plasma insulin values (<10 μU/ml). Thus, symptomatic hypoglycemia correlated better with increased125I-insulin binding than with plasma insulin values.Furthermore, Diazoxide therapy in two patients caused a mild but consistent decrease in the number of insulin receptor sites, and the institution of continuous nocturnal nasogastric feedings in a patient with glycogen storage disease type I was followed by amelioration of the hypoglycemia and a marked increase in125I-insulin specific binding from 5.2 to 9.5%.Speculation125I-Insulin binding to receptors of various cells or tissues may be altered in a variety of clinical situations. Thus, erythrocyte insulin binding sites are significantly decreased in adult-onset, nonobese diabetics that are non-insulin dependent. This patient population has chronic hyperglycemia, the opposite state from our patients with chronic hypoglycemia. Inasmuch as our patients had increased insulin binding sites and normal basal plasma insulin values, we may speculate that prolonged hypoglycemia and therefore tissue glucose depletion may be associated with an increase in insulin receptors and therefore an increase in the insulin bioeffect. This may explain why these patients become hypoglycemic in the presence of normal plasma insulin values. Increased erythrocyte125I-insulin binding may prove to be another index of long-term hypoglycemia and may perhaps prove more reliable than isolated plasma insulin or glucose values.